Miracle-dz/UniFAR-FTUs huggingface dataset:
Phosphoinositide-mediated ring anchoring resists perpendicular forces to promote medial cytokinesis

Many eukaryotic cells divide by assembling and constricting an actin- and myosin-based contractile ring (CR) that is physically linked to the plasma membrane (PM). In this study, we report that Schizosaccharomyces pombe cells lacking efr3, which encodes a conserved PM scaffold for the phosphatidylinositol-4 kinase Stt4, build CRs that can slide away from the cell middle during anaphase in a myosin V–dependent manner. The Efr3-dependent CR-anchoring mechanism is distinct from previously reported pathways dependent on the Fes/CIP4 homology Bin-Amphiphysin-Rvs167 (F-BAR) protein Cdc15 and paxillin Pxl1. In efr3&Dgr;, the concentrations of several membrane-binding proteins were reduced in the CR and/or on the PM. Our results suggest that proper PM lipid composition is important to stabilize the central position of the CR and resist myosin V–based forces to promote the fidelity of cell division.
Cytosolic Hsp70 and Hsp40 chaperones enable the biogenesis of mitochondrial β-barrel proteins

Mitochondrial &bgr;-barrel proteins are encoded in the nucleus, translated by cytosolic ribosomes, and then imported into the organelle. Recently, a detailed understanding of the intramitochondrial import pathway of &bgr;-barrel proteins was obtained. In contrast, it is still completely unclear how newly synthesized &bgr;-barrel proteins reach the mitochondrial surface in an import-competent conformation. In this study, we show that cytosolic Hsp70 chaperones and their Hsp40 cochaperones Ydj1 and Sis1 interact with newly synthesized &bgr;-barrel proteins. These interactions are highly relevant for proper biogenesis, as inhibiting the activity of the cytosolic Hsp70, preventing its docking to the mitochondrial receptor Tom70, or depleting both Ydj1 and Sis1 resulted in a significant reduction in the import of such substrates into mitochondria. Further experiments demonstrate that the interactions between &bgr;-barrel proteins and Hsp70 chaperones and their importance are conserved also in mammalian cells. Collectively, this study outlines a novel mechanism in the early events of the biogenesis of mitochondrial outer membrane &bgr;-barrel proteins.
The cost-effectiveness of improved hepatitis C virus therapies in HIV/hepatitis C virus coinfected patients

Objectives:To evaluate the effectiveness and cost–effectiveness of strategies to treat hepatitis C virus (HCV) in HIV/HCV coinfected patients in the United States. Participants:Simulated cohort of HIV/HCV genotype 1 coinfected, noncirrhotic, HCV treatment-naive individuals enrolled in US HIV guideline-concordant care. Design/interventions:Monte Carlo simulation comparing five strategies: no treatment; dual therapy with pegylated-interferon (PEG) and ribavirin (RBV); ‘PEG/RBV trial’ in which all patients initiate dual therapy and switch to triple therapy upon failure; ‘IL28B triage’ in which patients initiate either dual therapy or triple therapy based on their IL28B allele type; and PEG/RBV and telaprevir (TPV) triple therapy. Sensitivity analyses varied efficacies and costs and included a scenario with interferon (IFN)-free therapy. Main measures:Sustained virologic response (SVR), life expectancy, discounted quality-adjusted life expectancy (QALE), lifetime medical costs, and incremental cost-effectiveness ratios (ICERs) in $/quality-adjusted life years (QALY) gained. Results:‘PEG/RBV trial,’ ‘IL28B triage,’ and ‘triple therapy’ each provided 72% SVR and extended QALE compared with ‘dual therapy’ by 1.12, 1.14, and 1.15 QALY, respectively. The ICER of ‘PEG/RBV trial’ compared with ‘dual therapy’ was $37 500/QALY. ‘IL28B triage’ and ‘triple therapy’ provided little benefit compared with ‘PEG/RBV trial,’ and both had ICERs exceeding $300 000/QALY. In sensitivity analyses, IFN-free treatment attaining 90% SVR had an ICER less than $100 000/QALY compared with ‘PEG/RBV trial’ when its cost was $109 000 or less (125% of the cost of PEG/RBV/TVR). Conclusion:HCV protease inhibitors are most efficiently used in HIV/HCV coinfection after a trial of PEG/RBV, sparing protease inhibitors for those who attain rapid virologic response and SVR. The cost-effectiveness of IFN-free regimens for HIV/HCV coinfection will depend on the cost of these therapies.
Synergistic cooperation and crosstalk between MYD88L265P and mutations that dysregulate CD79B and surface IgM

