Miracle-dz/UniFAR-FTUs huggingface dataset:
“Like Holding an Umbrella Before It Rains”: Acceptability of Future Rectal Microbicides Among Men Who Have Sex With Men in India—A Modified Technology Acceptance Model

Topical rectal microbicides (RMs) are a new prevention technology in development that aims to reduce the risk of HIV acquisition from anal sex. We examined RM acceptability among men who have sex with men (MSM) in India. We conducted a qualitative exploratory study guided by a modified Technology Acceptance Model, with 10 focus groups (n = 61) of MSM and 10 key informant interviews. Data were explored using framework analysis. RM acceptability was influenced by technological contexts: perceived usefulness of RMs, perceived ease of use of RM and applicator, and habits around condom and lubricant use; individual and interpersonal contexts: perceived relevance and preferences for product formulation and dosing frequency; and MSM community/social contexts: perceived social approval, RM-related stigma, social support. Implementation of RMs for MSM in India may be supported by multi-level interventions that engage community-based organizations in destigmatizing and distributing RMs, ideally gel-based products that enable on-demand use before sex.
Focal Solute Trapping and Global Glymphatic Pathway Impairment in a Murine Model of Multiple Microinfarcts

Microinfarcts occur commonly in the aging brain as a consequence of diffuse embolic events and are associated with the development of vascular dementia and Alzheimer's disease. However, the manner in which disperse microscopic lesions reduce global cognitive function and increase the risk for Alzheimer's disease is unclear. The glymphatic system, which is a brain-wide perivascular network that supports the recirculation of CSF through the brain parenchyma, facilitates the clearance of interstitial solutes including amyloid β and tau. We investigated whether glymphatic pathway function is impaired in a murine model of multiple microinfarcts induced by intraarterial injection of cholesterol crystals. The analysis showed that multiple microinfarcts markedly impaired global influx of CSF along the glymphatic pathway. Although suppression of global glymphatic function was transient, resolving within 2 weeks of injury, CSF tracers also accumulated within tissue associated with microinfarcts. The effect of diffuse microinfarcts on global glymphatic pathway function was exacerbated in the mice aged 12 months compared with the 2- to 3-month-old mice. These findings indicate that glymphatic function is focally disrupted around microinfarcts and that the aging brain is more vulnerable to this disruption than the young brain. These observations suggest that microlesions may trap proteins and other interstitial solutes within the brain parenchyma, increasing the risk of amyloid plaque formation. SIGNIFICANCE STATEMENT Microinfarcts, small (<1 mm) ischemic lesions, are strongly associated with age-related dementia. However, how these microscopic lesions affect global cognitive function and predispose to Alzheimer's disease is unclear. The glymphatic system is a brain-wide network of channels surrounding brain blood vessels that allows CSF to exchange with interstitial fluid, clearing away cellular wastes such as amyloid β. We observed that, in mice, microinfarcts impaired global glymphatic function and solutes from the CSF became trapped in tissue associated with microinfarcts. These data suggest that small, disperse ischemic lesions can impair glymphatic function across the brain and trapping of solutes in these lesions may promote protein aggregation and neuroinflammation and eventually lead to neurodegeneration, especially in the aging brain.
Functionalized congeners of A3 adenosine receptor-selective nucleosides containing a bicyclo[3.1.0]hexane ring system.

(N)-Methanocarba nucleosides containing bicyclo[3.1. 0]hexane replacement of the ribose ring previously demonstrated selectivity as A(3) adenosine receptor (AR) agonists (5'-uronamides) or antagonists (5'-truncated). Here, these two series were modified in parallel at the adenine C2 position. N(6)-3-Chlorobenzyl-5'-N-methyluronamides derivatives with functionalized 2-alkynyl chains of varying length terminating in a reactive carboxylate, ester, or amine group were full, potent human A(3)AR agonists. Flexibility of chain substitution allowed the conjugation with a fluorescent cyanine dye (Cy5) and biotin, resulting in binding K(i) values of 17 and 36 nM, respectively. The distal end of the chain was predicted by homology modeling to bind at the A(3)AR extracellular regions. Corresponding l-nucleosides were nearly inactive in AR binding. In the 5'-truncated nucleoside series, 2-Cl analogues were more potent at A(3)AR than 2-H and 2-F, functional efficacy in adenylate cyclase inhibition varied, and introduction of a 2-alkynyl chain greatly reduced affinity. SAR parallels between the two series lost stringency at distal positions. The most potent and selective novel compounds were amine congener 15 (K(i) = 2.1 nM) and truncated partial agonist 22 (K(i) = 4.9 nM).
&bgr;-Arrestin-2 Deficiency Attenuates Abdominal Aortic Aneurysm Formation in Mice

