Miracle-dz/UniFAR-FTUs huggingface dataset:
Mechanism of control of F-actin cortex architecture by SWAP-70

ABSTRACT F-actin binding and bundling are crucial to a plethora of cell processes, including morphogenesis, migration, adhesion and many others. SWAP-70 was recently described as an in vitro F-actin-binding and -bundling protein. Fluorescence cross-correlation spectroscopy measurements with purified recombinant SWAP-70 confirmed that it forms stable oligomers that facilitate F-actin bundling. However, it remained unclear how SWAP-70 oligomerization and F-actin binding are controlled in living cells. We addressed this by biophysical approaches, including seFRET, FACS-FRET and FLIM-FRET. PIP3-mediated association with the cytoplasmic membrane and non-phosphorylated Y426 are required for SWAP-70 to dimerize and to bind F-actin. The dimerization region was identified near the C terminus where R546 is required for dimerization and, thus, F-actin bundling. The in vitro and in vivo data presented here reveal the functional relationship between the cytoplasm-to-membrane translocation and dimerization of SWAP-70, and F-actin binding and bundling, and demonstrate that SWAP-70 is a finely controlled modulator of membrane-proximal F-actin dynamics. This article has an associated First Person interview with the first author of the paper. Summary: A range of biochemical and biophysical methods, including FLIM/FRET, reveal the mechanisms of SWAP-70 dimerization and F-actin binding both in vitro and in living cells.
Large-scale spatial variation of chronic stress signals in moose

The physiological effects of short-term stress responses typically lead to increased individual survival as it prepares the body for fight or flight through catabolic reactions in the body. These physiological effects trade off against growth, immunocompetence, reproduction, and even long-term survival. Chronic stress may thus reduce individual and population performance, with direct implications for the management and conservation of wildlife populations. Yet, relatively little is known about how chronic stress levels vary across wild populations and factors contributing to increased chronic stress levels. One method to measure long-term stress in mammals is to quantify slowly incorporated stress hormone (cortisol) in hair, which most likely reflect a long-term average of the stress responses. In this study, we sampled 237 harvested moose Alces alces across Sweden to determine the relative effect of landscape variables and disturbances on moose hair cortisol levels. We used linear model combinations and Akaike’s Information Criterion (corrected for small sample sizes), and included variables related to human disturbance, ungulate competition, large carnivore density, and ambient temperature to estimate the covariates that best explained the variance in stress levels in moose. The most important variables explaining the variation in hair cortisol levels in moose were the long-term average temperature sum in the area moose lived and the distance to occupied wolf territory; higher hair cortisol levels were detected where temperatures were higher and closer to occupied wolf territories, respectively.
The DNA polymerases of Drosophila melanogaster

ABSTRACT DNA synthesis during replication or repair is a fundamental cellular process that is catalyzed by a set of evolutionary conserved polymerases. Despite a large body of research, the DNA polymerases of Drosophila melanogaster have not yet been systematically reviewed, leading to inconsistencies in their nomenclature, shortcomings in their functional (Gene Ontology, GO) annotations and an under-appreciation of the extent of their characterization. Here, we describe the complete set of DNA polymerases in D. melanogaster, applying nomenclature already in widespread use in other species, and improving their functional annotation. A total of 19 genes encode the proteins comprising three replicative polymerases (alpha-primase, delta, epsilon), five translesion/repair polymerases (zeta, eta, iota, Rev1, theta) and the mitochondrial polymerase (gamma). We also provide an overview of the biochemical and genetic characterization of these factors in D. melanogaster. This work, together with the incorporation of the improved nomenclature and GO annotation into key biological databases, including FlyBase and UniProtKB, will greatly facilitate access to information about these important proteins.
Gene therapy for cystic fibrosis: recent progress and current aims

