Miracle-dz/UniFAR-FTUs huggingface dataset:
immunocompetent human 3D organ-specific hormone-responding vaginal mucosa model of HIV-1 infection.

The lack of appropriate experimental models often limits our ability to investigate the establishment of infections in specific tissues. To reproduce the structural and spatial organization of vaginal mucosae to study human immunodeficiency virus type-1 (HIV-1) infection, we used the self-assembly technique to bioengineer tridimensional vaginal mucosae using human cells extracted from HIV-1-negative healthy pre- and postmenopausal donors. We produced a stroma, free of exogenous material, that can be adapted to generate near-to-native vaginal tissue with the best complexity obtain with seeded epithelial cells on the organ-specific stroma. The autologous engineered tissues had mechanical properties close to native mucosa and shared similar glycogen production, which declined in reconstructed tissues of the postmenopausal donor. The in vitro engineered tissues were also rendered immune-competent by adding human monocyte-derived macrophages on the epithelium or in the stroma layers. The model was infected with HIV-1, and viral replication and transcytosis were observed when immunocompetent reconstructed vaginal mucosa tissue has incorporated Monocyte-Derived Macrophages in the stroma and infected with free HIV-1 GFP viral particles. These data illustrate a natural permissiveness of immunocompetent untransformed human vaginal mucosae to HIV-1 infection. This model offers a physiological tool to explore viral load, HIV-1 transmission in an environment that may contribute to the virus's propagation, and new anti-viral treatments in vitro.
Protective Role of Galanin during Chemically Induced Inflammation in Zebrafish Larvae

Simple Summary The neuropeptide galanin is known for its protective role in the central nervous system, but not much is reported about its involvement in innate immunity. Our studies showed that galanin expression became upregulated after incubation in copper sulfate, which caused neuromast damage on the lateral line of the fish. Galanin presence protected the cells from the degenerative effects of the copper sulfate incubation compared to the galanin knockout larvae. Moreover, galanin treatment resulted in a higher expression of some inflammatory markers such as irg1l, il1b and tnfa, which indicated its possible role in immune responses and inflammatory processes. On the other side, galanin knockout caused more severe damage to the neuromasts, as well as downregulation in expression of the studied genes. Taken together, our results showed that galanin’s function was not only limited to the central nervous system as it was involved in other processes in the organism. Abstract During a pathological condition, many different systems are involved in the response of an affected organism. Galanin is considered to be a neuropeptide that plays an important role in the central nervous system; however, it is involved in many other biological processes, including the immune response. During our studies, we showed that galanin became upregulated in zebrafish larvae when exposed to copper sulfate. Moreover, the presence of normal levels of galanin, administration of a galanin analog NAX 5055 or galanin overexpression led to lowered lateral line damage and enhanced expression of inflammatory markers compared to the knockout larvae. The results showed that the neuroendocrine system acts multifunctionally and should be considered as a part of the complex neuro–immune–endocrine axis.
Fluoxetine Can Inhibit SARS-CoV-2 In Vitro

An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in the coronavirus disease pandemic, drastically affecting global health and economy. Though the understanding of the disease has improved, fighting the virus remains challenging. One of the strategies is repurposing existing drugs as inhibitors of SARS-CoV-2. Fluoxetine (FLX), a selective serotonin reuptake inhibitor, reportedly inhibits the replication of RNA viruses, especially Coxsackieviruses B (CVB), such as CV-B4 in vitro and in vivo. Therefore, in this study, we investigated the in vitro antiviral activity of FLX against SARS-CoV-2 in a model of acute infection. When 10 μM of FLX was added to SARS-CoV-2-infected Vero E6 cells, the virus-induced cytopathic effect was not observed. In this model, the level of infectious particles in the supernatant was lower than that in controls. The level was below the limit of detection of the assay up to day 3 post-infection when FLX was administered before viral inoculation or simultaneously followed by daily inoculation. In conclusion, FLX can inhibit SARS-CoV-2 in vitro. Further studies are needed to investigate the potential value of FLX to combat SARS-CoV-2 infections, treat SARS-CoV-2-induced diseases, and explain the antiviral mechanism of this molecule to pave way for novel treatment strategies.
The temporal nature of social context: Insights from the daily lives of patients with HIV.

