Δευτέρα, 20 Νοεμβρίου 2017

Organ doses and lifetime attributable risk evaluations for scoliosis examinations of adolescent patients with the EOS imaging system

Abstract

Purpose

The goal of this work is to evaluate organ doses and lifetime attributable risk of cancer incidence and mortality in scoliosis examinations of adolescent patients performed with EOS imaging system, in order to optimize patient dose and protocols.

Methods

An anthropomorphic phantom of a normal patient, with thermoluminescent dosimeters in correspondence with the main organs at risk, was imaged with both EOS and computed radiography (CR). For each modality, effective dose was calculated from the measured organ doses. Lifetime attributable risk was computed accordingly to the Committee on the Biological Effects of Ionizing Radiation (BEIR VII) and Public Health England (HPA) publications.

Results

Except for testes and eyes, which were excluded from the scan in CR protocol, for all the other organs the doses delivered with CR examination were higher than these delivered by EOS system. The effective dose in EOS examination (0.43 ± 0.04 mSv) is about two times less than the dose in computed radiography with anti-scatter grid examination (0.87 ± 0.09 mSv), and, consequently, also the cancer probability is lower (5.4 vs 9.7 number of any cancers induction cases per 100,000 person examined, for a 20-year-old male patient).

Conclusions

The EOS system is efficient in limiting patient dose. The shielding of testes and the exclusion of eyes from the scan could allow to further reduce the dose.



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Highlights on MRI of the fetal body

Abstract

Fetal MRI is a level III diagnostic tool performed subsequently a level II prenatal ultrasound (US), in cases of inconclusive ultrasonographic diagnosis or when a further investigation is required to confirm or improve the diagnosis, to plan an appropriate pregnancy management. Fetal MRI plays an increasingly important role in the prenatal diagnosis of fetal neck, chest and abdominal malformations, even if its role has been amply demonstrated, especially, in the field of fetal CNS anomalies. Due to its multiparametricity and multiplanarity, MRI provides a detailed evaluation of the whole fetal respiratory, gastrointestinal and genitourinary systems, especially on T2-weighted (W) images, with a good tissue contrast resolution. In the evaluation of the digestive tract, T1-W sequences are very important in relation to the typical hyperintensity of the large intestine, due to the presence of meconium. The objective of this review is to focus on the application of fetal MRI in neck, chest and abdominal diseases.



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Short interactive workshops reduce variability in contouring treatment volumes for spine stereotactic body radiation therapy: Experience with the ESTRO FALCON programme and EduCase™ training tool

We report the results of 4, 2-h contouring workshops on target volume definition for spinal stereotactic radiotherapy. They combined traditional teaching methods with a web-based contouring/contour-analysis platform and led to a significant reduction in delineation variability. Short, interactive workshops can reduce interobserver variability in spine SBRT target volume delineation.

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Clinical decision support of radiotherapy treatment planning: A data-driven machine learning strategy for patient-specific dosimetric decision making

Clinical decision support systems are a growing class of tools with the potential to impact healthcare. This study investigates the construction of a decision support system through which clinicians can efficiently identify which previously approved historical treatment plans are achievable for a new patient to aid in selection of therapy.

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Bladder exstrophy – CT


Case Report– 16 years male presents for CECT abdomen&  pelvis with swelling in lower abdomen & difficulty in passing urine since very long time. No past surgical history.

CT findings –

-     Marked widening of the symphysis pubis with absence of normal urinary bladder.
-     Focal defect seen in anterior abdominal wall near midline in suprapubic region with small protrusion of pelvic mesentry into it leading to external bulge in the abdominal wall with overlying thickening of the soft tissue planes.
-     Normal kidneys & bilateral upper 2/3 of ureters in location, contour, size & enhancement without any hydronephrosis. Delayed phase shows normal contrast excretion in both kidneys & ureters. Distal 1/3 of both ureters show mild dilatation with acute anteromedial course in lateral  pelvis reaching upto the abdominal wall defect in suprapubic region with further short segment of severe narrowing of caliber of ureters coursing anteriorly near midline upto the superior margin of base of penis simulating epispadias.  Penile shaft is blunted & smaller in size. Scrotum is unremarkable.

Findings are suggestive of urinary bladder exstrophy with epispadias.

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DISCUSSION BY DR MGK MURTHY & DR GA PRASAD

Bladder exstrophy is a rare congenital birth defect  occurring about 3 in 100, 000 births with males to female ratio of 3:1 & includes  malformation of the bladder and urethra in which the bladder is turned inside out, flattened and exposed to  outside the body & bladder neck fails to form.

The condition is caused by incomplete development of the infra- umbilical part of the anterior abdominal wall, associated with incomplete development of the anterior wall of the bladder owing to delayed rupture of the cloacal membrane. Persistence of the cloacal membrane prevents medial mesenchymal ingrowth, causing the abdominal wall to remain lateral and the posterior bladder wall to be exposed to the external surface . Trigone of the bladder and ureteral openings are exposed and sometimes there is mild prolapse.

The pubic symphysis is widened  with diastasis of rectus abdominis. Umbilicus is low set. In males the penis is short, stubby, curved upwards and is drawn into the exstrophic area. Unilateral or bilateral cryptorchidism  or Inguinal hernia may be present . In females, the urethra is short, often buried in the exstrophied bladder. The clitoris tends to be bifid. The labia are also widely separated. The vagina is short and orifice may be stenotic. Uterine prolapse or unicornuate uterus may be present Anus is anteriorly placed.


Antenatal USG findings of exstrophy - epispadias complex include –
-     Repeated failure to visualize the bladder.
-     Lower anterior abdominal wall mass.
-     Low set umbilicus with omphalocoele.
-     Abnormal genitalia.
-     Increased pelvic diameter.
-      Associated renal anomalies, myelomeningocoele and limb anomalies, which are more common in cloacal exstrophy.


Surgical steps include closing the bony pelvic ring & bladder / posterior urethra and / anterior abdominal wall defect and reconstruct the genitalia. Osteotomy of both iliac bones just lateral to SI joints. Later reconstruction of bladder neck and sphincter is done. Another option is urinary diversion if continence is poor following bladder reconstruction. This can be done by ureterosigmoid anastomosis or formation of ileal conduit, colonic conduit or continent urinary diversion.


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Versunkene Kulturen – unter dem Museum der Kulturen. Die Ausgrabung 2008/3 der Archäologischen Bodenforschung Basel-Stadt im Schürhof



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Klybeck-Nord und Kleinhüningen als Lebensraum



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Die Quartiere Kleinhüningen und Klybeck



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Die Dorfsiedlungen am Schweizer Blauen als räumliche Sozialstruktur



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Kontrollmeinungen und Selbstwissen



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Circadian profiling reveals higher histamine plasma levels and lower diamine oxidase serum activities in 24% of patients with suspected histamine intolerance compared to food allergy and controls

Abstract

Background

Histamine intolerance is thought to trigger manifold clinical symptoms after ingesting histamine-rich food due to reduced activity of diamine oxidase (DAO). No study has hitherto systematically assessed daily fluctuations of histamine levels and DAO activities in symptomatic patients. The aim of the study was to investigate the presence of histamine intolerance, to therefore establish day profiles of histamine levels and DAO activities, and to compare the results between patients with suspected histamine intolerance, food allergy and healthy controls.

Methods

We determined day profiles of histamine plasma levels and DAO serum activities in 33 patients with suspected histamine intolerance, in 21 patients with proven food allergy and in 10 healthy control patients. Clinical symptoms, food intolerances and further clinical and laboratory-chemical parameters were evaluated.

Results

24% (8 of 33) suspected histamine intolerant patients showed elevated histamine levels during the day. That might be caused by constantly and significantly reduced DAO activities in these patients compared to food allergy and control patients. The remaining 25 patients presented normal histamine levels and DAO activities, but an increased prevalence of multiple food intolerances compared to the other subgroup of suspected histamine intolerants. There was no correlation between subjective complaints and serological histamine parameters in patients with suspected histamine intolerance.

Conclusions

We determined by daily profiling that decreased DAO activities correlated with elevated histamine levels in a subgroup of suspected histamine intolerants. This finding discriminates these patients from food intolerant individuals with similar clinical symptoms, and strongly suggests the presence of histamine intolerance.

This article is protected by copyright. All rights reserved.



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IJMS, Vol. 18, Pages 2469: Bevacizumab for Patients with Recurrent Multifocal Glioblastomas

IJMS, Vol. 18, Pages 2469: Bevacizumab for Patients with Recurrent Multifocal Glioblastomas

International Journal of Molecular Sciences doi: 10.3390/ijms18112469

Authors: Michael Burger Stella Breuer Hans Cieplik Patrick Harter Kea Franz Oliver Bähr Joachim Steinbach

In patients with glioblastoma, antiangiogenic therapy with bevacizumab (BEV) has been shown to improve progression-free survival (PFS), but not overall survival (OS). Especially in patients with an unusual infiltrative phenotype as seen in multifocal glioblastoma, the use of BEV therapy is still more controversial. Therefore, we prepared a retrospective case series with 16 patients suffering from a multifocal glioblastoma treated with BEV. We compared these patients to a matched control cohort of 16 patients suffering from glioblastoma with a single lesion treated with BEV. The objective of this study was to evaluate whether the course of disease differs in glioblastoma patients with a multifocal disease pattern compared to those with a single lesion only. Patients were treated with BEV monotherapy or BEV in combination with irinotecan or lomustine (CCNU). Response rates and PFS were similar in both groups. There was a trend for an unfavorable OS in the patient group with multifocal glioblastoma, which was expected due to the generally worse prognosis of multifocal glioblastoma. We investigated whether BEV therapy affects the invasive growth pattern as measured by the appearance of new lesions on magnetic resonance imaging (MRI). Under BEV therapy, there was a trend for a lower frequency of new lesions both in multifocal and solitary glioblastoma. Based on these results, BEV therapy at relapse appears to be justified to no lesser extent in multifocal glioblastoma than in solitary glioblastoma.