ABSTRACT Introduction: Since identification of the disease causing gene over 25 years ago, cystic fibrosis (CF) has been at the forefront of gene therapy research. Despite initial optimism, CF gene therapy has proven considerably more challenging than initially anticipated. However, research conducted over the past two decades has clarified the strength and weaknesses of viral and non-viral gene transfer agents for CF gene therapy. Areas covered: The older literature related to CF gene therapy has been reviewed in many publications and we will, therefore, restrict this review to a brief description and discussion of the key lessons learnt, instead focusing on more recent progress in the field which was identified through literature searches. This review will summarize research leading up to the recent pivotal proof-of-concept study showing that non-viral gene therapy can stabilize the decline of lung function in CF patients and also highlight recent advances in viral vector development which may overcome problems related to loss of efficacy on repeated administration. Expert opinion: The demonstration that gene therapy can stabilize CF lung disease is an important milestone in gene therapy.
Intimate Partner Violence in Honduras: Ecological Correlates of Self-Reported Victimization and Fear of a Male Partner

The experience of intimate partner violence (IPV) is influenced by individual, relationship, community, and societal-level factors, including the prevalence and acceptance of societal violence in which the victim lives. These factors transcend a woman’s present circumstances and personal history and the gender and power relationships within her household. This is particularly relevant in Honduras, where a high level of IPV occurs within a traditionally patriarchal society and growing societal violence and crime. This study examines the factors—informed by a social ecological theoretical perspective—associated with the experience of IPV. We use data from the Honduras Demographic and Health Survey (ENDESA) 2011–2012 to estimate multilevel, multivariate models predicting the likelihood that a woman experiences emotional, physical, and/or sexual IPV and/or fear of her partner. Our models contain higher level contextual effects that capture regional variations in social violence and aggregated norms capturing acceptance of IPV. We find that a woman’s likelihood of experiencing violence is related to individual, relationship, and household-level characteristics, including marital status, age at first cohabitation, employment status, violence within the parental home, women’s accepting attitudes toward IPV, autonomy in decision-making, partner’s use of alcohol, the nature of the relationship with her partner (i.e., living together or not), and educational and age differences with her partner. Notably, women living in more violent areas—measured by violence statistics and aggregate community-level norms regarding spouse beating—were more likely to experience IPV. These findings contribute to our understanding of the risk of IPV and to the evidence that can be used to identify the most vulnerable women and opportunities for intervention to prevent further victimization. By using an analytical methodology that reflects the complexity of factors that place women at risk for IPV, we can isolate, address, and advocate for changing circumstances that make Honduran women vulnerable to IPV.
The topology of the ER-resident phospholipid methyltransferase Opi3 of Saccharomyces cerevisiae is consistent with in trans catalysis

Phospholipid N-methyltransferases (PLMTs) synthesize phosphatidylcholine by methylating phosphatidylethanolamine using S-adenosylmethionine as a methyl donor. Eukaryotic PLMTs are integral membrane enzymes located in the endoplasmic reticulum (ER). Recently Opi3, a PLMT of the yeast Saccharomyces cerevisiae was proposed to perform in trans catalysis, i.e. while localized in the ER, Opi3 would methylate lipid substrates located in the plasma membrane at membrane contact sites. Here, we tested whether the Opi3 active site is located at the cytosolic side of the ER membrane, which is a prerequisite for in trans catalysis. The membrane topology of Opi3 (and its human counterpart, phosphatidylethanolamine N-methyltransferase, expressed in yeast) was addressed by topology prediction algorithms and by the substituted cysteine accessibility method. The results of these analyses indicated that Opi3 (as well as phosphatidylethanolamine N-methyltransferase) has an N-out C-in topology and contains four transmembrane domains, with the fourth forming a re-entrant loop. On the basis of the sequence conservation between the C-terminal half of Opi3 and isoprenyl cysteine carboxyl methyltransferases with a solved crystal structure, we identified amino acids critical for Opi3 activity by site-directed mutagenesis. Modeling of the structure of the C-terminal part of Opi3 was consistent with the topology obtained by the substituted cysteine accessibility method and revealed that the active site faces the cytosol. In conclusion, the location of the Opi3 active site identified here is consistent with the proposed mechanism of in trans catalysis, as well as with conventional catalysis in cis.
Gut commensal derived-valeric acid protects against radiation injuries