BACKGROUND Patients' life contexts are increasingly recognized as important, as evidenced by growing attention to the Social Determinants of Health (SDoH). This attention may be particularly valuable for patients with complex needs, like those with HIV, who are more likely to experience age-related comorbidities, mental health or substance use issues. Understanding patient perceptions of their life context can advance SDoH approaches. OBJECTIVES We sought to understand how aging patients with HIV think about their life context and explored if and how their reported context was documented in their electronic medical records (EMRs). DESIGN We combined life story interviews and EMR data to understand the health-related daily life experiences of patients with HIV. Patients over 50 were recruited from two US Department of Veterans Affairs HIV clinics. Narrative analysis was used to organize data by life events and health-related metrics. KEY RESULTS EMRs of 15 participants documented an average of 19 diagnoses and 10 medications but generally failed to include social contexts salient to patients. In interviews, HIV was discussed primarily in response to direct interviewer questions. Instead, participants raised past trauma, current social engagement, and concern about future health with varying salience. This led us to organize the narratives temporally according to past-, present-, or future-orientation. "Past-focused" narratives dwelled on unresolved experiences with social institutions like the school system, military or marriage. "Present-focused" narratives emphasized daily life challenges, like social isolation. "Future-focused" narratives were dominated by concerns that aging would limit activities. CONCLUSIONS A temporally informed understanding of patients' life circumstances that are the foundation of their individualized SDoH could better focus care plans by addressing contextual concerns salient to patients. Trust-building may be a critical first step in caring for past-focused patients. Present-focused patients may benefit from support groups. Future-focused patients may desire discussing long term care options.
Increasing the resolution and precision of psychiatric genome‐wide association studies by re‐imputing summary statistics using a large, diverse reference panel

Genotype imputation across populations of mixed ancestry is critical for optimal discovery in large‐scale genome‐wide association studies (GWAS). Methods for direct imputation of GWAS summary‐statistics were previously shown to be practically as accurate as summary statistics produced after raw genotype imputation, while incurring orders of magnitude lower computational burden. Given that direct imputation needs a precise estimation of linkage‐disequilibrium (LD) and that most of the methods using a small reference panel for example, ~2,500‐subject coming from the 1000 Genome‐Project, there is a great need for much larger and more diverse reference panels. To accurately estimate the LD needed for an exhaustive analysis of any cosmopolitan cohort, we developed DISTMIX2. DISTMIX2: (a) uses a much larger and more diverse reference panel compared to traditional reference panels, and (b) can estimate weights of ethnic‐mixture based solely on Z‐scores, when allele frequencies are not available. We applied DISTMIX2 to GWAS summary‐statistics from the psychiatric genetic consortium (PGC). DISTMIX2 uncovered signals in numerous new regions, with most of these findings coming from the rarer variants. Rarer variants provide much sharper location for the signals compared with common variants, as the LD for rare variants extends over a lower distance than for common ones. For example, while the original PGC post‐traumatic stress disorder GWAS found only 3 marginal signals for common variants, we now uncover a very strong signal for a rare variant in PKN2, a gene associated with neuronal and hippocampal development. Thus, DISTMIX2 provides a robust and fast (re)imputation approach for most psychiatric GWAS‐studies.
Learning to Recognize Actions on Objects in Egocentric Video With Attention Dictionaries

We present EgoACO, a deep neural architecture for video action recognition that learns to pool action-context-object descriptors from frame level features by leveraging the verb-noun structure of action labels in egocentric video datasets. The core component is class activation pooling (CAP), a differentiable pooling layer that combines ideas from bilinear pooling for fine-grained recognition and from feature learning for discriminative localization. CAP uses self-attention with a dictionary of learnable weights to pool from the most relevant feature regions. Through CAP, EgoACO learns to decode object and scene context descriptors from video frame features. For temporal modeling we design a recurrent version of class activation pooling termed Long Short-Term Attention (LSTA). LSTA extends convolutional gated LSTM with built-in spatial attention and a re-designed output gate. Action, object and context descriptors are fused by a multi-head prediction that accounts for the inter-dependencies between noun-verb-action structured labels in egocentric video datasets. EgoACO features built-in visual explanations, helping learning and interpretation of discriminative information in video. Results on the two largest egocentric action recognition datasets currently available, EPIC-KITCHENS and EGTEA Gaze+, show that by decoding action-context-object descriptors, the model achieves state-of-the-art recognition performance.
Effect of Various Exercise Regimens on Selected Exercise-Induced Cytokines in Healthy People