Rationale: Abdominal aortic aneurysms (AAAs) are a chronic inflammatory vascular disease for which pharmacological treatments are not available. A mouse model of AAA formation involves chronic infusion of angiotensin II (AngII), and previous studies indicated a primary role for the AngII type 1a receptor in AAA formation. &bgr;-arrestin (&bgr;arr)-2 is a multifunctional scaffolding protein that binds G-protein–coupled receptors such as AngII type 1a and regulates numerous signaling pathways and pathophysiological processes. However, a role for &bgr;arr2 in AngII-induced AAA formation is currently unknown. Objective: To determine whether &bgr;arr2 played a role in AngII-induced AAA formation in mice. Methods and Results: Treatment of &bgr;arr2+/+ and &bgr;arr2−/− mice on the hyperlipidemic apolipoprotein E–deficient (apoE−/−) background or on normolipidemic C57BL/6 background with AngII for 28 days indicated that &bgr;arr2 deficiency significantly attenuated AAA formation. &bgr;arr2 deficiency attenuated AngII-induced expression of cyclooxygenase-2, monocyte chemoattractant protein-1, macrophage inflammatory protein 1&agr;, and macrophage infiltration. AngII also increased the levels of phosphorylated extracellular signal-regulated kinase 1/2 in apoE−/−/&bgr;arr2+/+ aortas, whereas &bgr;arr2 deficiency diminished this increase. Furthermore, inhibition of extracellular signal-regulated kinase 1/2 activation with CI1040 (100 mg/kg per day) reduced the level of AngII-induced cyclooxygenase-2 expression in apoE−/−/&bgr;arr2+/+ mice to the level observed in apoE−/−/&bgr;arr2−/− mice. AngII treatment also increased matrix metalloproteinase expression and disruption of the elastic layer in apoE−/−/&bgr;arr2+/+ aortas, and &bgr;arr2 deficiency reduced these effects. Conclusions: &bgr;arr2 contributes to AngII-induced AAA formation in mice by phosphorylated extracellular signal-regulated kinase 1/2–mediated cyclooxygenase-2 induction and increased inflammation. These studies suggest that for the AngII type 1a receptor, G-protein–independent, &bgr;arr2-dependent signaling plays a major role in AngII-induced AAA formation.
Nature And The American Three Centuries Of Changing Attitudes

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Development of Human Anti-Murine T-Cell Receptor Antibodies in Both Responding and Nonresponding Patients Enrolled in TCR Gene Therapy Trials

Purpose: Immune responses to gene-modified cells are a concern in the field of human gene therapy, as they may impede effective treatment. We conducted 2 clinical trials in which cancer patients were treated with lymphocytes genetically engineered to express murine T-cell receptors (mTCR) specific for tumor-associated antigens p53 and gp100. Experimental Design: Twenty-six patients treated with autologous lymphocytes expressing mTCR had blood and serum samples available for analysis. Patient sera were assayed for the development of a humoral immune response. Adoptive cell transfer characteristics were analyzed to identify correlates to immune response. Results: Six of 26 (23%) patients' posttreatment sera exhibited specific binding of human anti-mTCR antibodies to lymphocytes transduced with the mTCR. Antibody development was found in both responding and nonresponding patients. The posttreatment sera of 3 of these 6 patients mediated a 60% to 99% inhibition of mTCR activity as measured by a reduction in antigen-specific interferon-γ release. Detailed analysis of posttreatment serum revealed that antibody binding was β-chain specific in 1 patient whereas it was α-chain specific in another. Conclusions: A subset of patients treated with mTCR-engineered T cells developed antibodies directed to the mTCR variable regions and not to the constant region domains common to all mTCR. Overall, the development of a host immune response was not associated with the level of transduced cell persistence or response to therapy. In summary, patients treated with mTCR can develop an immune response to gene-modified cells in a minority of cases, but this may not affect clinical outcome. Clin Cancer Res; 16(23); 5852–61. ©2010 AACR.
Serologic Evidence for Influenza C and D Virus among Ruminants and Camelids, Africa, 1991–2015