ABSTRACT Background Hematopoietic and intestinal systems side effects are frequently found in patients who suffered from accidental or medical radiation exposure. In this case, we investigated the effects of gut microbiota produced-valeric acid (VA) on radiation-induced injuries. Methods Mice were exposed to total body irradiation (TBI) or total abdominal irradiation (TAI) to mimic accidental or clinical scenarios. High-performance liquid chromatography (HPLC) was performed to assess short-chain fatty acids (SCFAs) in fecal pellets. Oral gavage with VA was used to mitigate radiation-induced toxicity. Gross examination was performed to assess tissue injuries of thymus, spleen and small intestine. High-throughput sequencing was used to characterize the gut microbiota profile. Isobaric tags for relative and absolute quantitation (iTRAQ) were performed to analyze the difference of protein profile. Hydrodynamic-based gene delivery assay was performed to silence KRT1 in vivo. Results VA exerted the most significant radioprotection among the SCFAs. In detail, VA replenishment elevated the survival rate of irradiated mice, protected hematogenic organs, improved gastrointestinal (GI) tract function and intestinal epithelial integrity in irradiated mice. High-throughput sequencing and iTRAQ showed that oral gavage of VA restored the enteric bacteria taxonomic proportions, reprogrammed the small intestinal protein profile of mice following TAI exposure. Importantly, keratin 1 (KRT1) played a pivotal role in the radioprotection of VA. Conclusions Our findings provide new insights into gut microbiota-produced VA and underpin that VA might be employed as a therapeutic option to mitigate radiation injury in pre-clinical settings.
Clinically accurate prediction of glucose levels in patients with type 1 diabetes.

BACKGROUND AND AIMS Accurate prediction of glucose levels in patients with type 1 diabetes mellitus (T1DM) is critical both for their glycemic control and for the development of closed loop systems. METHODS Here, we utilized real-life retrospective continuous glucose monitoring data from 141 T1DM patients (9,083 connection days,1,592,506 glucose measurements) and in silico data generated by the UVA/Padova T1DM Simulator, to evaluate different computational methods for glucose prediction.We evaluated the performance of the models using both measures of numerical accuracy, measured by the root means square error (RMSE) and clinical accuracy, measured by the percentage of time in each of the Clarke Error Grid (CEG) zones and compared the predictions done by autoregressive models, tree- based methods, artificial neural networks, and a novel model that we devised and optimized for this task. RESULTS Our novel model, constructed on real-life data, achieved clinical accuracy of 99.3% and 95.8% in predicting glucose level 30 minutes and 60 minutes ahead, respectively, and reduced the percentage of glucose predictions in zones C-E of the CEG by 60.6% and 38.4% in these prediction horizons, compared to a standard autoregressive model. The model was superior to all other models across all age groups, and achieved higher clinical accuracy in subgroups of patients with high glucose variability and greater time spent in hypoglycemia. Compared to real-life data, when evaluated on in silico data, the model had a higher clinical and numerical accuracy. CONCLUSIONS A model optimizes for CEG zones may significantly improve clinical accuracy and clinical outcomes of treatment decisions in T1DM patients. Results obtained from simulated data may overestimate the performance of models on real-life data.
Upper limb bone health : cadaveric, imaging and clinical studies with special emphasis on peripheral quantitative computed tomography