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IJMS, Vol. 18, Pages 2472: Is the Benefit–Risk Ratio for Patients with Transfusion-Dependent Thalassemia Treated by Unrelated Cord Blood Transplantation Favorable?

IJMS, Vol. 18, Pages 2472: Is the Benefit–Risk Ratio for Patients with Transfusion-Dependent Thalassemia Treated by Unrelated Cord Blood Transplantation Favorable?

International Journal of Molecular Sciences doi: 10.3390/ijms18112472

Authors: Tang-Her Jaing

Transfusion-dependent thalassemia (TDT) is an inherited disorder characterized by absent or defective production of α- or β-hemoglobin chains. If untreated, the disease invariably culminates in death in early infancy due to cardiac failure or overwhelming infection. Although there is clear evidence of good health-related quality of life and return to normal life style, the choice to undergo hematopoietic stem cell transplantation (HSCT) remains a challenge because of the potential risk of transplant-related mortality (TRM) in TDT. Successful hematopoietic stem cell transplantation may cure the hematological manifestations of TDT, but introduces risks of TRM and morbidity. The low incidence of graft-versus-host disease (GVHD) provides the major rationale for pursuing unrelated cord blood transplantation (CBT). Considerable evidence suggests a lower rate of recurrence after CBT than after transplantation from adult donors. As the TRM, overall survival, and thalassemia-free survival for CBT improve, the utility of this stem cell source will expand to indications that have hitherto rarely used unrelated CBT. This paper summarizes the current progress in understanding the advances in unrelated CBT for thalassemia. Although as yet only in a limited number of patients, the results of unrelated CBT for thalassemia are encouraging.



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IJMS, Vol. 18, Pages 2464: Green Routes for the Production of Enantiopure Benzylisoquinoline Alkaloids

IJMS, Vol. 18, Pages 2464: Green Routes for the Production of Enantiopure Benzylisoquinoline Alkaloids

International Journal of Molecular Sciences doi: 10.3390/ijms18112464

Authors: Francesca Ghirga Alessandra Bonamore Lorenzo Calisti Ilaria D’Acquarica Mattia Mori Bruno Botta Alberto Boffi Alberto Macone

Benzylisoquinoline alkaloids (BIAs) are among the most important plant secondary metabolites, in that they include a number of biologically active substances widely employed as pharmaceuticals. Isolation of BIAs from their natural sources is an expensive and time-consuming procedure as they accumulate in very low levels in plant. Moreover, total synthesis is challenging due to the presence of stereogenic centers. In view of these considerations, green and scalable methods for BIA synthesis using fully enzymatic approaches are getting more and more attention. The aim of this paper is to review fully enzymatic strategies for producing the benzylisoquinoline central precursor, (S)-norcoclaurine and its derivatives. Specifically, we will detail the current status of synthesis of BIAs in microbial hosts as well as using isolated and recombinant enzymes.



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Reading about The road to a better normal: Breast Cancer patients and survivors in the EU workforce on The Economis… https://t.co/mZDLys7vad

Reading about The road to a better normal: Breast Cancer patients and survivors in the EU workforce on The Economis… https://t.co/mZDLys7vad

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Viruses, Vol. 9, Pages 351: Neurotropism In Vitro and Mouse Models of Severe and Mild Infection with Clinical Strains of Enterovirus 71

Viruses, Vol. 9, Pages 351: Neurotropism In Vitro and Mouse Models of Severe and Mild Infection with Clinical Strains of Enterovirus 71

Viruses doi: 10.3390/v9110351

Authors: Pin Yu Linlin Bao Lili Xu Fengdi Li Qi Lv Wei Deng Yanfeng Xu Chuan Qin

Enterovirus 71 (EV71) is a common etiological agent of hand, foot, and mouth disease and fatal neurological diseases in children. The neuropathogenicity of severe EV71 infection has been documented, but studies comparing mouse models of severe and mild EV71 infection are lacking. The aim of the study was to investigate the neurovirulence of EV71 strains and the differences in serum cytokine and chemokine levels in mouse models of severe and mild EV71 infection. Nine EV71 isolates belonging to the C4 subgenogroup (proposed as genotype D) displayed infectivity in human neuroblastoma SK-N-SH cells; moreover, ultrastructural observation confirmed viral particle replication. The survival rate of the severe model was 71.43% (5/7), and 60% (3/5) of the surviving severe model mice displayed sequelae of paralysis, whereas the only symptom in mild model mice was ruffled fur. Dynamic detection of serum cytokine and chemokine levels demonstrated that interleukin (IL)-5, IL-13, IL-6, monocyte chemotactic protein 1 (MCP-1), and chemokine (C-C motif) ligand 5 (also called Regulated upon Activation, Normal T-cell Expressed, and Secreted (CCL5/RANTES) were significantly up-regulated at the early period of infection, indicating that these factors might herald a severe outcome. Our findings suggest that elevated cytokines and chemokines may have potential value as prognostic markers in mouse models.



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Basement membrane (type IV) collagen is a heteropolymer

Type IV collagen was isolated in high yield from bovine kidney cortex. The protein revealed Mr = 380,000 and contained, in a 2:1 ratio, two different disulfide-linked polypeptide chains, C-1 and D-1 (Mr = 125,000). Carboxymethyl-cellulose chromatography before and after reduction proved that the two polypeptide chains are arranged in a single triple helical molecule with the chain composition (C-1)2(D-1). The disulfide bridges appear to be located 180 amino acid residues from the NH2 terminus of the chains.

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N-Terminal sequences of pig intestinal sucrase-isomaltase and pro-sucrase--isomaltase. Implications for the biosynthesis and membrane insertion of pro-sucrase--isomaltase

The hog sucrase—isomaltase complex is anchored to the small-intestinal brush border membrane, as in the rabbit, via a hydrophobic segment located in the N-terminal region of the isomaltase subunit. The immediate precursor of the ‘final’ sucrase—isomaltase (i.e., pro-sucrase—isomaltase as prepared from adult hogs whose pancreas had been disconnected from the duodenum) is an amphiphilic single polypeptide chain of M r 260 000–265 000. Its N-terminal sequence is virtually identical with (not merely homologous to) the corresponding region of the isomaltase subunit of ‘final’ sucrase-isomaltase. This shows that the isomaltase portion of pro-sucrase—isomaltase in the N-terminal ‘half’ of the precursor polypeptide chain. Thus the succession of domains in pro-sucrase—isomaltase and its mode of anchoring in the membrane could be deduced. On this basis a likely mechanism of biosynthesis and insertion is proposed.

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Complete amino acid sequence of human intestinal aminopeptidase N as deduced from cloned cDNA

The complete primary structure (967 amino acids) of an intestinal human aminopeptidase N (EC 3.4.11.2) was deduced from the sequence of a cDNA clone. Aminopeptidase N is anchored to the microvillar membrane via an uncleaved signal for membrane insertion. A domain constituting amino acid 250–555 positioned within the catalytic domain shows very clear homology to E. coli aminopeptidase N and contains Zn2+ ligands. Therefore these residues are part of the active site. However, no homology of the anchor/junctional peptide domain is found suggesting that the juxta- and intra-membraneous parts of the molecule have been added/preserved during development. It is speculated that this part carries the apical address.

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Aminopeptidase N is directly sorted to the apical domain in MDCK cells

In different epithelial cell types, integral membrane proteins appear to follow different sorting pathways to the apical surface. In hepatocytes, several apical proteins were shown to be transported there indirectly via the basolateral membrane, whereas in MDCK cells a direct sorting pathway from the trans-Golgi-network to the apical membrane has been demonstrated. However, different proteins had been studied in these cells. To compare the sorting of a single protein in both systems, we have expressed aminopeptidase N, which already had been shown to be sorted indirectly in hepatocytes, in transfected MDCK cells. As expected, it was predominantly localized to the apical domain of the plasma membrane. By monitoring the appearance of newly synthesized aminopeptidase N at the apical and basolateral surface, it was found to be directly sorted to the apical domain in MDCK cells, indicating that the sorting pathways are indeed cell type-specific.

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Humangeographie/Stadt- und Regionalforschung an der Universität Basel. Forschung - Lehre - Konzeptentwicklung

Geographie ist eine auf den Raum bezogene Mensch-Umwelt-Wissenschaft. Die Erdräume und ihre Inhalte sowie die darin wirkenden Kräfte und Prozesse werden in den einzelnen Teilgebieten der Geographie behandelt. Sowohl die Physiogeographie als auch die Humangeographie repräsentieren die Sichtweisen auf den Funktionszusammenhang von Natur, Technik und Gesellschaft. Geographen forschen für gegenwärtige und zukünftige gesellschaftliche Probleme und haben Lösungskompetenz für die Anforderungen der heutigen Welt. Welchen Beitrag die Humangeographie an der Universität Basel dabei leistet, zeigt der vorliegende Beitrag auf.

