Miracle-dz/UniFAR-FTUs huggingface dataset:
TDP-43 α-helical structure tunes liquid–liquid phase separation and function

Significance TDP-43 is an essential RNA-binding protein that assembles into protein inclusions in >95% of cases of amyotrophic lateral sclerosis (ALS). A partially helical region in the predominantly disordered C-terminal domain harbors several mutations associated with ALS and is important for TDP-43 function and liquid–liquid phase separation. We directly demonstrate that this helical region undergoes large structural changes upon helix–helix dimerization and that point mutations can enhance helix–helix assembly. Furthermore, we demonstrate that these point variants can be used to control the material properties of phase-separated TDP-43 constructs in cells and can enhance TDP-43 RNA-splicing function. Therefore, engineered forms of the TDP-43 helical domain could be used to control in-cell phase separation, dynamic assembly, and function. Liquid–liquid phase separation (LLPS) is involved in the formation of membraneless organelles (MLOs) associated with RNA processing. The RNA-binding protein TDP-43 is present in several MLOs, undergoes LLPS, and has been linked to the pathogenesis of amyotrophic lateral sclerosis (ALS). While some ALS-associated mutations in TDP-43 disrupt self-interaction and function, here we show that designed single mutations can enhance TDP-43 assembly and function via modulating helical structure. Using molecular simulation and NMR spectroscopy, we observe large structural changes upon dimerization of TDP-43. Two conserved glycine residues (G335 and G338) are potent inhibitors of helical extension and helix–helix interaction, which are removed in part by variants at these positions, including the ALS-associated G335D. Substitution to helix-enhancing alanine at either of these positions dramatically enhances phase separation in vitro and decreases fluidity of phase-separated TDP-43 reporter compartments in cells. Furthermore, G335A increases TDP-43 splicing function in a minigene assay. Therefore, the TDP-43 helical region serves as a short but uniquely tunable module where application of biophysical principles can precisely control assembly and function in cellular and synthetic biology applications of LLPS.
Understanding Students’ Mental Well-Being Challenges on a University Campus: Interview Study

Background Research shows that emerging adults face numerous stressors as they transition from adolescence to adulthood. This paper investigates university students’ lived experiences of maintaining mental well-being during major life events and challenges associated with this transitional period. As we continue to design health technology to support students’ mental health needs, it is imperative to understand the fundamental needs and issues particular to this phase of their life to effectively engage and lower the barriers to seeking help. Objective This study first aimed to understand how university students currently seek and receive support to maintain their mental well-being while going through frequent life events during this period of emerging adulthood. The study then aimed to provide design requirements for how social and technical systems should support the students’ mental well-being maintenance practice. Methods Semistructured interviews with 19 students, including graduate and undergraduate students, were conducted at a large university in the Midwest in the United States. Results This study’s findings identified three key needs: students (1) need to receive help that aligns with the perceived severity of the problem caused by a life event, (2) have to continuously rebuild relationships with support givers because of frequent life events, and (3) negotiate tensions between the need to disclose and the stigma associated with disclosure. The study also identified three key factors related to maintaining mental well-being: time, audience, and disclosure. Conclusions On the basis of this study’s empirical findings, we discuss how and when help should be delivered through technology to better address university students’ needs for maintaining their mental well-being, and we argue for reconceptualizing seeking and receiving help as a colearning process.
Influence of Gestational Weight Gain on the Risk of Preterm Birth for Underweight Women Living in Food Deserts