Different forms of physical activity—endurance, resistance or dynamic power—stimulate cytokine release from various tissues to the bloodstream. Receptors for exercise-induced cytokines are present in muscle tissue, adipose tissue, liver, brain, bones, cardiovascular system, immune system, pancreas, and skin. They have autocrine, paracrine and endocrine activities. Many of them regulate the myocyte growth and differentiation necessary for muscle hypertrophy and myogenesis. They also modify energy homeostasis, lipid, carbohydrate, and protein metabolism, regulate inflammation and exchange information (crosstalk) between remote organs. So far, interleukin 6 and irisin have been the best studied exercise-induced cytokines. However, many more can be grouped into myokines, hepatokines and adipomyokines. This review focuses on the less known exercise-induced cytokines such as myostatin, follistatin, decorin, brain-derived neurotrophic factor, fibroblast growth factor 21 and interleukin 15, and their relation to various forms of exercise, i.e., acute vs. chronic, regular training in healthy people.
The miR–181a–SFRP4 Axis Regulates Wnt Activation to Drive Stemness and Platinum Resistance in Ovarian Cancer

These results demonstrate that miR-181a is an activator of Wnt signaling that drives stemness and chemoresistance in HGSOC and may be targeted therapeutically in recurrent disease. Wnt signaling is a major driver of stemness and chemoresistance in ovarian cancer, yet the genetic drivers that stimulate its expression remain largely unknown. Unlike other cancers, mutations in the Wnt pathway are not reported in high-grade serous ovarian cancer (HGSOC). Hence, a key challenge that must be addressed to develop effective targeted therapies is to identify nonmutational drivers of Wnt activation. Using an miRNA sensor-based approach, we have identified miR-181a as a novel driver of Wnt/β-catenin signaling. miR-181ahigh primary HGSOC cells exhibited increased Wnt/β-catenin signaling, which was associated with increased stem-cell frequency and platinum resistance. Consistent with these findings, inhibition of β-catenin decreased stem-like properties in miR-181ahigh cell populations and downregulated miR-181a. The Wnt inhibitor SFRP4 was identified as a novel target of miR-181a. Overall, our results demonstrate that miR-181a is a nonmutational activator of Wnt signaling that drives stemness and chemoresistance in HGSOC, suggesting that the miR–181a–SFRP4 axis can be evaluated as a novel biomarker for β-catenin–targeted therapy in this disease. Significance: These results demonstrate that miR-181a is an activator of Wnt signaling that drives stemness and chemoresistance in HGSOC and may be targeted therapeutically in recurrent disease.
Take it to the resident: A model for engaging long-term stay residents in advance care planning

ABSTRACT Advance care planning involves a meaningful conversation about residents’ end of life goals with the health-care team and documenting these wishes in advance directives; however, these conversations are not taking place early enough or with strategies that allow nursing home residents’ preferences to be meaningfully integrated into care plans. This article outlines a new model that nursing home social workers can use to initiate advance care planning discussions called Take it to the Resident. This model was tested with 11 long-term stay nursing home residents. Data were collected through structured memos and field notes. Summative content analysis was utilized to analyze the data. Take it to the Resident facilitated a discussion about advance care planning and allowed residents to consider their wishes before engaging family members. Although discussions took place, some residents were hesitant to document their wishes formally through advance directives. The results of this study support the utility of continued testing of this model. Having empirically supported tools for nursing home social workers is critical to increasing advance care planning conversations and empowering residents to document their wishes.
Optimal Flow—A Pilot Study Balancing Sheep Movement and Welfare in Abattoirs