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Parks im trinationalen Eurodistrict Basel (TEB). Parkanlagen als Planungs- und Marketinginstrumente

Immer mehr Freiflächen im Trinationalen Eurodistrict Basel (TEB) werden zerschnitten oder verschwinden vollständig. Für die Erhaltung eines hohen Lebensstandards ist jedoch ein Erhalt von Grünflächen von grosser Bedeutung. Der Druck auf unbebaute Flächen ist sehr gross und wächst stetig an. Entsprechend erweist sich die Aufgabe, Grünflächen langfristig vor Überbauungen zu schützen, als sehr schwierig. Einen Lösungsansatz für die Problematik bilden zahlreiche Parkgründungen und Parkprojekte, die durch eine Inwertsetzung von Freiflächen deren nachhaltigen Schutz anstreben. Eine Grünfläche erhält mit der Ernennung zur Parklandschaft “ein Gesicht”: Parks tragen einen Namen und verfügen über Statuten, in denen Zielsetzungen und Pflegepläne verankert sind. Dadurch wird der Bevölkerung aufgezeigt, dass es sich um eine wertvolle und schützenswerte Ressource handelt. Die vorliegende Arbeit hatte zum Ziel, einen Beitrag zum Schutz der Freiflächen zu leisten. Durch eine klare Definition aller Parkbegriffe innerhalb des TEB konnten verschiedene Überblickskarten zusammengestellt und die grosse Diversität der verschiedenen Parktypen im TEB dargestellt werden. Die neuen Erkenntnisse wurden in einem Entwicklungskonzept für Parks zusammengefasst.

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Investigation of Antimicrobial, Antioxidant, and DNA Binding Studies of Bioactive Cu(II), Zn(II), Co(II), and Ni(II) Complexes of Pyrimidine Derivative Schiff Base Ligand

A new pyrimidine based Schiff base ligand (HL) and its four complexes of type [MLOAc]·H2O (Cu(II), 1; Zn(II), 2; Co(II), 3; and Ni(II), 4) have been synthesized and characterized by elemental analysis, MS, 1H-NMR, FT-IR, UV-visible, and ESR techniques. The electronic and ESR spectral data suggested that complexes 1–4 possess square planar geometry. Antimicrobial activities of HL and complexes 1–4 were tested against four bacteria (Staphylococcus aureus, Staphylococcus pneumonia, Salmonella enterica typhi, and Haemophilus influenzae) and two fungal strains (Aspergillus flavus and Aspergillus niger). These results show that complexes 1–4 have good antimicrobial activity compared to HL. The DNA cleavage activity of HL and complexes 1–4 was monitored by the agarose gel electrophoresis method. The antioxidant property of the prepared compounds was assessed by using 2,2′-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging method. DNA binding properties of HL and complexes 1–4 have been investigated by electronic absorption technique and viscometric measurements.

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Chronic Pelvic Pain: Assessment, Evaluation, and Objectivation

Chronic Pelvic Pain (CPP) and Chronic Pelvic Pain Syndrome (CPPS) have a significant impact on men and women of reproductive and nonreproductive age, with a considerable burden on overall quality of life (QoL) and on psychological, functional, and behavioural status. Moreover, diagnostic and therapeutic difficulties are remarkable features in many patients. Therefore evaluation, assessment and objectivation tools are often necessary to properly address each patient and consequently his/her clinical needs. Here we review the different tools for pain assessment, evaluation, and objectivation; specific features regarding CPP/CPPS will be highlighted. Also, recent findings disclosed with neuroimaging investigations will be reviewed as they provide new insights into CPP/CPPS pathophysiology and may serve as a tool for CPP assessment and objectivation.

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Mechanism of Subordinate Peak Skewing of FBG Sensor during Cracks Propagation Monitoring on Aluminum Alloy Structure

This study investigates the variety of the spectra features of fiber Bragg grating (FBG) around the crack tip during fatigue crack propagation. The study results reveal that the turning of the subordinate peak is significantly associated with crack lengths and corresponds to strain gradient along the FBG. Meanwhile, the strain distribution sensed by the FBG changes with the sensing section of the grating. FBG sensors could observe the monotonic plastic zone ahead of the fatigue crack tip. The cubic strain is distributed along the grating, with monotonic plastic zone propagation at the initial and terminal part of the grating, at approximately a 30% ratio of the entire grating. However, the monotonic plastic zone is sensed by the FBG, at 15% bias of the grating center, with the quadratic strain gradient pattern along the grating. In particular, when the initial and terminal parts of the grating experience highly inhomogeneous strain distribution, the spectrum distortion occurs.

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Multiband Radar Signal Coherent Processing Algorithm for Motion Target

In real application, most aerial targets are movable. In this paper, an effective multiple subbands coherent processing method is proposed for moving target. Firstly, an echoed signal model of motion target based on geometrical theory of diffraction is established and the influence of velocity on range profile of the target is analyzed. Secondly, a method based on minimum entropy principle is used to compensate velocity. Then, incoherent factors including a quadratic phase term, a linear phase factor, a fixed factor, and an amplitude difference term are analyzed. Subsequently, efficient methods are applied to estimate other incoherent factors, except that the quadratic term is small enough to be ignored. Finally, the feasibility and performance of the proposed method are investigated through numerical simulation.

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Consensus of Switched Multiagent Systems under Relative State Constraints

The consensus problem is presented for the switched multiagent system (MAS), where the MAS is switched between continuous- and discrete-time systems with relative state constraints. With some standard assumptions, we obtain the fact that the switched MAS with relative state constraints can achieve consensus under both fixed undirected graphs and switching undirected graphs. Furthermore, based on the absolute average value of initial states, we propose sufficient conditions for consensus of the switched MAS. The challenge of this study is that relative state constraints are considered, which will make the consensus problem much more complex. One of the main contributions is that, for the switched MAS with relative state constraints, we explore the solvability of the consensus problem. Finally, we present two simulation examples to show the effectiveness of the results.

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On Hofstadter Heart Sequences

The Hofstadter -sequence and the Hofstadter-Conway $10000 sequence are perhaps the two best known examples of meta-Fibonacci sequences. In this paper, we explore an unexpected connection between them. When the -sequence is subtracted from the Conway sequence, a chaotic pattern of heart-shaped figures emerges. We use techniques of Pinn and Tanny et al. to explore this sequence. Then, we introduce and analyze an apparent relative of the -sequence and illustrate how it also generates heart patterns when subtracted from the Conway sequence.

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Plasmablastic Lymphoma with Coexistence of Chronic Lymphocytic Leukemia in an Immunocompetent Patient: A Case Report and Mini-Review

Background. Plasmablastic lymphoma (PBL) is a rare, aggressive B-cell lymphoma with poor prognosis usually found in the oral cavity of HIV-positive patients. Chronic lymphocytic leukemia (CLL) is an indolent B-cell lymphoma with a variable clinical course. Transformation of CLL to PBL as Richter’s syndrome is rare while coexistence of CLL and PBL at diagnosis is even rarer. Case Report. We describe a case of a male immunocompetent patient with an ileum-cecum valve mass and a soft tissue mass at the left humerus with histologic evidence of PBL with coexistence of CLL in the bone marrow and peripheral blood. Amputation of the patient’s left arm was inevitable, and the patient was started on bortezomib and dexamethasone. However, prolonged hospitalization was complicated by aspiration pneumonia, and the patient passed away. Conclusions. No standard of care exists for patients with PBL, and prognosis remains dismal. Concomitant presentation of hematological malignancies becomes increasingly recognized, and further insight is needed in order to delineate whether they originate from the same clone or from different ones.

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Persistence of Toxic Activity of Fermentation Extracts from Bacillus thuringiensis var. israelensis after More Than Three Decades of Storage

This study was carried out to determine the persistence of toxicity of fermentation extracts of Bacillus thuringiensis var. israelensis after more than three decades of storage. For this purpose, a population of Aedes aegypti was established. The mortality rate of 20 spore-crystal extracts purified using the acetone-lactose coprecipitation method was measured and evaluated by bioassays according to a modified WHO protocol. The extracts with the highest mortality rate were determined in triplicate by their LD50 and LD98. All extracts showed toxicity at the highest tested dose (1000 ppm) and some, such as strains 3260 and 3501, still killed larvae at doses as low as 0.01 ppm. These data are surprising because no study on the activity of B. thuringiensis toxic proteins after such a long storage time has been reported.

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Protein key to cancer cells ability to spread is identified

U of G scientists have made a discovery that could reduce the spread of cancer by hindering a protein that binds cancer cells together and allows them to invade tissues. The groundbreaking study identified a protein, known as cadherin-22, as a potential...

