Miracle-dz/UniFAR-FTUs huggingface dataset:
Shambhala‐2: A Protocol for Uniformly Shaped Harmonization of Gene Expression Profiles of Various Formats

Uniformly shaped harmonization of gene expression profiles is central for the simultaneous comparison of multiple gene expression datasets. It is expected to operate with the gene expression data obtained using various experimental methods and equipment, and to return harmonized profiles in a uniform shape. Such uniformly shaped expression profiles from different initial datasets can be further compared directly. However, current harmonization techniques have strong limitations that prevent their broad use for bioinformatic applications. They can either operate with only up to two datasets/platforms or return data in a dynamic format that will be different for every comparison under analysis. This also does not allow for adding new data to the previously harmonized dataset(s), which complicates the analysis and increases calculation costs. We propose here a new method termed Shambhala‐2 that can transform multi‐platform expression data into a universal format that is identical for all harmonizations made using this technique. Shambhala‐2 is based on sample‐by‐sample cubic conversion of the initial expression dataset into a preselected shape of the reference definitive dataset. Using 8390 samples of 12 healthy human tissue types and 4086 samples of colorectal, kidney, and lung cancer tissues, we verified Shambhala‐2's capacity in restoring tissue‐specific expression patterns for seven microarray and three RNA sequencing platforms. Shambhala‐2 performed well for all tested combinations of RNAseq and microarray profiles, and retained gene‐expression ranks, as evidenced by high correlations between different single‐ or aggregated gene expression metrics in pre‐ and post‐Shambhalized samples, including preserving cancer‐specific gene expression and pathway activation features. © 2022 Wiley Periodicals LLC.
The acceptance of a prototype rear-view assistant for older cyclists: Two modalities of warnings compared

The aim of this study was to evaluate the effects on behaviour, mental effort and acceptance of a simple prototype of an electronic rear-view assistance system designed for older cyclists that are at risk of falls. The prototype was incorporated into a simple cycling simulator and provided information about traffic from behind in two modalities: visual and haptic. Twenty-one older participants (>64 years) completed three conditions: warnings in two modalities and a control condition without warnings. Mental effort and acceptance were assessed using subjective rating scales and by monitoring changes in cycling speed. Less mental effort was reported when using the rear-view assistant. Significantly more correct decisions regarding a safe left turn were made with system advice. No significant speed differences were found between the two modality conditions. It is concluded that the electronic rear-view assistance system can potentially support the older cyclist successfully by warning for traffic coming from behind.
Health Risk Assessment of Ortho-Toluidine Utilising Human Biomonitoring Data of Workers and the General Population

The aim of this work was to demonstrate how human biomonitoring (HBM) data can be used to assess cancer risks for workers and the general population. Ortho-toluidine, OT (CAS 95-53-4) is an aniline derivative which is an animal and human carcinogen and may cause methemoglobinemia. OT is used as a curing agent in epoxy resins and as intermediate in producing herbicides, dyes, and rubber chemicals. A risk assessment was performed for OT by using existing HBM studies. The urinary mass-balance methodology and generic exposure reconstruction PBPK modelling were both used for the estimation of the external intake levels corresponding to observed urinary levels. The external exposures were subsequently compared to cancer risk levels obtained from the evaluation by the Scientific Committee on Occupational Exposure Limits (SCOEL). It was estimated that workers exposed to OT have a cancer risk of 60 to 90:106 in the worst-case scenario (0.9 mg/L in urine). The exposure levels and cancer risk of OT in the general population were orders of magnitude lower when compared to workers. The difference between the output of urinary mass-balance method and the general PBPK model was approximately 30%. The external exposure levels calculated based on HBM data were below the binding occupational exposure level (0.5 mg/m3) set under the EU Carcinogens and Mutagens Directive.
Melatonin and andrographolide synergize to inhibit the colospheroid phenotype by targeting Wnt/beta‐catenin signaling

β‐catenin signaling, and angiogenesis are associated with colospheroid (CSC), development. CSCs, spheroids derived from colon cancer cells, are responsible for metastasis, drug resistance, and disease recurrence. Whether dysregulating β‐catenin and inhibiting angiogenesis reduce CSC growth is unknown. In this study, the molecular mechanism of CSC growth inhibition was evaluated using a novel combination of melatonin (MLT) and andrographolide (AGP). These drugs have anticarcinogenic, antioxidant, and antimetastatic properties. CSCs were obtained from two metastatic colon cancer cell lines (HT29 and HCT‐15). The viability and stemness were monitored (FDA propidium iodide staining and immunoblot for CD44, CD133, Nanog, Sox2, and Oct4). The drug combination synergistically diminished stemness via increased reactive oxygen species (ROS) levels, reduced mitochondrial membrane potential and ATP level. MLT + AGP induced cell death by inhibiting β‐catenin expression and its downregulatory signals, Cyclin D1, c‐Myc. MLT + AGP treated cells exhibited translocation of phospho‐β‐catenin to the nucleus and dephosphorylated‐β‐catenin. Downregulation of β‐catenin activation and its transcription factors (TCF4 and LEF1) and GTP binding/G‐protein related activity were found in the dual therapy. Angiogenic inhibition is consistent with downregulation of VEGF messenger RNA transcripts (VEGF189), phosphorylated VEGF receptor protein expression, matrigel invasion, and capillary tube inhibition. In vivo, the intravenous injection of MLT + AGP slowed HT29 metastatic colon cancer. Histopathology indicated significant reduction in microvascular density and tumor index. Immunohistochemistry for caspase 7, and β‐catenin found increased apoptosis and downregulation of β‐catenin signals. The mechanism(s) of decreased colospheroids growth were the inhibition of the Wnt/β‐catenin pathway. Our results provide a rationale for using MLT in combination with AGP for the inhibition of CRCs.
Nicotine‐conditioned place preference, reversal learning and social interaction in MK‐801‐induced schizophrenia model: Effects of post‐weaning enriched environment

