Miracle-dz/UniFAR-FTUs huggingface dataset:
Long-term survival and function of intrahepatic islet allografts in baboons treated with humanized anti-CD154.

Clinical islet cell transplantation has resulted in insulin independence in a limited number of cases. Rejection, recurrence of autoimmunity, and impairment of normal islet function by conventional immunosuppressive drugs, e.g., steroids, tacrolimus, and cyclosporin A, may all contribute to islet allograft loss. Furthermore, intraportal infusion of allogeneic islets results in the activation of intrahepatic macrophages and endothelial cells, followed by production of proinflammatory mediators that can contribute to islet primary nonfunction. We reasoned that the beneficial effects of anti-CD154 treatment on autoimmunity, alloreactivity, and proinflammatory events mediated by macrophages and endothelial cells made it an ideal agent for the prevention of islet allograft failure. In this study, a nonhuman primate model (Papio hamadryas) was used to assess the effect of humanized anti-CD154 (hu5c8) on allogeneic islet engraftment and function. Nonimmunosuppressed and tacrolimus-treated recipients were insulin independent posttransplant, but rejected their islet allografts in 8 days. Engraftment and insulin independence were achieved in seven of seven baboon recipients of anti-CD154 induction therapy administered on days -1, 3, and 10 relative to the islet transplant. Three of three baboons treated with 20 mg/kg anti-CD154 induction therapy experienced delayed rejection episodes, first detected by elevations in postprandial blood glucose levels, on postoperative day (POD) 31 for one and on POD 58 for the other two. Re-treatment with three doses of anti-CD154 resulted in reversal of rejection in all three animals and in a return to normoglycemia and insulin independence in two of three baboons. It was possible to reverse multiple episodes of rejection with this approach. A loss of functional islet mass, as detected by reduced first-phase insulin release in response to intravenous glucose tolerance testing, was observed after each episode of rejection. One of two baboons treated with 10 mg/kg induction therapy became insulin independent post-transplant but rejected the islet graft on POD 10; the other animal experienced a reversible rejection episode on POD 58 and remained insulin independent and normoglycemic until POD 264. Two additional baboon recipients of allogeneic islets and donor bone marrow (infused on PODs 5 and 11) were treated with induction therapy (PODs -1, 3, 10), followed by initiation of monthly maintenance therapy (for a period of 6 months) on POD 28. Rejection-free graft survival and insulin independence was maintained for 114 and 238 days, with preservation of functional islet mass observed in the absence of rejection. Prevention and reversal of rejection, in the absence of the deleterious effects associated with the use of conventional immunosuppressive drugs, make anti-CD154 a unique agent for further study in islet cell transplantation.
Viral serine palmitoyltransferase induces metabolic switch in sphingolipid biosynthesis and is required for infection of a marine alga

Significance This work investigates the metabolic basis of the interactions between the cosmopolitan bloom-forming alga Emiliania huxleyi and its specific large DNA virus. We demonstrate some of the basic metabolic principles used by the EhV virus to “engineer” its host sphingolipid metabolism, to produce a unique suite of virus-specific lipids. These sphingolipids were essential for the virus assembly and infectivity. These results present novel insight into the chemical “arm race” at sea that coevolved around a unique metabolic pathway. Furthermore, it may provide important evolutionary and biochemical insights into sphingolipid biosynthesis and its functional role in other host–pathogen interactions (e.g. HIV, hepatitis C virus, dengue virus). Marine viruses are the most abundant biological entities in the oceans shaping community structure and nutrient cycling. The interaction between the bloom-forming alga Emiliania huxleyi and its specific large dsDNA virus (EhV) is a major factor determining the fate of carbon in the ocean, thus serving as a key host-pathogen model system. The EhV genome encodes for a set of genes involved in the de novo sphingolipid biosynthesis, not reported in any viral genome to date. We combined detailed lipidomic and biochemical analyses to characterize the functional role of this virus-encoded pathway during lytic viral infection. We identified a major metabolic shift, mediated by differential substrate specificity of virus-encoded serine palmitoyltransferase, a key enzyme of sphingolipid biosynthesis. Consequently, unique viral glycosphingolipids, composed of unusual hydroxylated C17 sphingoid bases (t17:0) were highly enriched in the infected cells, and their synthesis was found to be essential for viral assembly. These findings uncover the biochemical bases of the virus-induced metabolic rewiring of the host sphingolipid biosynthesis during the chemical “arms race” in the ocean.
Association of genetic variation in the MET proto-oncogene with schizophrenia and general cognitive ability.