CD79B and MYD88 mutations are frequently and simultaneously detected in B cell malignancies. It is not known if these mutations cooperate or how crosstalk occurs. Here we analyze the consequences of CD79B and MYD88L265P mutations individually and combined in normal activated mouse B lymphocytes. CD79B mutations alone increased surface IgM but did not enhance B cell survival, proliferation, or altered NF-&kgr;B responsive markers. Conversely, B cells expressing MYD88L265P decreased surface IgM coupled with accumulation of endoglycosidase H–sensitive IgM intracellularly, resembling the trafficking block in anergic B cells repeatedly stimulated by self-antigen. Mutation or overexpression of CD79B counteracted the effect of MYD88L265P. In B cells chronically stimulated by self-antigen, CD79B and MYD88L265P mutations in combination, but not individually, blocked peripheral deletion and triggered differentiation into autoantibody secreting plasmablasts. These results reveal that CD79B and surface IgM constitute a rate-limiting checkpoint against B cell dysregulation by MYD88L265P and provide an explanation for the co-occurrence of MYD88 and CD79B mutations in lymphomas.
A possible Fourier transform infrared‐based plasma fingerprint of angiotensin‐converting enzyme inhibitor‐induced reversal of endothelial dysfunction in diabetic mice

Angiotensin‐converting enzyme inhibitors (ACE‐I) display vasoprotective activity and represent the cornerstone in the treatment of cardiovascular diseases. In this study, we tested whether Fourier transform infrared (FTIR)‐based analysis of blood plasma is sensitive to detect vasoprotective effects of treatment with perindopril including reversal of endothelial dysfunction in diabetes. For this purpose, plasma samples were collected from untreated db/db mice, db/db mice treated with 2 or 10 mg/kg perindopril and db+ mice. The effect of perindopril on endothelial function was examined in ex vivo aortic rings; 10 mg/kg but not 2 mg/kg of perindopril reversed endothelial dysfunction. In plasma of db/db mice, the balance between conformations of plasma proteins was noted, and treatment with perindopril at a high dose but not at a low dose reversed this effect. This was revealed by amide II/amide I ratio attributed to increased β‐sheet formation. Spectral markers at 3010, 1520/1238 cm−1, representative for unsaturation degree of lipids and phosphorylation of tyrosine, respectively, were also affected by perindopril treatment. In conclusion, although metabolic abnormalities associated with type 2 diabetes mellitus such as hypertriglyceridemia and hyperglycemia strongly affected spectral FTIR profile of diabetic plasma, we identified FTIR features that seem to be associated with the vasoprotective activity of ACE‐I.
Preexposure prophylaxis is efficacious for HIV-1 prevention among women using depot medroxyprogesterone acetate for contraception

Objective:To evaluate preexposure prophylaxis (PrEP) efficacy for HIV-1 prevention among women using depot medroxyprogesterone acetate (DMPA) for contraception and men whose HIV-1-infected partners use DMPA. Design:Secondary analysis of data from a randomized placebo-controlled trial of daily oral tenofovir and emtricitabine/tenofovir PrEP among heterosexual Kenyan and Ugandan HIV-1 serodiscordant couples. Methods:PrEP efficacy for HIV-1 prevention was compared among HIV-1-uninfected women using DMPA versus no hormonal contraception and among HIV-1 uninfected men whose HIV-1-infected female partners used DMPA versus no hormonal contraception. Results:Of 4747 HIV-1 serodiscordant couples, 901 HIV-1-uninfected women used DMPA at some point during follow-up, 1422 HIV-1-uninfected women used no hormonal contraception, 1568 HIV-1-uninfected men had female partners who used DMPA, and 2626 men had female partners who used no hormonal contraception. PrEP efficacy estimates for HIV-1 prevention, compared with placebo, were similar among women using DMPA and those using no hormonal contraception (64.7 and 75.5%, adjusted interaction P = 0.65). Similarly, for men whose female partners used DMPA, PrEP efficacy did not differ from men whose partners used no hormonal contraception (90.0 versus 81.7%, adjusted interaction P = 0.52). Conclusion:PrEP is efficacious for HIV-1 prevention among women using DMPA and men whose partners use DMPA, suggesting PrEP could mitigate the potential increased HIV-1 acquisition and transmission risks that have been associated with DMPA use. Women at risk for HIV-1 choosing DMPA could maintain this contraceptive method and add PrEP to achieve prevention of unintended pregnancy and HIV-1.
SORLA attenuates EphA4 signaling and amyloid β–induced neurodegeneration