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Laudation for Dr. Alexander Berghaus



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Comparative analysis of molecular activity in dermal mesenchymal stem cells from different passages

Abstract

Mesenchymal stem cells (MSCs) are used for tissue regeneration in several pathological conditions, including autoimmune diseases. However, the optimal sources and culture requirements for these cells are still under investigation. Here, we compared mRNA expression in dermal MSCs (DMSCs) at passage (P) 3 and P5 to provide a reference for future studies related to DMSCs expansion. In normal DMSCs, the expression of three of eight genes associated with basic cellular activity were different at P5 compared to that at P3: PLCB4 and SYTL2 were upregulated by 4.30- and 6.42-fold, respectively (P < 0.05), whereas SATB2 was downregulated by 39.25-fold (P < 0.05). At the same time, genes associated with proliferation, differentiation, inflammation, and apoptosis were expressed at similar levels at P3 and P5 (P > 0.05). In contrast, in DMSCs isolated from psoriatic patients we observed differential expression of three inflammation-associated genes at P5 compared to P3; thus IL6, IL8, and CXCL6 mRNA levels were upregulated by 16.02-, 31.15-, and 15.04-fold, respectively. Our results indicate that normal and psoriatic DMSCs showed different expression patterns for genes related to inflammation and basic cell activity at P3 and P5, whereas those for genes linked to proliferation, differentiation, and apoptosis were mostly similar.



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Kriminalität in Basel – Eine GIS-gestützte Analyse der Tatorte ausgewählter Delikte von 2005 bis 2009

In der Masterarbeit “Räumliche Strukturmuster städtischer Kriminalität in Basel” wurde auf Grundlage der Anzeigestatistik der Staatsanwaltschaft Basel-Stadt anhand eines zeitlich begrenzten Raumausschnitts (2005–2009) der Ist-Zustand der Kriminalität ermittelt und kartographisch dargestellt. In der untersuchten Zeitreihe wurde eine massive Zunahme der Einbruchsdiebstähle sowie ein starker Anstieg der Raubdelikte erfasst. Im Gegensatz dazu verzeichnen die Delikte Sachbeschädigung und Ladendiebstähle leichte Rückgänge, während bei den Fallzahlen der Körperverletzung keine nennenswerten Schwankungen zu beobachten sind. Die meisten Delikte wurden während der Freizeit, nachts und am Wochenende begangen. Teilweise ist ausserdem ein Einfluss der Ferienzeit zu erkennen. Starke Kriminalitätsbelastungen sind in den Wohnvierteln mit sozialen Desorganisationserscheinungen und tiefem sozialem Status zu finden. Ebenso widerspiegelt sich die Zentrumsfunktion der Innenstadt sowie die Verteilung des tertiären Sektors und städtischer Vergnügungsaktivitäten in den Tatortkonzentrationen.

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Abschätzung der Nutzungsreserven – Grundlagendaten für den konsequenten Vollzug des Raumplanungsgesetzes

Trotz entsprechendem Auftrag der Bundesverfassung und des Raumplanungsgesetzes, haushälterisch mit dem Boden umzugehen, schreitet die Zersiedelung in der Schweiz ungebremst voran.Um diese Entwicklung zu stoppen, ist ein konsequenter Vollzug von Art. 15 des Raumplanungsgesetzes, der die Bauzonendimensionierung regelt, notwendig. Im Rahmen einer Masterarbeit wurde am Beispiel des Kantons Basel-Landschaft ein Verfahren zur Abschätzung der Nutzungsreserven entwickelt, welches Grundlagendaten für den Vollzug dieses Verfassungsartikels generiert.

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Konsumentenstruktur und Einkaufsverhalten im Raum Basel

Eine im Frühjahr 2011 in drei Einkaufszentren und zwei Einkaufsstrassen im Raum Basel durchgeführte Befragung hatte das Ziel festzustellen, ob sich die verschiedenartigen Einkaufsstandorte ergänzen oder in einer Konkurrenzsituation zueinander stehen. Die Resultate zeigen, dass Einkaufszentren in bestimmten Bereichen dominieren, so etwa im Lebensmittel- und Elektronikbereich, Innenstädte dagegen bei den Dienstleistungen (Bank, Post, Arzt etc.). Entscheidend für einen erfolgreichen Standort sind vor allem Erreichbarkeit, Preisstruktur und Angebot. Die Kunden an den verschiedenen Standorten unterscheiden sich hinsichtlich ihrer personenbezogenen Merkmale wie Alter, Einkommen und Haushaltgrösse. Kaum eine Rolle bei der Wahl des Einkaufsortes spielte Familienfreundlichkeit. Aufgrund der Ergebnisse werden Empfehlungen für optimierte Standortstrategien ausgearbeitet.

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IJMS, Vol. 18, Pages 2471: Advanced Glycation End Products in the Pathogenesis of Psoriasis

IJMS, Vol. 18, Pages 2471: Advanced Glycation End Products in the Pathogenesis of Psoriasis

International Journal of Molecular Sciences doi: 10.3390/ijms18112471

Authors: Anastasia Papagrigoraki Martina Maurelli Micol del Giglio Paolo Gisondi Giampiero Girolomoni

Advanced glycation end products (AGEs) are extremely oxidant and biologically reactive compounds, which form through oxidation of sugars, lipids and amino acids to create aldehydes that bind covalently to proteins. AGEs formation and accumulation in human tissues is a physiological process during ageing but it is enhanced in case of persistent hyperglycemia, hyperlipidemia and oxidative or carbonyl stress, which are common in patients with moderate to severe psoriasis. Exogenous AGEs may derive from foods, UV irradiation and cigarette smoking. AGEs elicit biological functions by activating membrane receptors expressed on epithelial and inflammatory cell surface. AGEs amplify inflammatory response by favoring the release of cytokines and chemokines, the production of reactive oxygen species and the activation of metalloproteases. AGEs levels are increased in the skin and blood of patients with severe psoriasis independently of associated metabolic disorders. Intensified glycation of proteins in psoriasis skin might have a role in fueling cutaneous inflammation. In addition, AGEs released from psoriatic skin may increase metabolic and cardiovascular risk in patients with severe disease.



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Increased steroidogenesis promotes early-onset and severe vision loss in females with OPA1 dominant optic atrophy

Human Molecular Genetics, 2016, Vol. 25, pages 2539–2551. doi: 10.1093/hmg/ddw117

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Discovery of susceptibility loci associated with tuberculosis in Han Chinese

Abstract
Genome-wide association studies (GWASs) have revealed the worldwide heterogeneity of genetic factors in tuberculosis (TB) susceptibility. Despite having the third highest global TB burden, no TB-related GWAS has been performed in China. Here, we performed the first three-stage GWAS on TB in the Han Chinese population. In the stage 1 (discovery stage), after quality control, 691 388 SNPs present in 972 TB patients and 1537 controls were retained. After replication on an additional 3460 TB patients and 4862 controls (stages 2 and 3), we identified three significant loci associated with TB, the most significant of which was rs4240897 (logistic regression P = 1.41 × 10−11, odds ratio = 0.79). The aforementioned three SNPs were harbored by MFN2, RGS12 and human leukocyte antigen class II beta chain paralogue encoding genes, all of which are candidate immune genes associated with TB. Our findings provide new insight into the genetic background of TB in the Han Chinese population.

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A mutation in IFT43 causes non-syndromic recessive retinal degeneration

Abstract
The aim of this work is to identify the molecular cause of autosomal recessive early onset retinal degeneration in a consanguineous pedigree. Seventeen members of a four-generation Pakistani family were recruited and underwent a detailed ophthalmic examination. Exomes of four affected and two unaffected individuals were sequenced. Variants were filtered using exomeSuite to identify rare potentially pathogenic variants in genes expressed in the retina and/or brain and consistent with the pattern of inheritance. Effect of the variant observed in the gene Intraflagellar Transport Protein 43 (IFT43) was studied by heterologous expression in mIMCD3 and MDCK cells. Expression and sub-cellular localization of IFT43 in the retina and transiently transfected cells was examined by RT-PCR, western blot analysis, and immunohistochemistry. Affected members were diagnosed with early onset non-syndromic progressive retinal degeneration and the presence of bone spicules distributed throughout the retina at younger ages while the older affected members showed severe central choroidal atrophy. Whole-exome sequencing analysis identified a novel homozygous c.100 G > A change in IFT43 segregating with retinal degeneration and not present in ethnicity-matched controls. Immunostaining showed IFT43 localized in the photoreceptors, and to the tip of the cilia in transfected mIMCD3 and MDCK cells. The cilia in mIMCD3 and MDCK cells expressing mutant IFT43 were found to be significantly shorter (P < 0.001) than cells expressing wild-type IFT43. Our studies identified a novel homozygous mutation in the ciliary protein IFT43 as the underlying cause of recessive inherited retinal degeneration. This is the first report demonstrating the involvement of IFT43 in retinal degeneration.

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Pyroglutamate–amyloid-β peptide expression in Drosophila leads to caspase-dependent and endoplasmic reticulum stress–related progressive neurodegeneration

Abstract
Alzheimer‘s disease (AD) is the most common neurodegenerative disorder among the elderly. During the progression of AD, massive neuronal degeneration occurs in the late stage of the disease; however, the molecular mechanisms responsible for this neuronal loss remain unknown. AβpE3–42 (an N-terminal–truncated amyloid-β peptide that begins with pyroglutamate at the third position) is produced during late-stage AD. It also aggregates more rapidly in vitro and exhibits greater toxicity in neurons than full-length Aβ1–42. In the present study, we established a Drosophila melanogaster model that expresses Aβ3–42E3Q, which effectively produces AβpE3–42, and investigated the function of AβpE3–42 using the photoreceptor neurons of Drosophila. AβpE3–42 induced caspase-dependent apoptosis and caused progressive degeneration in photoreceptor neurons. Mutations in ER stress response genes or the administration of an inhibitor of the ER stress response markedly suppressed the degeneration phenotype, suggesting that the ER stress response plays an important role in neurodegeneration caused by AβpE3–42. We also confirmed that human Tau-dependent apoptotic induction was strongly enhanced by AβpE3–42. Thus, AβpE3–42 expression system in the fly may be a promising new tool for studying late-onset neurodegeneration in AD.