Abstract Objective Preterm birth (PTB) and food insecurity are two of the most significant public health crises in the United States. Effects of being underweight among populations with low food security are not well understood. We assess whether the protective effect of gestational weight gain (GWG) for women with low prepregnancy body mass index (BMI) differs by accessibility to sources of healthy food. Study Design Population-based retrospective cohort study using Ohio birth records analyzing all live births, 2006 to 2015. Analyses were stratified by maternal BMI (underweight, normal, overweight, and obese), Institute of Medicine (IOM) recommended GWG (under vs. met), and whether the U.S. Department of Agriculture (USDA) classified the residential census tract for each birth as a food desert. Food access data were retrieved from the USDA's 2018 Food Access Research Atlas. Covariates were selected using least absolute shrinkage and selection operator regression. Logistic regression models estimated the risk ratio (RR) of PTB for each group based on under or exceeded recommended GWG (reference = met), adjusting for coexisting risk factors. Results Analysis was performed on 1,124,299 births. PTB risk was highest for underweight women below GWG recommendations (no food desert: 21.3%, RR = 2.15, 95% confidence interval [CI]: 1.81–2.57; food desert: 21.0%, RR = 1.46, 95% CI: 0.96–2.21). Underweight women living in food deserts who exceeded GWG recommendations had lower PTB risk than those who met GWG recommendations (13.5 vs. 14.3%, RR = 0.85, 95% CI: 0.51–1.41). Factors other than GWG significantly associated with PTB included in the adjusted analysis include maternal age and race, education, marital status, interpregnancy interval, and presence of prepregnancy diabetes or hypertension. Conclusion Underweight women who do not meet GWG recommendations are at high risk for PTB. Increasing pregnancy weight gain to a level that exceeds IOM recommendations was not associated with a reduction in PTB risk for underweight women who reside in food deserts compared with women who met GWG recommendations. Key Points Women with low prepregnancy BMI are at high risk of PTB. Food insecurity increases the risk of PTB for underweight women. Excessive GWG for underweight women in food deserts does not reduce PTB risk.
Precision oncology in urothelial cancer

Genomics-driven, precision medicine has been adopted in virtually every tumour type and underlies the significant advances in cancer management to date. The paradigm shift from the indiscriminate use of chemotherapeutics, to strategies that harness our mechanistic knowledge of cancer biology has led to profound clinical benefit for patients, and will continue to mould present and future treatment approaches. In the realm of urothelial cancer, the present status of precision medicine includes a rich landscape that encompasses molecularly-matched therapy, predictive biomarkers that could help inform response to chemotherapy and immunotherapy, as well as novel strategies such as antibody drug conjugates that exploit the use of target proteins for enhanced tumour killing. Here, we present an overview on these clinically-impactful discoveries in urothelial cancer, discuss the limitations and challenges in the implementation of precision oncology, and offer our vision for its future.
Nature and sources of poisoning in patients admitted to a referral hospital in Gaborone, Botswana; findings and implications

ABSTRACT Background Intentional poisoning is becoming an important public health concern particularly among young women globally. Consequently, there is a need to analyze this further within countries to establish pertinent policies to reduce current incidence rates. This includes sub-Saharan African countries where there has been a scarcity of information. Consequently, we sought to establish the nature and sources of poisoning in patients admitted to a leading hospital in Botswana to help develop pertinent future policies for Botswana and surrounding countries. Methods Retrospectively reviewing the medical records of all patients admitted to Princess Marina Hospital (PMH), which is a leading tertiary hospital in the capital city of Botswana, due to acute poisoning over a six-year period. Results The records for 408 patients were reviewed. The majority of admissions (58%) were females, and the mean age of patients was 21(±14) years. Most poisoning cases (53%) were intentional. The 15–45 years age group was most likely to intentionally poison themselves compared to other age groups, with females four and half times more likely to intentionally poison themselves compared to males (AOR 4.53, 95% CI: 2.68–7.89, p < 0.001). Half of the patients were poisoned by medicines followed by household chemicals (22%), with females overall four times more likely to be poisoned by medicines compared to males. The medicine mostly ingested was paracetamol (30%). Failing relationships (57%) were the principal reason for intentional poisoning. Six patients died from poisoning representing a 1.5% mortality rate. Conclusions The findings suggest in-depth and urgent investigations on intentional poisoning are needed among young women across countries including sub-Saharan African countries to inform future policies on prevention strategies. Further, strategies for poisoning prevention should target social and family relationship problems. We will be following this up in the future.
Utility of Routine Preoperative 18F-Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography (18F-FDG PET/CT) in Identifying Pathologic Lymph Node Metastases at Radical Cystectomy.