Sortilin-related receptor with LDLR class A repeats (SORLA, SORL1, or LR11) is a genetic risk factor associated with Alzheimer’s disease (AD). Although SORLA is known to regulate trafficking of the amyloid &bgr; (A&bgr;) precursor protein to decrease levels of proteotoxic A&bgr; oligomers, whether SORLA can counteract synaptic dysfunction induced by A&bgr; oligomers remains unclear. Here, we show that SORLA interacts with the EphA4 receptor tyrosine kinase and attenuates ephrinA1 ligand–induced EphA4 clustering and activation to limit downstream effects of EphA4 signaling in neurons. Consistent with these findings, SORLA transgenic mice, compared with WT mice, exhibit decreased EphA4 activation and redistribution to postsynaptic densities, with milder deficits in long-term potentiation and memory induced by A&bgr; oligomers. Importantly, we detected elevated levels of active EphA4 in human AD brains, where EphA4 activation is inversely correlated with SORLA/EphA4 association. These results demonstrate a novel role for SORLA as a physiological and pathological EphA4 modulator, which attenuates synaptotoxic EphA4 activation and cognitive impairment associated with A&bgr;-induced neurodegeneration in AD.
Rotated palatal flap in immediate implant procedures

Immediate implant placement after tooth extraction is a successful treatment modality. Primary flap closure is important for satisfactory final results in these procedures. The purpose of this article was to evaluate a surgical approach that would enable predictable primary soft tissue closure over implants placed into fresh extraction sockets. In 24 patients, 26 consecutive implants were placed immediately following extraction of one anterior or premolar maxillary tooth. Primary closure was achieved by a surgical technique based on a rotated palatal flap (RPF), covering the implant. Deproteinized bovine bone was used as grafting material. The apicocoronal distance between the buccal alveolar crestal bone and the coronal aspect of the implant body was measured at time of implant placement (mean 2.6 mm, SD 1.72) and at second stage surgery (mean 0.6 mm, SD 0.70). The difference between both records was calculated. The mean gain in crestal bone was 2.0 mm (SD 1.69, P<0.001). In 1 patient, where the implant cover screw became exposed early, crestal bone loss was noted. This technique offers a predictable valuable treatment approach to achieve and maintain primary soft tissue coverage and crestal bone regeneration over implants immediately placed within a bony envelope, after extracting maxillary teeth, without the use of barrier membranes.
Childbearing and Women's Survival: New Evidence from Rural Bangladesh

Effects of childbearing on women's mortality and the implications of family planning programs in reducing these effects are examined in a 20-year prospective study of more than 2,000 women in Matlab, Bangladesh. Maternal mortality is defined as a death occurring in the six weeks after childbirth. But childbearing may affect women's survival beyond this brief period. Additional hypotheses considered relate to 1) cumulative exposure to childbearing, whether measured by parity or pace of childbearing, 2) age at first birth, and 3) effects beyond the reproductive ages. The results offer no support to cumulative exposure hypotheses, showing no link between parity or pace of childbearing and mortality risk. Instead, we identify an extended period of heightened mortality risk associated with each birth-the year of the birth and the two subsequent years. Family planning programs, by reducing the number of children and therefore a woman's exposure to extended maternal mortality risk, potentially increase survival. Research is needed to identify and address the specific causes of extended maternal mortality risk so that appropriate ameliorative programs may be developed. Copyright 2003 by The Population Council, Inc.
Residual immune activation in combined antiretroviral therapy-treated patients with maximally suppressed viremia