OBJECTIVE Despite increased exposure to cancer risk factors, several studies have demonstrated a lower incidence of cancer in schizophrenia patients than in the general population. Lower cancer rates in first-degree relatives of schizophrenia patients suggest that the inverse relationship between cancer and schizophrenia may be related to genetic factors. Few studies of schizophrenia have focused on cancer-related genes. The MET proto-oncogene is primarily linked to tumor metastasis, but MET is also involved in neurodevelopment and influences risk for autism. Thus, MET may be of particular interest as a candidate gene for neuropsychiatric diseases with a developmental etiology, including schizophrenia. METHOD The authors examined the relationship between 21 single-nucleotide polymorphisms in MET and schizophrenia in 173 Caucasian patients and 137 comparison subjects. They then genotyped a second independent sample (107 patients and 112 comparison subjects) for replication. Finally, they tested for MET's effects on general cognitive ability (g). RESULTS In the initial cohort, the authors identified four haplotype blocks and found one block to be globally associated with schizophrenia. In block 3, the most common haplotype was overrepresented in comparison subjects (frequency, 47%) relative to schizophrenia patients (frequency, 33%) (p=4.0 x 10(-4); odds ratio=0.56). The authors replicated the block 3 finding in the second sample with similar frequencies: 46% in comparison subjects and 36% in schizophrenia patients (p=0.03; odds ratio=0.66). Moreover, the protective haplotype was associated with a higher g in the combined comparison sample. CONCLUSION These data suggest that MET variation influences schizophrenia risk and neurocognition, supporting a neurodevelopmental role across CNS-relevant phenotypes. These results add to the growing evidence suggesting an intriguing relationship between cancer-related genes and schizophrenia susceptibility.
Nanoscale patterning of STIM1 and Orai1 during store-operated Ca2+ entry

Significance Almost all cell types rely on calcium signals to maintain homeostasis and trigger specific cell responses. In eukaryotic cells, store-operated Ca2+ entry (SOCE) is one of the mechanisms used to ensure control over cytosolic Ca2+ signaling and internal Ca2+ stores. Mutations in either Orai1 or stromal interaction molecule 1 (STIM1) lead to lethal severe combined immune deficiencies. Using a morphological approach with transmission and freeze–fracture electron microscopy, we describe STIM1-Orai1 interactions and visualize the distribution of individual Orai1 channels on the cell surface. This approach confirms STIM1-Orai1 interaction at specialized endoplasmic reticulum (ER)–plasma membrane junctions following ER depletion and provides new insight on STIM1-Orai1 stoichiometry. Stromal interacting molecule (STIM) and Orai proteins constitute the core machinery of store-operated calcium entry. We used transmission and freeze–fracture electron microscopy to visualize STIM1 and Orai1 at endoplasmic reticulum (ER)–plasma membrane (PM) junctions in HEK 293 cells. Compared with control cells, thin sections of STIM1-transfected cells possessed far more ER elements, which took the form of complex stackable cisternae and labyrinthine structures adjoining the PM at junctional couplings (JCs). JC formation required STIM1 expression but not store depletion, induced here by thapsigargin (TG). Extended molecules, indicative of STIM1, decorated the cytoplasmic surface of ER, bridged a 12-nm ER-PM gap, and showed clear rearrangement into small clusters following TG treatment. Freeze–fracture replicas of the PM of Orai1-transfected cells showed extensive domains packed with characteristic “particles”; TG treatment led to aggregation of these particles into sharply delimited “puncta” positioned upon raised membrane subdomains. The size and spacing of Orai1 channels were consistent with the Orai crystal structure, and stoichiometry was unchanged by store depletion, coexpression with STIM1, or an Orai1 mutation (L273D) affecting STIM1 association. Although the arrangement of Orai1 channels in puncta was substantially unstructured, a portion of channels were spaced at ∼15 nm. Monte Carlo analysis supported a nonrandom distribution for a portion of channels spaced at ∼15 nm. These images offer dramatic, direct views of STIM1 aggregation and Orai1 clustering in store-depleted cells and provide evidence for the interaction of a single Orai1 channel with small clusters of STIM1 molecules.
Prolonged Hypothermia Causes Primary Nonfunction in Preserved Canine Renal Allografts due to Humoral Rejection