PURPOSE To determine the diagnostic performance of 18F-FDG PET/CT for detecting nodal metastases in patients with muscle-invasive urothelial bladder cancer prior to radical cystectomy. MATERIALS AND METHODS Preoperative 18F-FDG PET/CT scans (n = 208) were retrospectively reviewed. Scans were routinely performed in 185 patients with muscle-invasive urothelial bladder cancer between August 2012 and February 2017, all of whom underwent radical cystectomy and pelvic lymph node dissection. Analyses were stratified by clinical node involvement and chemotherapy status. The diagnostic performance of 18F-FDG PET/CT was assessed according to sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS Lymph node metastases at time of PLND were present in 21.8% of those without suspicious nodes on computed tomography (clinically node negative) and 52.6% of those with suspicious nodes on CT (clinically node positive). Median metastatic focus size was 5 mm. In clinically node negative patients, 18F-FDG PET/CT rarely detected nodal metastases (sensitivity 7-23%). In clinically node positive patients, a negative 18F-FDG PET/CT was useful in ruling out lymph node metastases (sensitivity 92-100%). This study was limited by its mixed population and focus on pelvic nodal metastases only. CONCLUSIONS 18F-FDG PET/CT appears to be most useful for better characterization of enlarged nodes identified by CT. Routine preoperative 18F-FDG PET/CT has limited utility in clinically node-negative patients.
Twist-chair conformation of the tetraoxepane ring remains unchanged in tetraoxaspirododecane diamines.

A detailed structural analysis has been performed for N,N'-bis(4-chlorophenyl)-7,8,11,12-tetraoxaspiro[5.6]dodecane-9,10-diamine, C20H22Cl2N2O4, (I), N,N'-bis(2-fluorophenyl)-7,8,11,12-tetraoxaspiro[5.6]dodecane-9,10-diamine, C20H22F2N2O4, (II), and N,N'-bis(4-fluorophenyl)-7,8,11,12-tetraoxaspiro[5.6]dodecane-9,10-diamine, C20H22F2N2O4, (III). The seven-membered ring with two peroxide groups adopts a twist-chair conformation in all three compounds. The lengths of the C-N and O-O bonds are slightly shorter than the average statistical values found in the literature for azepanes and 1,2,4,5-tetraoxepanes. The geometry analysis of compounds (I)-(III), the topological analysis of the electron density at the (3, -1) bond critical points within Bader's quantum theory of `Atoms in molecules' (QTAIM) and NBO (natural bond orbital) analysis at the B3LYP/6-31G(d,2p) level of theory showed that there are nO→σ*(C-O), nN→σ*(C-O) and nO→σ*(C-N) stereoelectronic effects. The molecules of compounds (I) and (III) are packed in the crystals as zigzag chains due to strong N-H.O and C-H.O hydrogen-bond interactions, whereas the molecules of compound (II) form chains in the crystals bound by N-H.O, C-H. π and C-H.O contacts. All these data show that halogen atoms and their positions have a minimal effect on the geometric parameters, stereoelectronic effects and crystal packing of compounds (I)-(III), so that the twist-chair conformation of the tetraoxepane ring remains unchanged.
Sociodemographic characteristics of adolescents preferring home-based HIV self-testing over facility-based voluntary counseling and testing: a cross-sectional study in Kisangani, Democratic Republic of the Congo

HIV self-testing (HIVST) offers an alternative to facility-based voluntary counseling and testing (VCT) services, particularly for vulnerable populations such as adolescents. This study aimed to determine the sociodemographic factors associated with adolescents preferring home-based HIVST over facility-based VCT in Kisangani, Democratic Republic of the Congo. A representative cross-sectional study using random sampling in clusters at three levels was conducted among adolescents (aged 15–19 years) to assess their hypothetical preference in home-based HIVST over facility-based VCT by a face-to-face, paper-based, semi-structured questionnaire, and logistic regression for statistical analysis. In 353 households, 754 adolescents were assessed for eligibility, of whom 628 were eligible. A total of 597 adolescents completed the study questionnaire. A majority of participants were aged 18–19 and of female gender. More than two-thirds of participants had never been tested for HIV and had no knowledge about HIVST before this survey. Among 597 adolescents who had completed the study questionnaire, a slight majority of participants (323/597; 54.1% [95% CI: 50.0–58.0]) preferred home-based HIVST over facility-based VCT. In a multivariate analysis, male gender (adjusted OR: 1.5, 95% CI: 1.1–2.1), marriage or partnered civil status (adjusted OR: 1.8, 95% CI: 1.1–3.1), and previous knowledge about HIVST (adjusted OR: 4.2, 95% CI: 2.6–6.8) were associated with preference for home-based HIVST over facility-based VCT. This study demonstrates that more adolescents preferred home-based HIVST over facility-based VCT in Kisangani. These observations suggest the existence of a specific sociodemographic profile associated with the acceptance of HIVST in adolescents living in sub-Saharan Africa.
Endothelium-Targeted Deletion of microRNA-15a/16-1 Promotes Poststroke Angiogenesis and Improves Long-Term Neurological Recovery