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Neurodevelopmental disease-associated de novo mutations and rare sequence variants affect TRIO GDP/GTP exchange factor activity

Abstract
Bipolar disorder, schizophrenia, autism and intellectual disability are complex neurodevelopmental disorders, debilitating millions of people. Therapeutic progress is limited by poor understanding of underlying molecular pathways. Using a targeted search, we identified an enrichment of de novo mutations in the gene encoding the 330-kDa triple functional domain (TRIO) protein associated with neurodevelopmental disorders. By generating multiple TRIO antibodies, we show that the smaller TRIO9 isoform is the major brain protein product, and its levels decrease after birth. TRIO9 contains two guanine nucleotide exchange factor (GEF) domains with distinct specificities: GEF1 activates both Rac1 and RhoG; GEF2 activates RhoA. To understand the impact of disease-associated de novo mutations and other rare sequence variants on TRIO function, we utilized two FRET-based biosensors: a Rac1 biosensor to study mutations in TRIO (T)GEF1, and a RhoA biosensor to study mutations in TGEF2. We discovered that one autism-associated de novo mutation in TGEF1 (K1431M), at the TGEF1/Rac1 interface, markedly decreased its overall activity toward Rac1. A schizophrenia-associated rare sequence variant in TGEF1 (F1538Intron) was substantially less active, normalized to protein level and expressed poorly. Overall, mutations in TGEF1 decreased GEF1 activity toward Rac1. One bipolar disorder-associated rare variant (M2145T) in TGEF2 impaired inhibition by the TGEF2 pleckstrin-homology domain, resulting in dramatically increased TGEF2 activity. Overall, genetic damage to both TGEF domains altered TRIO catalytic activity, decreasing TGEF1 activity and increasing TGEF2 activity. Importantly, both GEF changes are expected to decrease neurite outgrowth, perhaps consistent with their association with neurodevelopmental disorders.

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Activated Braf induces esophageal dilation and gastric epithelial hyperplasia in mice

Abstract
Germline mutations in BRAF are a major cause of cardio-facio-cutaneous (CFC) syndrome, which is characterized by heart defects, characteristic craniofacial dysmorphology and dermatologic abnormalities. Patients with CFC syndrome also commonly show gastrointestinal dysfunction, including feeding and swallowing difficulties and gastroesophageal reflux. We have previously found that knock-in mice expressing a Braf Q241R mutation exhibit CFC syndrome-related phenotypes, such as growth retardation, craniofacial dysmorphisms, congenital heart defects and learning deficits. However, it remains unclear whether BrafQ241R/+ mice exhibit gastrointestinal dysfunction. Here, we report that BrafQ241R/+ mice have neonatal feeding difficulties and esophageal dilation. The esophagus tissues from BrafQ241R/+ mice displayed incomplete replacement of smooth muscle with skeletal muscle and decreased contraction. Furthermore, the BrafQ241R/+ mice showed hyperkeratosis and a thickened muscle layer in the forestomach. Treatment with MEK inhibitors ameliorated the growth retardation, esophageal dilation, hyperkeratosis and thickened muscle layer in the forestomach in BrafQ241R/+ mice. The esophageal dilation with aberrant skeletal-smooth muscle boundary in BrafQ241R/+ mice were recovered after treatment with the histone H3K27 demethylase inhibitor GSK-J4. Our results provide clues to elucidate the pathogenesis and possible treatment of gastrointestinal dysfunction and failure to thrive in patients with CFC syndrome.

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Amyotrophic lateral sclerosis-associated mutant SOD1 inhibits anterograde axonal transport of mitochondria by reducing Miro1 levels

Abstract
Defective axonal transport is an early neuropathological feature of amyotrophic lateral sclerosis (ALS). We have previously shown that ALS-associated mutations in Cu/Zn superoxide dismutase 1 (SOD1) impair axonal transport of mitochondria in motor neurons isolated from SOD1 G93A transgenic mice and in ALS mutant SOD1 transfected cortical neurons, but the underlying mechanisms remained unresolved. The outer mitochondrial membrane protein mitochondrial Rho GTPase 1 (Miro1) is a master regulator of mitochondrial axonal transport in response to cytosolic calcium (Ca2+) levels ([Ca2+]c) and mitochondrial damage. Ca2+ binding to Miro1 halts mitochondrial transport by modifying its interaction with kinesin-1 whereas mitochondrial damage induces Phosphatase and Tensin Homolog (PTEN)-induced Putative Kinase 1 (PINK1) and Parkin-dependent degradation of Miro1 and consequently stops transport. To identify the mechanism underlying impaired axonal transport of mitochondria in mutant SOD1-related ALS we investigated [Ca2+]c and Miro1 levels in ALS mutant SOD1 expressing neurons. We found that expression of ALS mutant SOD1 reduced the level of endogenous Miro1 but did not affect [Ca2+]c. ALS mutant SOD1 induced reductions in Miro1 levels were Parkin dependent. Moreover, both overexpression of Miro1 and ablation of PINK1 rescued the mitochondrial axonal transport deficit in ALS mutant SOD1-expressing cortical and motor neurons. Together these results provide evidence that ALS mutant SOD1 inhibits axonal transport of mitochondria by inducing PINK1/Parkin-dependent Miro1 degradation.

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A human patient-derived cellular model of Joubert syndrome reveals ciliary defects which can be rescued with targeted therapies

Abstract
Joubert syndrome (JBTS) is the archetypal ciliopathy caused by mutation of genes encoding ciliary proteins leading to multi-system phenotypes, including a cerebello-retinal-renal syndrome. JBTS is genetically heterogeneous, however mutations in CEP290 are a common underlying cause. The renal manifestation of JBTS is a juvenile-onset cystic kidney disease, known as nephronophthisis, typically progressing to end-stage renal failure within the first two decades of life, thus providing a potential window for therapeutic intervention. In order to increase understanding of JBTS and its associated kidney disease and to explore potential treatments, we conducted a comprehensive analysis of primary renal epithelial cells directly isolated from patient urine (human urine-derived renal epithelial cells, hURECs). We demonstrate that hURECs from a JBTS patient with renal disease have elongated and disorganized primary cilia and that this ciliary phenotype is specifically associated with an absence of CEP290 protein. Treatment with the Sonic hedgehog (Shh) pathway agonist purmorphamine or cyclin-dependent kinase inhibition (using roscovitine and siRNA directed towards cyclin-dependent kinase 5) ameliorated the cilia phenotype. In addition, purmorphamine treatment was shown to reduce cyclin-dependent kinase 5 in patient cells, suggesting a convergence of these signalling pathways. To our knowledge, this is the most extensive analysis of primary renal epithelial cells from JBTS patients to date. It demonstrates the feasibility and power of this approach to directly assess the consequences of patient-specific mutations in a physiologically relevant context and a previously unrecognized convergence of Shh agonism and cyclin-dependent kinase inhibition as potential therapeutic targets.

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A novel SYN1 missense mutation in non-syndromic X-linked intellectual disability affects synaptic vesicle life cycle, clustering and mobility

Abstract
Intellectual Disability is a common and heterogeneous disorder characterized by limitations in intellectual functioning and adaptive behaviour, whose molecular mechanisms remain largely unknown. Among the numerous genes found to be involved in the pathogenesis of intellectual disability, 10% are located on the X-chromosome. We identified a missense mutation (c.236 C > G; p.S79W) in the SYN1 gene coding for synapsin I in the MRX50 family, affected by non-syndromic X-linked intellectual disability. Synapsin I is a neuronal phosphoprotein involved in the regulation of neurotransmitter release and neuronal development. Several mutations in SYN1 have been identified in patients affected by epilepsy and/or autism. The S79W mutation segregates with the disease in the MRX50 family and all affected members display intellectual disability as sole clinical manifestation. At the protein level, the S79W Synapsin I mutation is located in the region of the B-domain involved in recognition of highly curved membranes. Expression of human S79W Synapsin I in Syn1 knockout hippocampal neurons causes aberrant accumulation of small clear vesicles in the soma, increased clustering of synaptic vesicles at presynaptic terminals and increased frequency of excitatory spontaneous release events. In addition, the presence of S79W Synapsin I strongly reduces the mobility of synaptic vesicles, with possible implications for the regulation of neurotransmitter release and synaptic plasticity. These results implicate SYN1 in the pathogenesis of non-syndromic intellectual disability, showing that alterations of synaptic vesicle trafficking are one possible cause of this disease, and suggest that distinct mutations in SYN1 may lead to distinct brain pathologies.