Influenza D virus has been identified in America, Europe, and Asia. We detected influenza D virus antibodies in cattle and small ruminants from North (Morocco) and West (Togo and Benin) Africa. Dromedary camels in Kenya harbored influenza C or D virus antibodies, indicating a potential new host for these viruses.
New knowledge and insights about the malignant transformation of endometriosis

Endometriosis may be a definitive risk factor for ovarian cancer, the most fatal gynecological cancer. The ability of endometriosis to transform into malignancy, first described by Dr. Sampson in 1925, is considered a rare occurrence, affecting approximately 1% of ovarian endometriomas.
1 Visual-textual A ention Driven Fine-grained Representation Learning

Fine-grained image classication is to recognize hundreds of subcategories belonging to the same basiclevel category, which is a highly challenging task due to the quite subtle visual distinctions among similar subcategories. Most existing methods generally learn part detectors to discover discriminative regions for beer classication accuracy. However, not all localized parts are benecial and indispensable for image classication, and the seing for number of part detectors relies heavily on prior knowledge as well as experimental results. As is known to all, when we describe the object of an image into text via natural language, we only focus on the pivotal characteristics, and rarely pay aention to common characteristics as well as the background areas. is is an involuntary transfer from human visual aention to textual aention, which leads to the fact that textual aention tells us how many and which parts are discriminative and signicant. So textual aention of natural language descriptions could help us to discover visual aention in image. Inspired by this, we propose a visual-textual aention driven ne-grained representation learning (VTA) approach, and its main contributions are: (1) Fine-grained visual-textual paern mining devotes to discovering discriminative visual-textual pairwise information for boosting classication through jointly modeling vision and text with generative adversarial networks (GANs), which automatically and adaptively discovers discriminative parts. (2) Visual-textual representation learning jointly combine visual and textual information, which preserves the intra-modality and inter-modality information to generate complementary ne-grained representation, and further improve classication performance. Comprehensive experimental results on the widely-used CUB-200-2011 and Oxford Flowers-102 datasets demonstrate the eectiveness of our VTA approach, which achieves the best classication accuracy compared with state-of-the-art methods.
Low atazanavir concentrations in cerebrospinal fluid

Objective:Protease inhibitors may not penetrate into the central nervous system in therapeutic concentrations, which may allow ongoing HIV replication and injury. The objective of this study was to determine atazanavir penetration into cerebrospinal fluid (CSF). Design:Single random plasma or paired plasma and CSF samples were drawn from participants enrolled in a multicenter, observational cohort study and taking atazanavir with or without ritonavir between October 2003 and October 2005. Methods:Plasma samples were assayed by high performance liquid chromatography and immunoassay; lower limit of detection was 45 ng/ml. CSF samples were assayed by immunoassay (ARK ATV-test); lower limit of detection was 5 ng/ml. Results:One hundred and seventeen participants (43 ± 7.7 years, 79% men, 81 ± 15 kg) had plasma or plasma and CSF paired samples drawn a median (interquartile range) of 10 (5–17) h postdose. Median (interquartile range) plasma atazanavir concentrations with or without ritonavir were 1278 (525–2265) and 523 (283–1344) ng/ml. The median (interquartile range) CSF concentrations with or without ritonavir were 10.3 (<5–21.1) and 7.9 (6.6–22) ng/ml. Nineteen of 79 (24%) CSF samples were less than 5 ng/ml. CSF concentrations were less than 1% of plasma concentrations and near the atazanavir wild-type IC50 of 1–11 ng/ml. Conclusion:Atazanavir CSF concentrations are highly variable and 100-fold lower than plasma concentrations, even with ritonavir boosting. CSF concentrations of atazanavir do not consistently exceed the wild-type IC50 of atazanavir and may not protect against HIV replication in the CSF.
A new method for computational drug repositioning using drug pairwise similarity