Supplemental Digital Content is available in the text. Rationale: Angiogenesis promotes neurological recovery after stroke and is associated with longer survival of stroke patients. Cerebral angiogenesis is tightly controlled by certain microRNAs (miRs), such as the miR-15a/16-1 cluster, among others. However, the function of the miR-15a/16-1 cluster in endothelium on postischemic cerebral angiogenesis is not known. Objective: To investigate the functional significance and molecular mechanism of endothelial miR-15a/16-1 cluster on angiogenesis in the ischemic brain. Methods and Results: Endothelial cell-selective miR-15a/16-1 conditional knockout (EC-miR-15a/16-1 cKO) mice and wild-type littermate controls were subjected to 1 hour middle cerebral artery occlusion followed by 28-day reperfusion. Deletion of miR-15a/16-1 cluster in endothelium attenuates post-stroke brain infarction and atrophy and improves the long-term sensorimotor and cognitive recovery against ischemic stroke. Endothelium-targeted deletion of the miR-15a/16-1 cluster also enhances post-stroke angiogenesis by promoting vascular remodeling and stimulating the generation of newly formed functional vessels, and increases the ipsilateral cerebral blood flow. Endothelial cell-selective deletion of the miR-15a/16-1 cluster up-regulated the protein expression of pro-angiogenic factors VEGFA (vascular endothelial growth factor), FGF2 (fibroblast growth factor 2), and their receptors VEGFR2 (vascular endothelial growth factor receptor 2) and FGFR1 (fibroblast growth factor receptor 1) after ischemic stroke. Consistently, lentiviral knockdown of the miR-15a/16-1 cluster in primary mouse or human brain microvascular endothelial cell cultures enhanced in vitro angiogenesis and up-regulated pro-angiogenic proteins expression after oxygen-glucose deprivation, whereas lentiviral overexpression of the miR-15a/16-1 cluster suppressed in vitro angiogenesis and down-regulated pro-angiogenic proteins expression. Mechanistically, miR-15a/16-1 translationally represses pro-angiogenic factors VEGFA, FGF2, and their receptors VEGFR2 and FGFR1, respectively, by directly binding to the complementary sequences within 3′-untranslated regions of those messenger RNAs. Conclusions: Endothelial miR-15a/16-1 cluster is a negative regulator for postischemic cerebral angiogenesis and long-term neurological recovery. Inhibition of miR-15a/16-1 function in cerebrovascular endothelium may be a legitimate therapeutic approach for stroke recovery.
The phospholipase A effector PlaA from Legionella pneumophila: expression, purification and crystallization.

Legionella pneumophila encodes an extracellular secreted phospholipase A named PlaA that is translocated by the type II secretion system. It plays an essential role in maintaining the integrity of Legionella-containing vacuoles in L. pneumophila pathogenesis. Here, it is shown that PlaA has a main lysophospholipase activity to hydrolyze fatty-acyl groups in lysophospholipids. Although it has a very low phospholipase A activity to catalyze the hydrolysis of fatty-acyl groups in phospholipids, PlaA can bind phospholipids such as 1,2-dipalmitoylphosphatidylcholine with a dissociation constant of 11.1 µM. Sequence-alignment analysis combined with activity assays revealed that PlaA contains a distinct substrate-binding site among the known structures of the phospholipase A family, implying that PlaA may present a novel mechanism for substrate recognition. Native PlaA and its selenomethionine (SeMet)-substituted form were purified and crystallized by vapour diffusion in hanging drops at 296 K. Diffraction data were collected to a resolution of 2.0 Å for native PlaA protein and to a resolution of 2.7 Å for SeMet-substituted PlaA protein. The crystals of native PlaA belonged to the monoclinic space group P21, while the crystals of SeMet-substituted PlaA belonged to the primitive orthorhombic space group P212121. Initial phases for PlaA were obtained from SeMet SAD data sets.
A Simplified Cluster Analysis of Electron Track Structure for Estimating Complex DNA Damage Yields