Residual immune activation was studied in 51 HIV-infected individuals, 16 with viral load between 1 and 20 copies/ml and 35 with viral load less than 1 copy/ml, and compared with results in 20 healthy blood donors. Higher T-cell activation and IP-10/CXCL10, MIG/CXCL9 and sCD14 plasma levels persisted in both HIV+ groups. The proportion of activated HLA-DR+ CD4 T cells was inversely correlated with the CD4 nadir and the current CD4 cell counts.
Effect of HIV co-infection on adherence to a 12-week regimen of hepatitis C virus therapy with ledipasvir and sofosbuvir

Objective:As the treatment of hepatitis C virus (HCV) infection has evolved to directly acting antiviral agents, the impact of these directly acting antiviral-only regimens on improving adherence to HCV treatment in HIV/HCV coinfected populations has not been evaluated. The study compared adherence to ledipasvir/sofosbuvir (LDV/SOF) in HCV monoinfected and HIV/HCV coinfected individuals. Design:Adherence was measured from participants in two phase 2 open-label studies (NCT01805882 and NCT01878799). Methods:HCV treatment-naive, genotype 1 study individuals [HCV monoinfected participants (N = 20) and HIV/HCV coinfected participants, antiretroviral untreated (N = 13) or on combination antiretroviral therapy (N = 37)] were treated with LDV (90 mg) and SOF (400 mg) administered as one tablet once daily for 12 weeks. Adherence was measured using three tools: medication event monitoring system cap, pill count, and patient report. Results:Participants were predominately African American (83%) and male (73%), with a median age of 59 years. Participants had prompt HCV viral load decline and high adherence rates (97 ± 0.5% by medication event monitoring system). Participant adherence decreased significantly from early (baseline week 4) as compared with late (weeks 8–12) in therapy in all three groups – HCV monoinfected (P = 0.01), HIV/HCV antiretroviral untreated (P = 0.02), and HIV/HCV antiretroviral treated participants (P = 0.01). Conclusion:Adherence to LDV/SOF in this urban population was high and comparable between HCV monoinfected and HIV/HCV coinfected participants regardless of antiretroviral use.
The CHANGE program: comparing an interactive versus prescriptive obesity intervention on university students' self-esteem and quality of life.

BACKGROUND Previous studies incorporating Motivational Interviewing administered via Co-Active Life Coaching tools (MI-via-CALC) have elicited positive results among adults with obesity. However, there is a paucity of this research that includes sufficient power and a comparison group. This study's purpose was to compare MI-via-CALC with a validated obesity intervention among university students. METHODS Participants (n = 45) were randomised to either a telephone-based 12-week: (a) MI-via-CALC program whereby a certified coach worked with subjects to achieve goals through dialogue; or (b) lifestyle modification treatment following the LEARN Program for Weight Management. Participants completed the Rosenberg Self-Esteem Scale and Short Form Functional Health Status Scale (SF-36) at baseline, mid-, and post-treatment, and 3 and 6 months following the program. RESULTS Analyses revealed that both conditions elicited significant time effects between baseline and 6 months for self-esteem and all dimensions of the SF-36 (e.g. overall health). CONCLUSIONS MI-via-CALC compares favorably with LEARN as an obesity treatment. Given that self-esteem and quality of life are essential for promoting behavior change among individuals with obesity, this study offers unique insights into their change processes. Future research should provide both treatments and allow participants to choose based on their personal preferences, learning styles, and needs.
New phylotypes of mesophilic filamentous anoxygenic phototrophic bacteria enriched from sulfide-containing environments.

Agar-based solid media with increasing concentrations of organic matter were used to isolate new members of the Chloroflexaceae (phylum Chloroflexi) from mesophilic environments containing sulfide. Inorganic media yielded less than 10% positive enrichments, which were not able to be maintained after repetitive inoculations in fresh medium. The use of casaminoacids and complex organic acid mixtures increased the number of positive enrichments (up to 45%) from both water and sediment samples. Two different green filamentous bacteria, SisoF2 and SalF, could be stably maintained as co-cultures for long periods and their phylogeny inferred from the analysis of complete sequences of the 16S rRNA gene. Ribotype SalF showed a high homology (95-98%) to previously isolated Oscillochloris trichoides strains. The 16S rRNA gene sequence retrieved from culture SisoF2 was largely divergent (< 92% similarity) from any sequence derived from either cultured representatives or environmental samples, suggesting that ribotype SisoF2 may constitute a new genus within the phylum. The presence of the new morphotypes in the environment from where they were enriched was analysed by high-resolution phylogenetic fingerprinting.
Endocytosis sustains release at photoreceptor ribbon synapses by restoring fusion competence