Simple Summary Sheep in Australia are transported to abattoirs for slaughter by trucks and usually left in lairage (holding pens) overnight. They are then moved through the abattoir via a series of pens that ultimately leads to a single file race immediately before slaughter. This movement has the potential to induce considerable stress among the sheep, thus compromising welfare. This study introduces the concept of ‘Optimal Flow’, where sheep movement through the abattoir is the most efficient balance between speed and minimising overt signs of distress in sheep. The results of the pilot study suggest that Optimal Flow at this abattoir occurs when sheep are given enough space to move freely. Abstract Abattoirs are faced with the challenge of moving livestock efficiently through the plant, while also engaging in handling practices that assure good animal welfare. Achieving optimal outcomes for both of these goals can bring them into conflict. An additional source of conflict can arise from the design of the abattoir. These problems are compounded by the dearth of research available to inform how livestock should be handled to achieve all of these goals. We applied the concept of ‘Optimal Flow’ to describe conditions under which rate of movement is maximised while overt signs of distress in sheep are minimised. Effectively, this represents the point at which trade-offs between speed and welfare converge. The current pilot study examined the behavioural interactions between humans (n = 5), livestock herding dogs (n = 7), and sheep (n = 3235) in a large Australian abattoir to describe the factors associated with an increase or decrease in rate of sheep movement per minute. It revealed that distress behaviours in sheep were associated with dog presence and with a decrease in livestock movement rate. However, we found that as sheep density increased, there was increased livestock movement rate as well as an elevated incidence of distress behaviours. Optimal Flow at this abattoir was achieved by maintaining sheep at lower densities. Our report discusses the possible confounds in this interpretation.
Calculation of Stopping-Power Ratio from Multiple CT Numbers Using Photon-Counting CT System: Two- and Three-Parameter-Fitting Method

The two-parameter-fitting method (PFM) is commonly used to calculate the stopping-power ratio (SPR). This study proposes a new formalism: a three-PFM, which can be used in multiple spectral computed tomography (CT). Using a photon-counting CT system, seven rod-shaped samples of aluminium, graphite, and poly(methyl methacrylate) (PMMA), and four types of biological phantom materials were placed in a water-filled sample holder. The X-ray tube voltage and current were set at 150 kV and 40 μA respectively, and four CT images were obtained at four threshold settings. A semi-empirical correction method that corrects the difference between the CT values from the photon-counting CT images and theoretical values in each spectral region was also introduced. Both the two- and three-PFMs were used to calculate the effective atomic number and electron density from multiple CT numbers. The mean excitation energy was calculated via parameterisation with the effective atomic number, and the SPR was then calculated from the calculated electron density and mean excitation energy. Then, the SPRs from both methods were compared with the theoretical values. To estimate the noise level of the CT numbers obtained from the photon-counting CT, CT numbers, including noise, were simulated to evaluate the robustness of the aforementioned PFMs. For the aluminium and graphite, the maximum relative errors for the SPRs calculated using the two-PFM and three-PFM were 17.1% and 7.1%, respectively. For the PMMA and biological phantom materials, the maximum relative errors for the SPRs calculated using the two-PFM and three-PFM were 5.5% and 2.0%, respectively. It was concluded that the three-PFM, compared with the two-PFM, can yield SPRs that are closer to the theoretical values and is less affected by noise.
Gold Nanocomposite Contact Lenses for Color Blindness Management

Color vision deficiency (CVD) is an ocular congenital disorder that affects 8% of males and 0.5% of females. The most prevalent form of color vision deficiency (color blindness) affects protans and deutans and is more commonly known as “red–green color blindness”. Since there is no cure for this disorder, CVD patients opt for wearables that aid in enhancing their color perception. The most common wearable used by CVD patients is a form of tinted glass/lens. Those glasses filter out the problematic wavelengths (540–580 nm) for the red–green CVD patients using organic dyes. However, few studies have addressed the fabrication of contact lenses for color vision deficiency, and several problems related to their effectiveness and toxicity were reported. In this study, gold nanoparticles are integrated into contact lens material, thus forming nanocomposite contact lenses targeted for red–green CVD application. Three distinct sets of nanoparticles were characterized and incorporated with the hydrogel material of the lenses (pHEMA), and their resulting optical and material properties were assessed. The transmission spectra of the developed nanocomposite lenses were analogous to those of the commercial CVD wearables, and their water retention and wettability capabilities were superior to those in some of the commercially available contact lenses used for cosmetic/vision correction purposes. Hence, this work demonstrates the potential of gold nanocomposite lenses in CVD management and, more generally, color filtering applications.
Optimizing Dose and Timing in Magnetic Tracer Techniques for Sentinel Lymph Node Detection in Early Breast Cancers: The Prospective Multicenter SentiDose Trial