The traditional de novo drug discovery is known as a high cost and high risk process. In response, recently there is an increasing interest in discovering new indications for known drugs - a process known as drug repositioning - using computational methods. In this study, we present a new systematic approach for identifying potential new indications of an existing drug through its relation to similar drugs. Different from the previous similarity-based methods, we adapted a novel bipartite-graph based method when considering common drug targets and their interaction information. Furthermore, we added drug structure information into the calculation of drug pairwise similarity. In cross-validation experiments, our method achieved a sensitivity of 0.77 and specificity of 0.92 (AUC = 0.888) and compared favorably to the state of the art. When compared with a control group of drug uses, our drug repositioning results were found to be significantly enriched in both the biomedicai literature and clinical trials. Our results indicate that combining chemical structure and drug target information results in better prediction performance and that the proposed approach successfully captures the implicit information between drug targets.
Mechanisms of the gabapentinoids and α 2 δ‐1 calcium channel subunit in neuropathic pain

The gabapentinoid drugs gabapentin and pregabalin are key front‐line therapies for various neuropathies of peripheral and central origin. Originally designed as analogs of GABA, the gabapentinoids bind to the α2δ‐1 and α2δ‐2 auxiliary subunits of calcium channels, though only the former has been implicated in the development of neuropathy in animal models. Transgenic approaches also identify α2δ‐1 as key in mediating the analgesic effects of gabapentinoids, however the precise molecular mechanisms remain unclear. Here we review the current understanding of the pathophysiological role of the α2δ‐1 subunit, the mechanisms of analgesic action of gabapentinoid drugs and implications for efficacy in the clinic. Despite widespread use, the number needed to treat for gabapentin and pregabalin averages from 3 to 8 across neuropathies. The failure to treat large numbers of patients adequately necessitates a novel approach to treatment selection. Stratifying patients by sensory profiles may imply common underlying mechanisms, and a greater understanding of these mechanisms could lead to more direct targeting of gabapentinoids.
Membrane anchoring of diacylglycerol lactones substituted with rigid hydrophobic acyl domains correlates with biological activities

Synthetic diacylglycerol lactones (DAG lactones) are effective modulators of critical cellular signaling pathways downstream of the lipophilic second messenger diacylglycerol that activate a host of protein kinase C (PKC) isozymes as well as other non‐kinase proteins that share with PKC similar C1 membrane‐targeting domains. A fundamental determinant of the biological activity of these amphiphilic molecules is the nature of their interactions with cellular membranes. This study characterizes the membrane interactions and bilayer anchoring of a series of DAG lactones in which the hydrophobic moiety is a ‘molecular rod’, namely a rigid 4‐[2‐(R‐phenyl)ethynyl]benzoate moiety in the acyl position. Use of assays employing chromatic biomimetic vesicles and biophysical techniques revealed that the mode of membrane anchoring of the DAG lactone derivatives was markedly affected by the presence of the hydrophobic diphenyl rod and by the size of the functional unit at the terminus of the rod. Two primary mechanisms of interaction were observed: surface binding of the DAG lactones at the lipid/water interface and deep insertion of the ligands into the alkyl core of the lipid bilayer. These membrane‐insertion properties could explain the different patterns of the PKC translocation from the cytosol to membranes that is induced by the molecular‐rod DAG lactones. This investigation emphasizes that the side residues of DAG lactones, rather than simply conferring hydrophobicity, profoundly influence membrane interactions, and thus may further contribute to the diversity of biological actions of these synthetic biomimetic ligands.
Character Strengths and Virtues in Relation to Well-Being in Gay and Lesbian Individuals

A cross-sectional survey study was completed in which ninety-two self-identified gay and lesbian university students responded to online research instruments which assessed psychological well-being as well as character strengths and virtues. Participants were grouped using cluster analysis based on well-being scores and discriminant analysis was used to differentiate between groups based on two virtue factors (Interpersonal Strengths and Practical Wisdom). Results suggest that individuals with high autonomy and low overall well-being score lower in interpersonal character strengths compared to individuals with balanced well-being. As interpersonal strengths are key to social support and thus to well-being for gay and lesbian individuals, further attention is warranted to study the relationship between autonomy, interpersonal character strengths, and social support in this population.
HIV and Aging