Introduction Osteoporotic fractures are a major health care problem. A radial fracture is an important risk factor for osteoporosis that should initiate the assessment of bone health. Purpose 1) To validate pQCT measures of bone in aged cadaveric radii. 2) To examine side-side differences in radial bone variables after disuse. 3) To test a novel intervention for secondary prevention of osteoporosis after an index radial fracture. Methods Study Design: Part I: Parts IA and IB are descriptive cadaveric studies. Part 2: Cross-sectional observational studies of bone response to disuse; Part 3: Part 3A is a 6-month intervention of secondary prevention of osteoporosis following a fragility fracture. Part 3B uses a questionnaire to ascertain barriers to investigation after fracture. Participants: Part I: Cadaveric specimens from women (73 to 88 years) for Parts IA and IB. Part 2A: Women (52-87 years) who sustained a distal radius fracture and Part 2B: women and men (52 to 79 years) who had suffered a stroke. Part 3A: Women and men (50-90 years) with a fragility fracture; and Part 3B: physicians in British Columbia. Results Part I: With different pQCT acquisition-analysis protocols, total bone area varied by 3-34%; cortical area varied by 3-30% and total content by 6-45% from a criterion standard. Total bone content of the distal radius explained between 74 and 81% of bone strength. Part 2: There was a significant decrease in bone strength in participants who had upper limb disuse because of stroke or fracture. Part 3: A patient and physician intervention improved bone health investigation rate by a factor of 3.1 times (RR) after fragility fracture. BC doctors reported few barriers to investigating osteoporosis. Summary: Peripheral QCT acquisition and analysis protocols significantly influenced outcome variables. Patients do not have "normal" bone strength after fracture or stroke. In particular, there is an increased risk for non-dominant radial fractures to have lower bone strength and be associated with poorer limb function, compared with a dominant radial fracture. Physicians report no barriers to investigation after a fragility radial fracture and a systematic intervention may best address secondary prevention of osteoporosis.
Cancer-related masculinity threat in young adults with testicular cancer: the moderating role of benefit finding

ABSTRACT Background and Objectives: Perceiving benefit from a health-related stressor such as cancer has been associated with better psychological adjustment in various cancer populations; however, it has not been studied in the context of young adulthood or gender-related cancer threat. This study investigated the role of benefit finding in psychological adjustment among young adults with testicular cancer, and whether BF moderates cancer-related masculine threat. Design: This study utilizes a cross-sectional design with a diverse sample of young adult testicular cancer survivors. Methods: Men with a history of testicular cancer (N = 171; M age = 25.2, SD = 3.32) completed questionnaires of benefit finding, cancer-related masculine threat, and indicators of psychological adjustment. Results: Multiple regression analysis revealed that cancer-related masculine threat was associated with worse adjustment across indicators and that benefit finding was related to higher positive affect and lower depressive symptoms. Benefit finding attenuated the potentially adverse effect of cancer-related masculine threat on negative affect and depressive symptoms such that cancer-related masculine threat demonstrated a stronger association with negative affect and depressive symptoms for people with relatively low BF. Conclusions: For young adult men with testicular cancer, finding benefit appears to promote well-being in the face of masculine cancer threat.
High failure rates of protease inhibitor-based antiretroviral treatment in rural Tanzania – A prospective cohort study

Background Poor adherence to antiretroviral drugs and viral resistance are the main drivers of treatment failure in HIV-infected patients. In sub-Saharan Africa, avoidance of treatment failure on second-line protease inhibitor therapy is critical as treatment options are limited. Methods In the prospective observational study of the Kilombero & Ulanga Antiretroviral Cohort in rural Tanzania, we assessed virologic failure (viral load ≥1,000 copies/mL) and drug resistance mutations in bio-banked plasma samples 6–12 months after initiation of a protease inhibitor-based treatment regimen. Additionally, viral load was measured before start of protease inhibitor, a second time between 1–5 years after start, and at suspected treatment failure in patients with available bio-banked samples. We performed resistance testing if viral load was ≥1000 copies/ml. Risk factors for virologic failure were analyzed using logistic regression. Results In total, 252 patients were included; of those 56% were female and 21% children. Virologic failure occurred 6–12 months after the start of a protease inhibitor in 26/199 (13.1%) of adults and 7/53 of children (13.2%). The prevalence of virologic failure did not change over time. Nucleoside reverse transcriptase inhibitors drug resistance mutation testing performed at 6–12 months showed a positive signal in only 9/16 adults. No cases of resistance mutations for protease inhibitors were seen at this time. In samples taken between 1–5 years protease inhibitor resistance was demonstrated in 2/7 adults. In adult samples before protease inhibitor start, resistance to nucleoside reverse transcriptase inhibitors was detected in 30/41, and to non-nucleoside reverse-transcriptase inhibitors in 35/41 patients. In 15/16 pediatric samples, resistance to both drug classes but not for protease inhibitors was present. Conclusion Our study confirms high early failure rates in adults and children treated with protease inhibitors, even in the absence of protease inhibitors resistance mutations, suggesting an urgent need for adherence support in this setting.
Aerodynamic Performance of a Passive Pitching Model on Bionic Flapping Wing Micro Air Vehicles