Based on the clinical observations of severe cognitive deficits in schizophrenia patients and the relationship between environmental parameters and the severity of schizophrenia symptoms, the present study investigated these parameters in an dizocilpine (MK‐801)‐induced schizophrenia model in rats. In addition to, it evaluated whether a post‐weaning enriched environment (EE) would affect the nicotine‐induced conditioned place preference (CPP) and the motor and cognitive deficits caused by MK‐801 treatment. Male Wistar rat pups were injected peritoneally with MK‐801 (1 mg/kg) on a daily basis between the 6th and the 10th postnatal days (P) and were exposed to either an enriched or a standard cage from P21 until the end of the experiments. The rats were evaluated in open‐field and three‐chamber social interaction tests. Moreover, spatial and reversal learning was assessed by the Morris water maze (MWM). The animals were conditioned with 0.6 mg/kg nicotine and tested for CPP. Increased self‐grooming, exploratory behaviour, potentiated nicotine‐CPP and decreased social behaviours, delayed spatial learning and memory and impaired reversal learning in the water maze were observed in the MK‐801 treatment group. Housing in an EE improved cognitive and behavioural deficits associated with postnatal MK‐801 treatment. The results suggested that neonatal N‐methyl‐d‐aspartate (NMDA) receptor hypofunction may cause susceptibility to these behaviours and indicated the importance of environmental conditions in the development of schizophrenia and probably other neuropsychiatric disorders.
Tight junctions: from molecules to gastrointestinal diseases

ABSTRACT Intestinal epithelium functions as a tissue barrier to prevent interaction between the internal compartment and the external milieu. Intestinal barrier function also determines epithelial polarity for the absorption of nutrients and the secretion of waste products. These vital functions require strong integrity of tight junction proteins. In fact, intestinal tight junctions that seal the paracellular space can restrict mucosal-to-serosal transport of hostile luminal contents. Tight junctions can form both an absolute barrier and a paracellular ion channel. Although defective tight junctions potentially lead to compromised intestinal barrier and the development and progression of gastrointestinal (GI) diseases, no FDA-approved therapies that recover the epithelial tight junction barrier are currently available in clinical practice. Here, we discuss the impacts and regulatory mechanisms of tight junction disruption in the gut and related diseases. We also provide an overview of potential therapeutic targets to restore the epithelial tight junction barrier in the GI tract.
Comparative miRNA transcriptomics of macaques and mice reveals MYOC is an inhibitor for Cryptococcus neoformans invasion into the brain

ABSTRACT Cryptococcal meningoencephalitis (CM) is emerging as an infection in HIV/AIDS patients shifted from primarily ARTnaive to ART-experienced individuals, as well as patients with COVID-19 and immunocompetent hosts. This fungal infection is mainly caused by the opportunistic human pathogen Cryptococcus neoformans. Brain or central nervous system (CNS) dissemination is the deadliest process for this disease; however, mechanisms underlying this process have yet to be elucidated. Moreover, illustrations of clinically relevant responses in cryptococcosis are currently limited due to the low availability of clinical samples. In this study, to explore the clinically relevant responses during C. neoformans infection, macaque and mouse infection models were employed and miRNA-mRNA transcriptomes were performed and combined, which revealed cytoskeleton, a major feature of HIV/AIDS patients, was a centric pathway regulated in both infection models. Notably, assays of clinical immune cells confirmed an enhanced macrophage “Trojan Horse” in patients with HIV/AIDS, which could be shut down by cytoskeleton inhibitors. Furthermore, myocilin, encoded by MYOC, was found to be a novel enhancer for the macrophage “Trojan Horse,” and an enhanced fungal burden was achieved in the brains of MYOC-transgenic mice. Taken together, the findings from this study reveal fundamental roles of the cytoskeleton and MYOC in fungal CNS dissemination, which not only helps to understand the high prevalence of CM in HIV/AIDS but also facilitates the development of novel therapeutics for meningoencephalitis caused by C. neoformans and other pathogenic microorganisms.
Sex differences in psychosocial and demographic factors associated with sustained HIV viral suppression in the Miami-Dade County Ryan White Program, 2017