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Trichothiodystrophy causative TFIIEβ mutation affects transcription in highly differentiated tissue

Abstract
The rare recessive developmental disorder Trichothiodystrophy (TTD) is characterized by brittle hair and nails. Patients also present a variable set of poorly explained additional clinical features, including ichthyosis, impaired intelligence, developmental delay and anemia. About half of TTD patients are photosensitive due to inherited defects in the DNA repair and transcription factor II H (TFIIH). The pathophysiological contributions of unrepaired DNA lesions and impaired transcription have not been dissected yet. Here, we functionally characterize the consequence of a homozygous missense mutation in the general transcription factor II E, subunit 2 (GTF2E2/TFIIEβ) of two unrelated non-photosensitive TTD (NPS-TTD) families. We demonstrate that mutant TFIIEβ strongly reduces the total amount of the entire TFIIE complex, with a remarkable temperature-sensitive transcription defect, which strikingly correlates with the phenotypic aggravation of key clinical symptoms after episodes of high fever. We performed induced pluripotent stem (iPS) cell reprogramming of patient fibroblasts followed by in vitro erythroid differentiation to translate the intriguing molecular defect to phenotypic expression in relevant tissue, to disclose the molecular basis for some specific TTD features. We observed a clear hematopoietic defect during late-stage differentiation associated with hemoglobin subunit imbalance. These new findings of a DNA repair-independent transcription defect and tissue-specific malfunctioning provide novel mechanistic insight into the etiology of TTD.

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A constitutive BCL2 down-regulation aggravates the phenotype of PKD1 -mutant-induced polycystic kidney disease

Abstract
The main identified function of BCL2 protein is to prevent cell death by apoptosis. Mouse knock-out for Bcl2 demonstrates growth retardation, severe polycystic kidney disease (PKD), grey hair and lymphopenia, and die prematurely after birth. Here, we report a 40-year-old male referred to for abdominal and thoracic aortic dissection with associated aortic root aneurysm, PKD, lymphocytopenia with a history of T cell lymphoblastic lymphoma, white hair since the age of 20, and learning difficulties. PKD, which was also detected in the father and sister, was related to an inherited PKD1 mutation. The combination of PKD with grey hair and lymphocytopenia was also reminiscent of Bcl2−/− mouse phenotype. BCL2 gene transcript and protein level were observed to be dramatically decreased in patient peripheral blood T-cells and in his aorta vascular wall cells, which was not detected in parents and sister T-cells, suggesting an autosomal recessive inheritance. Accordingly, spontaneous apoptosis of patient T-cells was increased and could be rescued through stimulation with an anti-CD3 antibody. Direct sequencing of BCL2 gene exons, promoter and 3’UTR region as well as BCL2 mRNA sequencing failed in identifying any pathogenic variant. Array-CGH was also normal and whole exome sequencing of the patient, parents and sister DNA did not detect any significant variant in genes encoding BCL2-interacting proteins. miRNA array identified an up-regulation of miR-181a, which is a known regulator of BCL2 expression. Altogether, miR-181a-mediated decrease in BCL2 gene expression could be a modifying factor that aggravates the phenotype of a PKD1 constitutive variant.

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Loss of the imprinted, non-coding Snord116 gene cluster in the interval deleted in the Prader Willi syndrome results in murine neuronal and endocrine pancreatic developmental phenotypes

Abstract
Global neurodevelopmental delay is a prominent characteristic of individuals with Prader-Willi syndrome (PWS). The neuromolecular bases for these delays are unknown. We identified neuroanatomical changes in the brains of mice deficient for a gene in the minimal critical deletion region for PWS (Snord116p−/m+). In Snord116p−/m+ mice, reduced primary forebrain neuron cell body size is apparent in embryonic day 15.5 fetuses, and persists until postnatal day 30 in cerebellar Purkinje neurons. Snord116 is a snoRNA gene cluster of unknown function that can localize to the nucleolus. In cerebellar Purkinje neurons from postnatal day 30 Snord116p−/m+ mice the reduction in neuronal cell body size was associated with decreased neuronal nucleolar size. We also identified developmental changes in the endocrine pancreas of Snord116p−/m+ animals that persist into adulthood. Mice lacking Snord116 have smaller pancreatic islets; within the islet the percentage of δ-cells is increased, while the percentage of α-cells is reduced. The α-cell markers, Sst and Hhex, are upregulated in Snord116p−/m+ isolated islets while Ins1, Ins2, Pdx1, Nkx6-1, and Pax6 are downregulated. There is a 3-fold increase in the percentage of polyhormonal cells in the neonatal pancreata of Snord116p−/m+ mice, due primarily to an increase in cells co-positive with somatostatin. Snord116 may play a role in islet cell lineage specification. The Snord116 gene cluster is important for developmental processes in the brain as well as the endocrine pancreas.

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Heterozygous loss of TSC2 alters p53 signaling and human stem cell reprogramming

Abstract
Tuberous sclerosis complex (TSC) is a pediatric disorder of dysregulated growth and differentiation caused by loss of function mutations in either the TSC1 or TSC2 genes, which regulate mTOR kinase activity. To study aberrations of early development in TSC, we generated induced pluripotent stem cells using dermal fibroblasts obtained from patients with TSC. During validation, we found that stem cells generated from TSC patients had a very high rate of integration of the reprogramming plasmid containing a shRNA against TP53. We also found that loss of one allele of TSC2 in human fibroblasts is sufficient to increase p53 levels and impair stem cell reprogramming. Increased p53 was also observed in TSC2 heterozygous and homozygous mutant human stem cells, suggesting that the interactions between TSC2 and p53 are consistent across cell types and gene dosage. These results support important contributions of TSC2 heterozygous and homozygous mutant cells to the pathogenesis of TSC and the important role of p53 during reprogramming.

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The mitochondrial metallochaperone SCO1 maintains CTR1 at the plasma membrane to preserve copper homeostasis in the murine heart

Abstract
SCO1 is a ubiquitously expressed, mitochondrial protein with essential roles in cytochrome c oxidase (COX) assembly and the regulation of copper homeostasis. SCO1 patients present with severe forms of early onset disease, and ultimately succumb from liver, heart or brain failure. However, the inherent susceptibility of these tissues to SCO1 mutations and the clinical heterogeneity observed across SCO1 pedigrees remain poorly understood phenomena. To further address this issue, we generated Sco1hrt/hrt and Sco1stm/stm mice in which Sco1 was specifically deleted in heart and striated muscle, respectively. Lethality was observed in both models due to a combined COX and copper deficiency that resulted in a dilated cardiomyopathy. Left ventricular dilation and loss of heart function was preceded by a temporal decrease in COX activity and copper levels in the longer-lived Sco1stm/stm mice. Interestingly, the reduction in copper content of Sco1stm/stm cardiomyocytes was due to the mislocalisation of CTR1, the high affinity transporter that imports copper into the cell. CTR1 was similarly mislocalized to the cytosol in the heart of knockin mice carrying a homozygous G115S substitution in Sco1, which in humans causes a hypertrophic cardiomyopathy. Our current findings in the heart are in marked contrast to our prior observations in the liver, where Sco1 deletion results in a near complete absence of CTR1 protein. These data collectively argue that mutations perturbing SCO1 function have tissue-specific consequences for the machinery that ultimately governs copper homeostasis, and further establish the importance of aberrant mitochondrial signaling to the etiology of copper handling disorders.

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Low-dose rapamycin extends lifespan in a mouse model of mtDNA depletion syndrome

Abstract
Mitochondrial disorders affecting oxidative phosphorylation (OxPhos) are caused by mutations in both the nuclear and mitochondrial genomes. One promising candidate for treatment is the drug rapamycin, which has been shown to extend lifespan in multiple animal models, and which was previously shown to ameliorate mitochondrial disease in a knock-out mouse model lacking a nuclear-encoded gene specifying an OxPhos structural subunit (Ndufs4). In that model, relatively high-dose intraperitoneal rapamycin extended lifespan and improved markers of neurological disease, via an unknown mechanism. Here, we administered low-dose oral rapamycin to a knock-in (KI) mouse model of authentic mtDNA disease, specifically, progressive mtDNA depletion syndrome, resulting from a mutation in the mitochondrial nucleotide salvage enzyme thymidine kinase 2 (TK2). Importantly, low-dose oral rapamycin was sufficient to extend Tk2KI/KI mouse lifespan significantly, and did so in the absence of detectable improvements in mitochondrial dysfunction. We found no evidence that rapamycin increased survival by acting through canonical pathways, including mitochondrial autophagy. However, transcriptomics and metabolomics analyses uncovered systemic metabolic changes pointing to a potential ‘rapamycin metabolic signature.’ These changes also implied that rapamycin may have enabled the Tk2KI/KI mice to utilize alternative energy reserves, and possibly triggered indirect signaling events that modified mortality through developmental reprogramming. From a therapeutic standpoint, our results support the possibility that low-dose rapamycin, while not targeting the underlying mtDNA defect, could represent a crucial therapy for the treatment of mtDNA-driven, and some nuclear DNA-driven, mitochondrial diseases.

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In vitro characterization of mitochondrial function and structure in rat and human cells with a deficiency of the NADH: ubiquinone oxidoreductase Ndufc2 subunit

Abstract
Ndufc2, a subunit of the NADH: ubiquinone oxidoreductase, plays a key role in the assembly and activity of complex I within the mitochondrial OXPHOS chain. Its deficiency has been shown to be involved in diabetes, cancer and stroke. To improve our knowledge on the mechanisms underlying the increased disease risk due to Ndufc2 reduction, we performed the present in vitro study aimed at the fine characterization of the derangements in mitochondrial structure and function consequent to Ndufc2 deficiency. We found that both fibroblasts obtained from skin of heterozygous Ndufc2 knock-out rat model showed marked mitochondrial dysfunction and PBMC obtained from subjects homozygous for the TT genotype of the rs11237379/NDUFC2 variant, previously shown to associate with reduced gene expression, demonstrated increased generation of reactive oxygen species and mitochondrial damage. The latter was associated with increased oxidative stress and significant ultrastructural impairment of mitochondrial morphology with a loss of internal cristae. In both models the exposure to stress stimuli, such as high-NaCl concentration or LPS, exacerbated the mitochondrial damage and dysfunction. Resveratrol significantly counteracted the ROS generation. These findings provide additional insights on the role of an altered pattern of mitochondrial structure–function as a cause of human diseases. In particular, they contribute to underscore a potential genetic risk factor for cardiovascular diseases, including stroke.