Reducing weight and increasing lift have been an important goal of using flapping wing micro air vehicles (FWMAVs). However, FWMAVs with mechanisms to limit the angle of attack (α) artificially by active force cannot meet specific requirements. This study applies a bioinspired model that passively imitates insects' pitching wings to resolve this problem. In this bionic passive pitching model, the wing root is equivalent to a torsional spring. α obtained by solving the coupled dynamic equation is similar to that of insects and exhibits a unique characteristic with two oscillated peaks during the middle of the upstroke/downstroke under the interaction of aerodynamic, torsional, and inertial moments. Excess rigidity or flexibility deteriorates the aerodynamic force and efficiency of the passive pitching wing. With appropriate torsional stiffness, passive pitching can maintain a high efficiency while enhancing the average lift by 10% than active pitching. This observation corresponds to a clear enhancement in instantaneous force and a more concentrated leading edge vortex. This phenomenon can be attributed to a vorticity moment whose component in the lift direction grows at a rapid speed. A novel bionic control strategy of this model is also proposed. Similar to the rest angle in insects, the rest angle of the model is adjusted to generate a yaw moment around the wing root without losing lift, which can assist to change the attitude and trajectory of a FWMAV during flight. These findings may guide us to deal with various conditions and requirements of FWMAV designs and applications.
Synthetic lethality between VPS4A and VPS4B triggers an inflammatory response in colorectal cancer

Somatic copy number alterations play a critical role in oncogenesis. Loss of chromosomal regions containing tumor suppressors can lead to collateral deletion of passenger genes. This can be exploited therapeutically if synthetic lethal partners of such passenger genes are known and represent druggable targets. Here, we report that VPS4B gene, encoding an ATPase involved in ESCRT‐dependent membrane remodeling, is such a passenger gene frequently deleted in many cancer types, notably in colorectal cancer (CRC). We observed downregulation of VPS4B mRNA and protein levels from CRC patient samples. We identified VPS4A paralog as a synthetic lethal interactor for VPS4B in vitro and in mouse xenografts. Depleting both proteins profoundly altered the cellular transcriptome and induced cell death accompanied by the release of immunomodulatory molecules that mediate inflammatory and anti‐tumor responses. Our results identify a pair of novel druggable targets for personalized oncology and provide a rationale to develop VPS4 inhibitors for precision therapy of VPS4B‐deficient cancers.
Host Wnt5a Potentiates Microenvironmental Regulation of Ovarian Cancer Metastasis.

The non-canonical Wnt ligand Wnt5a is found in high concentrations in ascites of women with ovarian cancer. In this study, we elucidated the role of Wnt5a in ovarian cancer metastasis. Wnt5a promoted ovarian tumor cell adhesion to peritoneal mesothelial cells as well as migration and invasion, leading to colonization of peritoneal explants. Host components of the ovarian tumor microenvironment, notably peritoneal mesothelial cells and visceral adipose, secreted Wnt5a. Conditional knockout of host WNT5A significantly reduced peritoneal metastatic tumor burden. Tumors formed in WNT5A knockout mice had elevated cytotoxic T cells, increased M1 macrophages and decreased M2 macrophages, indicating that host Wnt5a promotes an immunosuppressive microenvironment. The Src family kinase Fgr was identified as a downstream effector of Wnt5a. These results highlight a previously unreported role for host-expressed Wnt5a in ovarian cancer metastatis, and suggest Fgr as a novel target for inhibition of ovarian cancer metastatic progression.