Complex DNA damage, defined as at least two vicinal lesions within 10–20 base pairs (bp), induced after exposure to ionizing radiation, is recognized as fatal damage to human tissue. Due to the difficulty of directly measuring the aggregation of DNA damage at the nano-meter scale, many cluster analyses of inelastic interactions based on Monte Carlo simulation for radiation track structure in liquid water have been conducted to evaluate DNA damage. Meanwhile, the experimental technique to detect complex DNA damage has evolved in recent decades, so both approaches with simulation and experiment get used for investigating complex DNA damage. During this study, we propose a simplified cluster analysis of ionization and electronic excitation events within 10 bp based on track structure for estimating complex DNA damage yields for electron and X-ray irradiations. We then compare the computational results with the experimental complex DNA damage coupled with base damage (BD) measured by enzymatic cleavage and atomic force microscopy (AFM). The computational results agree well with experimental fractions of complex damage yields, i.e., single and double strand breaks (SSBs, DSBs) and complex BD, when the yield ratio of BD/SSB is assumed to be 1.3. Considering the comparison of complex DSB yields, i.e., DSB + BD and DSB + 2BD, between simulation and experimental data, we find that the aggregation degree of the events along electron tracks reflects the complexity of induced DNA damage, showing 43.5% of DSB induced after 70 kVp X-ray irradiation can be classified as a complex form coupled with BD. The present simulation enables us to quantify the type of complex damage which cannot be measured through in vitro experiments and helps us to interpret the experimental detection efficiency for complex BD measured by AFM. This simple model for estimating complex DNA damage yields contributes to the precise understanding of the DNA damage complexity induced after X-ray and electron irradiations.
Outcomes of bedside peripherally inserted central catheter placement: a retrospective study at a single institution

Background: Bedside insertion of peripherally inserted central catheters (PICCs) has higher rates of malposition than fluoroscopic-guided PICC placement. This study evaluated the success rate of bedside PICC placement, variations in tip location, and risk factors for malposition. Methods: This retrospective study included patients who underwent bedside PICC placement from January 2013 to September 2014 in a single institution. The procedure was conducted under ultrasound guidance or by a blind method. After PICC placement, tip location was determined by chest X-ray. Results: The overall venous access success rate with bedside PICC placement was 98.1% (1,302/ 1,327). There was no significant difference in the venous access success rate between ultrasound-guided placement (868/880, 98.6%) and a blind approach placement (434/447, 97.1%). Optimal tip position was achieved on the first attempt in 1,192 cases (91.6%). Repositioning was attempted in 65 patients; 60 PICCs were repositioned at the bedside, two PICCs were repositioned under fluoroscopic guidance, and three PICCs moved to the desired position without intervention. Final optimal tip position after repositioning was achieved in 1,229 (94.4%). In logistic regression analysis, five factors associated with tip malposition included female sex (Exp(B), 1.687; 95% confidence interval [CI], 1.180 to 2.412; P=0.004), older age (Exp(B), 1.026; 95% CI, 1.012 to 1.039; P<0.001), cancer (Exp(B), 0.650; 95% CI, 0.455 to 0.929; P=0.018), lung disease (Exp(B), 2.416; 95% CI, 1.592 to 3.666; P<0.001), and previous catheter insertions (Exp(B), 1.262; 95% CI, 1.126 to 1.414; P<0.001). Conclusions: Bedside PICC placement without fluoroscopy is effective and safe in central venous catheters. Potential risk factors associated with catheter tip malposition include older age, female sex, cancer, pulmonary disease, and previous central vein catheterizations.