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Activating the unfolded protein response in osteocytes causes hyperostosis consistent with craniodiaphyseal dysplasia

Abstract
Bone remodeling is a balanced process between bone synthesis and degradation, maintaining homeostasis and a constant bone mass in adult life. Imbalance will lead to conditions such as osteoporosis or hyperostosis. Osteoblasts build bone, becoming embedded in bone matrix as mature osteocytes. Osteocytes have a role in sensing and translating mechanical loads into biochemical signals, regulating the differentiation and activity of osteoblasts residing at the bone surface through the secretion of Sclerostin (SOST), an inhibitor of WNT signaling. Excessive mechanical load can lead to activation of cellular stress responses altering cell behavior and differentiation. The unfolded protein response (UPR) is a shared pathway utilized by cells to cope with stress stimuli. We showed that in a transgenic mouse model, activation of the UPR in early differentiating osteocytes delays maturation, maintaining active bone synthesis. In addition, expression of SOST is delayed or suppressed; resulting in active WNT signaling and enhanced periosteal bone formation, and the combined outcome is generalized hyperostosis. A clear relationship between the activation of the unfolded protein response was established and the onset of hyperostosis that can be suppressed with a chemical chaperone, sodium 4-phenobutyrate (4-PBA). As the phenotype is highly consistent with craniodiaphyseal dysplasia (CDD; OMIM 122860), we propose activation of the UPR could be part of the disease mechanism for CDD patients as these patients are heterozygous for SOST mutations that impair protein folding and secretion. Thus, therapeutic agents ameliorating protein folding or the UPR can be considered as a potential therapeutic treatment.

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GLI1 inactivation is associated with developmental phenotypes overlapping with Ellis–van Creveld syndrome

Abstract
GLI1, GLI2 and GLI3 form a family of transcription factors which regulate development by mediating the action of Hedgehog (Hh) morphogens. Accordingly, inactivating variants in GLI2 and GLI3 are found in several developmental disorders. In contrast, loss-of-function mutations in GLI1 have remained elusive, maintaining enigmatic the role of this gene in the human embryo. We describe eight patients from three independent families having biallelic truncating variants in GLI1 and developmental defects overlapping with Ellis–van Creveld syndrome (EvC), a disease caused by diminished Hh signaling. Two families had mutations in the last exon of the gene and a third family was identified with an N-terminal stop gain variant predicted to be degraded by the NMD-pathway. Analysis of fibroblasts from one of the patients with homozygous C-terminal truncation of GLI1 demonstrated that the corresponding mutant GLI1 protein is fabricated by patient cells and becomes upregulated in response to Hh signaling. However, the transcriptional activity of the truncated GLI1 factor was found to be severely impaired by cell culture and in vivo assays, indicating that the balance between GLI repressors and activators is altered in affected subjects. Consistent with this, reduced expression of the GLI target PTCH1 was observed in patient fibroblasts after chemical induction of the Hh pathway. We conclude that GLI1 inactivation is associated with a phenotypic spectrum extending from isolated postaxial polydactyly to an EvC-like condition.

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Effects of rainfall intensity and slope gradient on runoff and sediment yield characteristics of bare loess soil

Abstract

Soil erosion is a universal phenomenon on the Loess Plateau but it exhibits complex and typical mechanism which makes it difficult to understand soil loss laws on slopes. We design artificial simulated rainfall experiments including six rainfall intensities (45, 60, 75, 90, 105, 120 mm/h) and five slopes (5°, 10°, 15°, 20°, 25°) to reveal the fundamental changing trends of runoff and sediment yield on bare loess soil. Here, we show that the runoff yield within the initial 15 min increased rapidly and its trend gradually became stable. Trends of sediment yield under different rainfall intensities are various. The linear correlation between runoff and rainfall intensity is obvious for different slopes, but the correlations between sediment yield and rainfall intensity are weak. Runoff and sediment yield on the slope surface both presents an increasing trend when the rainfall intensity increases from 45 mm/h to 120 mm/h, but the increasing trend of runoff yield is higher than that of sediment yield. The sediment yield also has an overall increasing trend when the slope changes from 5° to 25°, but the trend of runoff yield is not obvious. Our results may provide data support and underlying insights needed to guide the management of soil conservation planning on the Loess Plateau.



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Mineralogical and geochemical characterization of waste rocks from a gold mine in northeastern Thailand: application for environmental impact protection

Abstract

Waste rocks from gold mining in northeastern Thailand are classified as sandstone, siltstone, gossan, skarn, skarn-sulfide, massive sulfide, diorite, and limestone/marble. Among these rocks, skarn-sulfide and massive sulfide rocks have the potential to generate acid mine drainage (AMD) because they contain significant amounts of sulfide minerals, i.e., pyrrhotite, pyrite, arsenopyrite, and chalcopyrite. Moreover, both sulfide rocks present high contents of As and Cu, which are caused by the occurrence of arsenopyrite and chalcopyrite, respectively. Another main concern is gossan contents, which are composed of goethite, hydrous ferric oxide (HFO), quartz, gypsum, and oxidized pyroxene. X-ray maps using electron probe micro-analysis (EPMA) indicate distribution of some toxic elements in Fe-oxyhydroxide minerals in the gossan waste rock. Arsenic (up to 1.37 wt.%) and copper (up to 0.60 wt.%) are found in goethite, HFO, and along the oxidized rim of pyroxene. Therefore, the gossan rock appears to be a source of As, Cu, and Mn. As a result, massive sulfide, skarn-sulfide, and gossan have the potential to cause environmental impacts, particularly AMD and toxic element contamination. Consequently, the massive sulfide and skarn-sulfide waste rocks should be protected from oxygen and water to avoid an oxidizing environment, whereas the gossan waste rocks should be protected from the formation of AMD to prevent heavy metal contamination.



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Radiation therapy-induced metastasis: radiobiology and clinical implications

Abstract

Radiation therapy is an effective means of achieving local control in a wide range of primary tumours, with the reduction in the size of the tumour(s) thought to mediate the observed reductions in metastatic spread in clinical trials. However, there is evidence to suggest that the complex changes induced by radiation in the tumour environment can also present metastatic risks that may counteract the long-term efficacy of the treatment. More than 25 years ago, several largely theoretical mechanisms by which radiation exposure might increase metastatic risk were postulated. These include the direct release of tumour cells into the circulation, systemic effects of tumour and normal tissue irradiation and radiation-induced changes in tumour cell phenotype. Here, we review the data that has since emerged to either support or refute these putative mechanisms focusing on how the unique radiobiology underlying modern radiotherapy modalities might alter these risks.



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Reply to prognosis of sentinel lymph node biopsy in patients with thick melanoma by a propensity score matching prospective study



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Landschaft hören. Geographie und Unweltwahrnehmung im Forschungsfeld "Klanglandschaft"



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Die Baumgärten des Domleschg. Eine verwurzelte Landnutzung im Wandel



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Zur Dynamik von städtischem Grundbesitz im Stadtumland



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[Rezension von] Dardel E., L'homme et la terre. Nature de la réalité géographique. Nouvelle édition, Edition du CTHS, Paris 1990 (1952)



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[Rezension von] Agnew J.A., Duncan J.S. (eds), The power of place. Bringing tohether geographical and sociological imaginations. Unwin Hyman, Boston 1989



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[Rezension von] Barnes T.J., Duncan J.S. (eds), Writing worlds. Discourse, texte and metaphor in the representation of landscape, Routledge, London/N.York 1992



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[Rezension von] Porteous J.D., Landscapes of the mind. Worlds of sense and metaphor. UTP, Toronto 1990



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[Rezension von] Eyles J., Smith D. (eds), Qualitative methods in human geography. Polity, Cambridge 1988



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Resource Partitioning between Two Piranhas (Serrasalmus gibbus and Serrasalmus rhombeus) in an Amazonian Reservoir

The exploitation of resources by closely related species with similar niches may be mediated by differences in activity patterns, which may vary in nycthemeral scale and seasonal scale. Piranhas Serrasalmus gibbus and Serrasalmus rhombeus are Neotropical predators that occur sympatrically in many environments of the Amazon basin. To evaluate the strategies adopted by these two species in a restricted environment (a reservoir), nycthemeral and seasonal samples were made, identifying the composition of the diet and their activity patterns. A total of 402 specimens were collected: 341 S. gibbus and 61 S. rhombeus. Both species fed themselves primarily on fish, with some seasonal variation being found in S. gibbus during the flood season, when plant material was consumed. There was considerable temporal overlap in the foraging behavior of the two species, although S. rhombeus presented a bimodal pattern of abundance over the 24-hour cycle. S. rhombeus was more active during the nighttime, between dusk and early morning, whereas S. gibbus was active throughout the nycthemeral cycle. These findings indicate low levels of competition between the two species, which allowed for a considerable overlap in nighttime foraging, following distinct nycthemeral patterns of foraging activity and allowing their coexistence.