Canine kidney preservation models have historically used autotransplants to avoid the complications of rejection, although clinically all transplants are allografts. This study investigated the effects of preservation time and method on early kidney function in a canine allograft vs. autograft model. Kidneys were harvested from beagles, preserved by cold storage (CS) in UW solution for 0, 24 or 72 h, or by machine perfusion (MP) with Belzer MPS for 72 h. In some experiments 45 min of warm ischemia (WI) was performed in situ before harvest. Allograft recipients received steroid immunosuppression. Kidney function was assessed by serum creatinine and survival for 7 days. Allografts preserved for 0 and 24 h performed as well as autografts. Allografts preserved for 72 h by either CS or MP had a higher incidence of primary nonfunction (PNF) compared with autografts, as determined by survival (50% vs. 100%, p < 0.003). Primary nonfunction kidneys had thrombotic microangiopathy, vascular and peritubular capillary binding of IgM and complement C4d, and evidence of circulating donor‐specific antibodies; all consistent with humoral rejection. These responses were dependant on hypothermia time and were not attributable to ischemia, immunosuppression, preservation solution, or cellular rejection. In conclusion, prolonged hypothermia can cause PNF in allografts owing to acute humoral rejection.
Charge trapping and breakdown mechanism in HfAlO/TaN gate stack analyzed using carrier separation

Charge trapping and breakdown mechanism in p- and n-channel MOSFETs with an HfAl/sub x/O/sub y/ and TaN metal electrode are investigated. Using carrier separation measurement technique, it is possible to clearly distinguish two different breakdown mechanisms: a high-K bulk initiated and an interfacial layer initiated breakdown. A model of charge trapping at different spatial locations in HfAl/sub x/O/sub y/ with a TaN gate structure is proposed to explain the polarity dependence of charge trapping characteristics and breakdown mechanisms.
Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end‐stage renal disease on hemodialysis

An open‐label, parallel‐group, single‐dose study was conducted to assess the pharmacokinetics, pharmacodynamics, and safety of apixaban in 8 subjects with end‐stage renal disease (ESRD) on hemodialysis compared with 8 subjects with normal renal function. A single oral 5‐mg dose of apixaban was administered once to healthy subjects and twice to subjects with ESRD, separated by ≥7 days: 2 hours before (on hemodialysis) and immediately after a 4‐hour hemodialysis session (off hemodialysis). Blood samples were collected for determination of apixaban pharmacokinetic parameters, measures of clotting (prothrombin time, international normalized ratio, activated partial thromboplastin time), and anti‐factor Xa (FXa) activity. Compared with healthy subjects, apixaban Cmax and AUCinf were 10% lower and 36% higher, respectively, in subjects with ESRD off hemodialysis. Hemodialysis in subjects with ESRD was associated with reductions in apixaban Cmax and AUCinf of 13% and 14%, respectively. The percent change from baseline in clotting measures was similar in healthy subjects and subjects with ESRD, and differences in anti‐FXa activity were similar to differences in apixaban concentration. A single 5‐mg oral dose of apixaban was well tolerated in both groups. In conclusion, ESRD resulted in a modest increase (36%) in apixaban AUC and no increase in Cmax, and hemodialysis had a limited impact on apixaban clearance.
Effects of testosterone therapy on BMI, blood pressure, and laboratory profile of transgender men: a systematic review