The bad news is research increasingly shows that diseases that typically strike HIV-negative people in their 60s and 70s are occurring in people with HIV in their 40s and 50s. These concerns have brought the issue of aging with HIV to center stage. One of the biggest unanswered questions is why this is occurring. Whether it’s heart attacks, bone fractures, kidney disease or certain cancers, the rates of these conditions in HIV-positive people are alarming. It’s unclear how much HIV contributes to these conditions and how much is explainable by other factors (such as smoking, HIV drugs and coinfection with other viruses).
Fatigue in Younger and Older Drivers: Effectiveness of an Alertness-Maintaining Task

Objective: The aim of this study was to examine the effects of an alertness-maintaining task (AMT) in older, fatigued drivers. Background: Fatigue during driving increases crash risk, and previous research suggests that alertness and driving in younger adults may be improved using a secondary AMT during boring, fatigue-eliciting drives. However, the potential impact of an AMT on driving has not been investigated in older drivers whose ability to complete dual tasks has been shown to decline and therefore may be negatively affected with an AMT in driving. Method: Younger (n = 29) and older drivers (n = 39) participated in a 50-minute simulated drive designed to induce fatigue, followed by four 10-minute sessions alternating between driving with and without an AMT. Results: Younger drivers were significantly more affected by fatigue on driving performance than were older drivers but benefitted significantly from the AMT. Older drivers did not demonstrate increased driver errors with fatigue, and driving did not deteriorate significantly during participation in the AMT condition, although their speed was significantly more variable with the AMT. Conclusion: Consistent with earlier research, an AMT applied during fatiguing driving is effective in improving alertness and reducing driving errors in younger drivers. Importantly, older drivers were relatively unaffected by fatigue, and use of an AMT did not detrimentally affect their driving performance. Application: These results support the potential use of an AMT as a new automotive technology to improve fatigue and promote driver safety, though the benefits of such technology may differ between different age groups.
Stereospecific PARP Trapping by BMN 673 and Comparison with Olaparib and Rucaparib

Anti-PARP drugs were initially developed as catalytic inhibitors to block the repair of DNA single-strand breaks. We recently reported that several PARP inhibitors have an additional cytotoxic mechanism by trapping PARP–DNA complexes, and that both olaparib and niraparib act as PARP poisons at pharmacologic concentrations. Therefore, we have proposed that PARP inhibitors should be evaluated based both on catalytic PARP inhibition and PARP–DNA trapping. Here, we evaluated the novel PARP inhibitor, BMN 673, and compared its effects on PARP1 and PARP2 with two other clinical PARP inhibitors, olaparib and rucaparib, using biochemical and cellular assays in genetically modified chicken DT40 and human cancer cell lines. Although BMN 673, olaparib, and rucaparib are comparable at inhibiting PARP catalytic activity, BMN 673 is ∼100-fold more potent at trapping PARP–DNA complexes and more cytotoxic as single agent than olaparib, whereas olaparib and rucaparib show similar potencies in trapping PARP–DNA complexes. The high level of resistance of PARP1/2 knockout cells to BMN 673 demonstrates the selectivity of BMN 673 for PARP1/2. Moreover, we show that BMN 673 acts by stereospecific binding to PARP1 as its enantiomer, LT674, is several orders of magnitude less efficient. BMN 673 is also approximately 100-fold more cytotoxic than olaparib and rucaparib in combination with the DNA alkylating agents methyl methane sulfonate (MMS) and temozolomide. Our study demonstrates that BMN 673 is the most potent clinical PARP inhibitor tested to date with the highest efficiency at trapping PARP–DNA complexes. Mol Cancer Ther; 13(2); 433–43. ©2013 AACR.
OMX: a new platform for multimodal, multichannel wide-field imaging.

This article discusses the design principles and applications of the OMX microscope, a new platform that provides unprecedented mechanical and thermal stabilities coupled with a photon budget that is dramatically improved over traditional microscope platforms. These characteristics make the OMX microscope outstanding for fast live cell imaging and super-resolution imaging. Moreover, its open flexible architecture makes it particularly amenable to adding other modes of microscopy to the platform.