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The Optimization and Mathematical Modeling of Quality Attributes of Parboiled Rice Using a Response Surface Method

The response surface methodology was used to optimize the hydrothermal processing conditions based on the rice quality parameters of the Rong Youhua Zhan rice variety (Indica). The effect of soaking temperature (29.77, 40, 55, 70, and 80.23°C), soaking time (67.55, 90, 120, 150, and 170.45 min), and steaming time (1.59, 5, 10, 15, and 18.41 min), each tested at five levels, on percentage of head rice yield (HRY), hardness, cooking time, lightness, and color were determined, with values of 0.96, 0.94, 0.90, 0.88, and 0.94, respectively. HRY, hardness, cooking time, and color increased with process severity while lightness decreased, although HRY decreased after reaching a maximum. The predicted optimum soaking temperature, soaking time, and steaming time were 69.88°C, 150 min, and 6.73 min, respectively, and the predicted HRY, hardness, cooking time, lightness, and color under these conditions were 73.43%, 29.95 N, 32.14 min, 83.03 min, and 12.24 min, respectively, with a composite desirability of 0.9658. The parboiling industry could use the findings of the current study to obtain the desired quality of parboiled rice. This manuscript will be helpful for researchers working on commercializing parboiled rice processes in China as well as in other countries.

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Natural Bioactive Compounds: Alternative Approach to the Treatment of Glioblastoma Multiforme

Glioblastoma multiforme (GBM) is the most frequent, primary malignant brain tumor prevalent in humans. GBM characteristically exhibits aggressive cell proliferation and rapid invasion of normal brain tissue resulting in poor patient prognosis. The current standard of care of surgical resection followed by radiotherapy and chemotherapy with temozolomide is not very effective. The inefficacy of the chemotherapeutic agents may be attributed to the challenges in drug delivery to the tumor. Several epidemiological studies have demonstrated the chemopreventive role of natural, dietary compounds in the development and progression of cancer. Many of these studies have reported the potential of using natural compounds in combination with chemotherapy and radiotherapy as a novel approach for the effective treatment of cancer. In this paper, we review the role of several natural compounds individually and in combination with chemotherapeutic agents in the treatment of GBM. We also assess the potential of drug delivery approaches such as the Gliadel wafers and role of nanomaterial based drug delivery systems for the effective treatment of GBM.

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Cross-Checking Multiple Data Sources Using Multiway Join in MapReduce

As data sources accumulate information and data size escalates it becomes more and more difficult to maintain the correctness and validity of these datasets. Therefore, tools must emerge to facilitate this daunting task. Fact checking usually involves a large number of data sources that talk about the same thing but we are not sure which holds the correct information or which has any information at all about the query we care for. A join among all or some data sources can guide us through a fact-checking process. However, when we want to perform this join on a distributed computational environment such as MapReduce, it is not obvious how to distribute efficiently the records in the data sources to the reduce tasks in order to join any subset of them in a single MapReduce job. To this end, we propose an efficient approach using the multiway join to cross-check these data sources in a single round.

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The Effects of Different Factors on the Behavior of Neural Stem Cells

The repair of central nervous system (CNS) injury has been a worldwide problem in the biomedical field. How to reduce the damage to the CNS and promote the reconstruction of the damaged nervous system structure and function recovery has always been the concern of nerve tissue engineering. Multiple differentiation potentials of neural stem cell (NSC) determine the application value for the repair of the CNS injury. Thus, how to regulate the behavior of NSCs becomes the key to treating the CNS injury. So far, a large number of researchers have devoted themselves to searching for a better way to regulate the behavior of NSCs. This paper summarizes the effects of different factors on the behavior of NSCs in the past 10 years, especially on the proliferation and differentiation of NSCs. The final purpose of this review is to provide a more detailed theoretical basis for the clinical repair of the CNS injury by nerve tissue engineering.

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A Molecular and Clinical Review of Stem Cell Therapy in Critical Limb Ischemia

Peripheral artery disease (PAD) is one of the major vascular complications in individuals suffering from diabetes and in the elderly that can progress to critical limb ischemia (CLI), portending significant burden in terms of patient morbidity and mortality. Over the last two decades, stem cell therapy (SCT) has risen as an attractive alternative to traditional surgical and/or endovascular revascularization to treat this disorder. The primary benefit of SCT is to induce therapeutic neovascularization and promote collateral vessel formation to increase blood flow in the ischemic limb and soft tissue. Existing evidence provides a solid rationale for ongoing in-depth studies aimed at advancing current SCT that may change the way PAD/CLI patients are treated.

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Radiation therapy-induced metastasis: radiobiology and clinical implications

Abstract

Radiation therapy is an effective means of achieving local control in a wide range of primary tumours, with the reduction in the size of the tumour(s) thought to mediate the observed reductions in metastatic spread in clinical trials. However, there is evidence to suggest that the complex changes induced by radiation in the tumour environment can also present metastatic risks that may counteract the long-term efficacy of the treatment. More than 25 years ago, several largely theoretical mechanisms by which radiation exposure might increase metastatic risk were postulated. These include the direct release of tumour cells into the circulation, systemic effects of tumour and normal tissue irradiation and radiation-induced changes in tumour cell phenotype. Here, we review the data that has since emerged to either support or refute these putative mechanisms focusing on how the unique radiobiology underlying modern radiotherapy modalities might alter these risks.



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Prevalence of hearing loss among noise-exposed workers within the agriculture, forestry, fishing, and hunting sector, 2003-2012

Background

The purpose of this study was to estimate the prevalence of hearing loss among noise-exposed US workers within the Agriculture, Forestry, Fishing, and Hunting (AFFH) sector.

Methods

Audiograms for 1.4 million workers (17 299 within AFFH) from 2003 to 2012 were examined. Prevalence, and the adjusted risk for hearing loss as compared with the reference industry (Couriers and Messengers), were estimated.

Results

The overall AFFH sector prevalence was 15% compared to 19% for all industries combined, but many of the AFFH sub-sectors exceeded the overall prevalence. Forestry sub-sector prevalences were highest with Forest Nurseries and Gathering of Forest Products at 36% and Timber Tract Operations at 22%. The Aquaculture sub-sector had the highest adjusted risk of all AFFH sub-sectors (PR = 1.70; CI = 1.42-2.04).

Conclusions

High risk industries within the AFFH sector need continued hearing conservation efforts. Barriers to hearing loss prevention and early detection of hearing loss need to be recognized and addressed.



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Workplace violence injury in 106 US hospitals participating in the Occupational Health Safety Network (OHSN), 2012-2015

Background

Workplace violence is a substantial occupational hazard for healthcare workers in the United States.

Methods

We analyzed workplace violence injury surveillance data submitted by hospitals participating in the Occupational Health Safety Network (OHSN) from 2012 to 2015.

Results

Data were frequently missing for several important variables. Nursing assistants (14.89, 95%CI 10.12-21.91) and nurses (8.05, 95%CI 6.14-10.55) had the highest crude workplace violence injury rates per 1000 full-time equivalent (FTE) workers. Nursing assistants' (IRR 2.82, 95%CI 2.36-3.36) and nurses' (IRR 1.70, 95%CI 1.45-1.99) adjusted workplace violence injury rates were significantly higher than those of non-patient care personnel. On average, the overall rate of workplace violence injury among OHSN-participating hospitals increased by 23% annually during the study period.

Conclusion

Improved data collection is needed for OHSN to realize its full potential. Workplace violence is a serious, increasingly common problem in OHSN-participating hospitals. Nursing assistants and nurses have the highest injury risk.



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[Rezension von] Lenz Ramona, Mobilitäten in Europa. Migration und Tourismus auf Kreta und Zypern im Kontext des europäischen Grenzregimes. VS, Wiesbaden 2010



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[Rezension von] Schaumburg (2013): Bonyatsi. Heirat, Status und Beziehungsstrategien in einem südafrikanischen Township. Kölner Ethnologische Studien, 34. Berlin: Lit.



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IJMS, Vol. 18, Pages 2436: Calcium-Dependent Protein Kinases in Phytohormone Signaling Pathways

IJMS, Vol. 18, Pages 2436: Calcium-Dependent Protein Kinases in Phytohormone Signaling Pathways

International Journal of Molecular Sciences doi: 10.3390/ijms18112436

Authors: Wuwu Xu Wenchao Huang

Calcium-dependent protein kinases (CPKs/CDPKs) are Ca2+-sensors that decode Ca2+ signals into specific physiological responses. Research has reported that CDPKs constitute a large multigene family in various plant species, and play diverse roles in plant growth, development, and stress responses. Although numerous CDPKs have been exhaustively studied, and many of them have been found to be involved in plant hormone biosynthesis and response mechanisms, a comprehensive overview of the manner in which CDPKs participate in phytohormone signaling pathways, regulating nearly all aspects of plant growth, has not yet been undertaken. In this article, we reviewed the structure of CDPKs and the mechanism of their subcellular localization. Some CDPKs were elucidated to influence the intracellular localization of their substrates. Since little work has been done on the interaction between CDPKs and cytokinin signaling pathways, or on newly defined phytohormones such as brassinosteroids, strigolactones and salicylic acid, this paper mainly focused on discussing the integral associations between CDPKs and five plant hormones: auxins, gibberellins, ethylene, jasmonates, and abscisic acid. A perspective on future work is provided at the end.



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