Testosterone is the main hormonal agent used for cross‐sex hormone therapy in female‐to‐male transgender persons. Our aim was to systematically review the literature concerning the effects of testosterone on body mass index (BMI), blood pressure, hematocrit, hemoglobin, lipid profile, and liver enzymes in transgender men. PUBMED and EMBASE were searched for studies published until March 2017. Studies were included if they reported interventions with any dose of testosterone and comparison of variables before and during treatment. Of 455 potentially eligible articles, 13 were reviewed. Study duration ranged from 6 to 60 months, sample size ranged from 12 to 97 patients, and the most common treatment was parenteral testosterone undecanoate 1000 mg/12 weeks. Slight but significant increases in BMI were reported (from 1.3 to 11.4%). Three out of seven studies assessing the impact of different testosterone formulations on blood pressure detected modest increases or clinically irrelevant changes in this variable. In another study, however, two patients developed hypertension, which was resolved after cessation of testosterone therapy. Decreases in HDL‐cholesterol and increases in LDL‐cholesterol were consistently observed. Eight studies observed a relationship between testosterone and increased hemoglobin (range: 4.9–12.5%) and hematocrit (range: 4.4–17.6%), but discontinuation of androgen therapy was not necessary. In one study, two patients developed erythrocytosis (hematocrit >52%) after 9 and 12 months of treatment. One study analyzing testosterone formulations observed smaller increases in hemoglobin and hematocrit with testosterone gel. Six studies assessing liver function showed slight or no changes. Overall, the quality of evidence was low, given the lack of randomized clinical/controlled trials and the small sample sizes. In conclusion, exogenous testosterone administration to transgender men was associated with modest increases in BMI, hemoglobin/hematocrit, and LDL‐cholesterol, and with decreases in HDL‐cholesterol. Long‐term studies are needed to assess the long‐term risks of testosterone therapy, particularly as they relate to cardiometabolic risks such as diabetes, dyslipidemia and the metabolic syndrome.
Phosphorylation‐dependent inhibition of mineralization by osteopontin ASARM peptides is regulated by PHEX cleavage

The SIBLING family (small integrin‐binding ligand N‐linked glycoproteins) of mineral‐regulating proteins, which includes matrix extracellular phosphoglycoprotein (MEPE) and osteopontin (OPN), contains an acidic serine‐ and aspartate‐rich motif (ASARM). X‐linked hypophosphatemia caused by inactivating mutations of the PHEX gene results in elevated mineralization‐inhibiting MEPE‐derived ASARM peptides. Although the OPN ASARM motif shares 60% homology with MEPE ASARM, it is still unknown whether OPN ASARM similarly inhibits mineralization. In this study we have examined the role of OPN ASARM and its interaction with PHEX enzyme using an osteoblast cell culture model, mass spectrometry, mineral‐binding assays, and computational modeling. MC3T3‐E1 osteoblast cultures were treated with differently phosphorylated OPN ASARM peptides [with 5 phosphoserines (OpnAs5) or 3 phosphoserines (OpnAs3)] or with control nonphosphorylated peptide (OpnAs0). Phosphorylated peptides dose‐dependently inhibited mineralization, and binding of phosphorylated peptides to mineral was confirmed by a hydroxyapatite‐binding assay. OpnAs0 showed no binding to hydroxyapatite and did not inhibit culture mineralization. Computational modeling of peptide‐mineral interactions indicated a favorable change in binding energy with increasing phosphorylation consistent with hydroxyapatite‐binding experiments and inhibition of culture mineralization. Addition of PHEX rescued inhibition of mineralization by OpnAs3. Mass spectrometry of cleaved peptides after ASARM‐PHEX incubations identified OpnAs3 as a PHEX substrate. We conclude that OPN ASARM inhibits mineralization by binding to hydroxyapatite in a phosphorylation‐dependent manner and that this inhibitor can be cleaved by PHEX, thus providing a mechanistic explanation for how loss of PHEX activity in X‐linked hyposphosphatemia can lead to extracellular matrix accumulation of ASARM resulting in the osteomalacia. © 2010 American Society for Bone and Mineral Research
MHC Class II Ligation Induces CD58 (LFA-3)-Mediated Adhesion in Human T Cells