Endocytosis is an essential process at sites of synaptic release. Not only are synaptic vesicles recycled by endocytosis, but the removal of proteins and lipids by endocytosis is needed to restore release site function at active zones after vesicle fusion. Synaptic exocytosis from vertebrate photoreceptors involves synaptic ribbons that serve to cluster vesicles near the presynaptic membrane. In this study, we hypothesize that this clustering increases the likelihood that exocytosis at one ribbon release site may disrupt release at an adjacent site and therefore that endocytosis may be particularly important for restoring release site competence at photoreceptor ribbon synapses. To test this, we combined optical and electrophysiological techniques in salamander rods. Pharmacological inhibition of dynamin-dependent endocytosis rapidly inhibits release from synaptic ribbons and slows recovery of ribbon-mediated release from paired pulse synaptic depression. Inhibiting endocytosis impairs the ability of second-order horizontal cells to follow rod light responses at frequencies as low as 2 Hz. Inhibition of endocytosis also increases lateral membrane mobility of individual Ca2+ channels, showing that it changes release site structure. Visualization of single synaptic vesicles by total internal reflection fluorescence microscopy reveals that inhibition of endocytosis reduces the likelihood of fusion among vesicles docked near ribbons and increases the likelihood that they will retreat from the membrane without fusion. Vesicle advance toward the membrane is also reduced, but the number of membrane-associated vesicles is not. Endocytosis therefore appears to be more important for restoring later steps in vesicle fusion than for restoring docking. Unlike conventional synapses in which endocytic restoration of release sites is evident only at high frequencies, endocytosis is needed to maintain release from rod ribbon synapses even at modest frequencies.
Dimerization of the voltage-sensing phosphatase controls its voltage-sensing and catalytic activity

Multimerization is a key characteristic of most voltage-sensing proteins. The main exception was thought to be the Ciona intestinalis voltage-sensing phosphatase (Ci-VSP). In this study, we show that multimerization is also critical for Ci-VSP function. Using coimmunoprecipitation and single-molecule pull-down, we find that Ci-VSP stoichiometry is flexible. It exists as both monomers and dimers, with dimers favored at higher concentrations. We show strong dimerization via the voltage-sensing domain (VSD) and weak dimerization via the phosphatase domain. Using voltage-clamp fluorometry, we also find that VSDs cooperate to lower the voltage dependence of activation, thus favoring the activation of Ci-VSP. Finally, using activity assays, we find that dimerization alters Ci-VSP substrate specificity such that only dimeric Ci-VSP is able to dephosphorylate the 3-phosphate from PI(3,4,5)P3 or PI(3,4)P2. Our results indicate that dimerization plays a significant role in Ci-VSP function.
Isolation and genetic characterization of an improved benzene-tolerant mutant of Pseudomonas putida S12.

Pseudomonas putida S12.49, a mutant stain of P. putida S12 that tolerates up to 20 mM benzene, was obtained by evolutionary selection. The genetic basis for the strongly enhanced benzene tolerance was investigated by proteome and transcriptome analysis. Indications were found that the highly benzene-tolerant phenotype is the resultant of multi-level systemic changes. The solvent extrusion pump SrpABC was constitutively expressed in P. putida S12.49, which could be attributed to the disruption of the srpS regulator gene by the indigenous mutator element ISS12. The occurrence of this and two additional transposition events was in good agreement with the increased transcriptional activity of transposase-encoding genes in strain S12.49. These observations suggested that transposition events are an important force driving the generation of the genetic diversity apparently required to obtain highly solvent-tolerant phenotypes. In addition, various expression responses relating to energy generation indicated system changes that accommodated the energy demand associated with the high-level expression of the proton-driven solvent extrusion pump. The relatively modest effect of a respiratory chain uncoupler on benzene tolerance in P. putida S12.49 indicated the involvement of an alternative, non-respiratory mechanism to maintain the proton gradient.