Simple Summary Superparamagnetic iron oxide (SPIO) nanoparticles have comparable performance to the combination of radioisotope and blue dye (RI + BD) for sentinel lymph node (SLN) biopsy in breast cancer. In this multicenter prospective study, lower SPIO doses (undiluted 1.5 vs. 1.0 mL) in different timeframes (perioperative vs. 1–7 days preoperative) and injection sites (subareolar vs. peritumoral) were compared to the previous standard (diluted 2.0 mL perioperatively) from the earlier Nordic trial. RI + BD were co-administered as background. In total, 534 patients were analyzed. SPIO SLN detection rates were similar (97.5% vs. 100% vs. 97.6%, p = 0.11) and respectively non-inferior to the dual technique. Significantly more SLNs were retrieved in the preoperative 1.0 mL cohort compared with 1.5 mL and the Nordic cohorts (2.18 vs. 1.85 vs. 1.83, p = 0.003). Thus, SPIO at 1.5 and 1.0 mL was non-inferior to both Sienna+® and the dual technique for SLN detection. Abstract Superparamagnetic iron oxide nanoparticles (SPIO) are non-inferior to radioisotope and blue dye (RI + BD) for sentinel lymph node (SLN) detection. Previously, 2 mL SPIO (Sienna+®) in 3 mL NaCl was used. In this dose-optimizing study, lower doses of a new refined SPIO solution (Magtrace®) (1.5 vs. 1.0 mL) were tested in different timeframes (0–24 h perioperative vs. 1–7 days preoperative) and injections sites (subareolar vs. peritumoral). Two consecutive breast cancer cohorts (n = 328) scheduled for SLN-biopsy were included from 2017 to 2019. All patients received isotope ± blue dye as back-up. SLNs were identified primarily with the SentiMag® probe and thereafter a gamma-probe. The primary endpoint was SLN detection rate with SPIO. Analyses were performed as a one-step individual patient-level meta-analysis using patient-level data from the previously published Nordic Trial (n = 206) as a third, reference cohort. In 534 patients, the SPIO SLN detection rates were similar (97.5% vs. 100% vs. 97.6%, p = 0.11) and non-inferior to the dual technique. Significantly more SLNs were retrieved in the preoperative 1.0 mL cohort compared with 1.5 and the 2.0 mL cohorts (2.18 vs. 1.85 vs. 1.83, p = 0.003). Lower SPIO volumes injected up to 7 days before the operation have comparable efficacy to standard SPIO dose and RI + BD for SLN detection.
Ebulin l Is Internalized in Cells by Both Clathrin-Dependent and -Independent Mechanisms and Does Not Require Clathrin or Dynamin for Intoxication

Ebulin l is an A-B toxin, and despite the presence of a B chain, this toxin displays much less toxicity to cells than the potent A-B toxin ricin. Here, we studied the binding, mechanisms of endocytosis, and intracellular pathway followed by ebulin l and compared it with ricin. COS-1 cells and HeLa cells with inducible synthesis of a mutant dynamin (K44A) were used in this study. The transport of these toxins was measured using radioactively or fluorescently labeled toxins. The data show that ebulin l binds to cells to a lesser extent than ricin. Moreover, the expression of mutant dynamin does not affect the endocytosis, degradation, or toxicity of ebulin l. However, the inhibition of clathrin-coated pit formation by acidification of the cytosol reduced ebulin l endocytosis but not toxicity. Remarkably, unlike ricin, ebulin l is not transported through the Golgi apparatus to intoxicate the cells and ebulin l induces apoptosis as the predominant cell death mechanism. Therefore, after binding to cells, ebulin l is taken up by clathrin-dependent and -independent endocytosis into the endosomal/lysosomal system, but there is no apparent role for clathrin and dynamin in productive intracellular routing leading to intoxication.