MHC class II positive T cells found in areas of inflammation are believed to play an important pathogenetic role in autoimmunity. In experimental models , class II molecules have been shown to regulate adhesion between human T cells. It is, however, not known in detail how class II molecules are functionally linked to adhesion molecules. Some data suggest that β2 integrin (CD11a/CD18) molecules play a role in class-II-induced homotypic adhesion in B cells, monocytes, and virus-transformed or neoplastic cell lines. We have previously obtained evidence that adhesion molecules other than β2 integrins might play a role in class-II-mediated adhesion in T cells. To study further class-II-mediated adhesion in T cells, we have taken advantage of (allo)antigen-specific β2-integrin-negative, CD4-positive T cell lines obtained from a leukocyte adhesion deficiency patient. We show that class II ligation induces homotypic adhesion in both β2-integrin-positive and negative, CD4-positive T cell lines. Anti-CD18 monoclonal antibody (mAb) weakly inhibited the adhesion response in β2-integrin-positive T cells and had no effect on β2-integrin-negative T cells. In contrast, an anti-CD58 (LFA-3) mAb almost completely inhibited the adhesion response in β2-integrin-negative T cells. Antibodies against the CD58 ligand, CD2, partly inhibited the adhesion response in β2-integrin-negative T cells whereas antibodies against other adhesion molecules did not. The adhesion response in β2-integrin-positive T cells was partly inhibited by antibodies against CD58 and CD2. Taken together, these data provide the first evidence that CD58 molecules are involved in class-II-induced homotypic adhesion between T cells.
Repetitive Learning Control Design for LED Light Tracking

A lighting system composed of three color light-emitting diode (LED) strings is considered. On the basis of a simplified dynamic model (with uncertainties) for the aforementioned system, the tracking of (possibly complex) periodic reference signals (with known period) for both the light color and intensity is achieved by designing, for each LED string, a decentralized repetitive learning control. Experimental results illustrate the effectiveness of the proposed approach in a practical user-friendly scenario: the color coordinates are obtained by an external low-cost red, green, blue sensor which allows for measuring the overall lighting effects (including external disturbances) while increasing the overall energy saving. A detailed theoretical analysis of the learning control design for first-order linear systems with zero relative degree under suitable assumptions is also included.
Nadi Tarangini: A Pulse Based Diagnostic System

Ayurveda is a traditional medicine and natural healing system in India. Nadi-Nidan (pulse-based diagnosis) is a prominent method in Ayurveda, and is known to dictate all the salient features of a human body. In this paper, we provide details of our procedure for obtaining the complete spectrum of the nadi pulses as a time series. The system Nadi Tarangini contains a diaphragm element equipped with strain gauge, a transmitter cum amplifier, and a digitizer for quantifying analog signal. The system acquires the data with 16-bit accuracy with practically no external electronic or interfering noise. Prior systems for obtaining the nadi pulses have been few and far between, when compared to systems such as ECG. The waveforms obtained with our system have been compared with these other similar equipment developed earlier, and is shown to contain more details. The pulse waveform is also shown to have the desirable variations with respect to age of patients, and the pressure applied at the sensing element. The system is being evaluated by Ayurvedic practitioners as a computer-aided diagnostic tool.
Feline Nasal and Paranasal Sinus Tumours: Clinicopathological Study, Histomorphological Description and Diagnostic Immunohistochemistry of 123 Cases

Histological examination was performed in 123 cats with primary nasal and paranasal sinus tumours; 117 had undergone surgical biopsy and six necropsy. Special stains and immunohistochemistry were performed on poorly differentiated cases. Ninety-two percent (113/123) of the tumours were malignant. There was an increased risk for old cats (mean age of 10.9 years), and a male predilection (59% males). Clinical signs and breeds varied with the histological type of tumour. Thirty-nine percent (48/123) of the cases presented with nasal discharge, 21% (26/123) with dyspnea, 20% (24/123) with facial swelling, and 15% (19/123) with epistaxis. Forty-three percent (53/123) of the tumours were of epithelial origin. Adenocarcinomas (18/53) and squamous cell carcinomas (17/53) were the most common epithelial tumours. Fifty percent (26/53) of the epithelial tumours originated from the pseudo-stratified respiratory epithelium of the nasal cavity, 28% (15/53) from the stratified squamous epithelium of the vestibule, 9% (5/53) from olfactory epithelium, 9% (5/53) from submucosal glands and 4% (2/53) from minor salivary glands. Malignant lymphoma (35/123) was the most common tumour. Seventy-one percent (25/35) of the malignant lymphomas were B-cell tumours and 29% (10/35) were T-cell tumours. Six cases of malignant lymphomas were proved to be epitheliotropic T-cell lymphomas. This is the first report of a primary nasal epitheliotropic T-cell lymphoma in cats.