ABSTRACT This exploratory study examined sex differences in psychosocial and demographic factors associated with sustained HIV viral suppression (SVS). The study population included 6,489 Miami-Dade Ryan White Program (RWP) clients receiving services during 2017; administrative data was analyzed. SVS was defined as having all viral load tests during 2017 below 200 copies/ml. Multilevel logistic regression models accounted for clustering by medical case management site. Models were stratified by sex. Overall, a higher proportion of females did not achieve SVS (23.5%) than males (18.1%). For females (n = 1,503), having acquired HIV perinatally and not having a partner oradult household member were associated with not achieving SVS. For males (n = 4,986), lacking access to food, Black or Haitian race/ethnicity, problematic substance use, and unknown physician were associated with not achieving SVS. For both sexes, younger age, lower household income, ever having an AIDS diagnosis, feeling depressed or anxious, and experiencing homelessness were associated with not achieving SVS. Elements of the transition from adolescent to adult HIV care that may differentially impact female clients and factors associated with disclosure should be explored further. Male clients may require additional support for food security. Improving culturally specific care for Haitian and non-Hispanic Black male clients should also be explored.
Allergen immunotherapy effectively reduces the risk of exacerbations and lower respiratory tract infections in both seasonal and perennial allergic asthma: a nationwide epidemiological study

Background Allergic asthma is associated with increased risk of respiratory tract infections and exacerbations. It remains unclear whether this susceptibility is conditioned by seasonal or by perennial allergy. Aim To investigate perennial allergy compared with seasonal allergy as a risk factor for lower respiratory tract infections and exacerbations in asthma and whether this risk can be reduced by allergen immunotherapy (AIT). Methodology This is a prospective register-based nationwide study of 18–44-year-olds treated with AIT during 1995–2014. Based on the type of AIT and use of anti-asthmatic drugs, patients were subdivided into two groups: perennial allergic asthma (PAA) versus seasonal allergic asthma (SAA). Data on antibiotics against lower respiratory tract infections (LRTI) and oral corticosteroids for exacerbations were analysed before starting AIT (baseline) and 3 years after completing AIT (follow-up). Results We identified 2688 patients with asthma treated with AIT, of whom 1249 had PAA and 1439 had SAA. At baseline, patients with SAA had more exacerbations (23.8% versus 16.5%, p≤0.001), but there were no differences in LRTI. During the 3-year follow-up, we observed a highly significant reduction of exacerbations with an average decrease of 57% in PAA and 74% in SAA. In addition, we observed a significant reduction of LRTI in both PAA and SAA: 17% and 20% decrease, respectively. Conclusion AIT effectively reduced the risk of exacerbations and lower respiratory tract infections in both seasonal and perennial allergic asthma. Perennial allergy is seemingly not a stronger risk factor for respiratory infections and exacerbations than seasonal allergy. Allergen immunotherapy effectively reduced the risk of lower respiratory tract infections and exacerbations in both seasonal and perennial allergic asthma and is potentially an early intervention strategy https://bit.ly/3sBEd5J
Discovering sparse control strategies in neural activity

Biological circuits such as neural or gene regulation networks use internal states to map sensory input to an adaptive repertoire of behavior. Characterizing this mapping is a major challenge for systems biology. Though experiments that probe internal states are developing rapidly, organismal complexity presents a fundamental obstacle given the many possible ways internal states could map to behavior. Using C. elegans as an example, we propose a protocol for systematic perturbation of neural states that limits experimental complexity and could eventually help characterize collective aspects of the neural-behavioral map. We consider experimentally motivated small perturbations—ones that are most likely to preserve natural dynamics and are closer to internal control mechanisms—to neural states and their impact on collective neural activity. Then, we connect such perturbations to the local information geometry of collective statistics, which can be fully characterized using pairwise perturbations. Applying the protocol to a minimal model of C. elegans neural activity, we find that collective neural statistics are most sensitive to a few principal perturbative modes. Dominant eigenvalues decay initially as a power law, unveiling a hierarchy that arises from variation in individual neural activity and pairwise interactions. Highest-ranking modes tend to be dominated by a few, “pivotal” neurons that account for most of the system’s sensitivity, suggesting a sparse mechanism of collective control.
Progesterone Gel and Placebo Prolonged Pregnancy More Effectively Than Intravenous Tocolysis Alone in Women with Preterm Labor

The aim of this trial was to evaluate the effect of progesterone gel compared to placebo in prolonging pregnancy among women with preterm labor. Methods: A randomized controlled trial in Sweden in 2009–18. Women with early preterm labor were randomized to daily doses of progesterone gel 90 mg (n = 28) or placebo (n = 30) after standard intravenous tocolytics. Women with intravenous tocolytics alone (n = 29) served as controls. Results: The median latency to delivery was 68 (range 28–88) days with progesterone and 72 (range 9–90) days with placebo (p = 0.84), compared to 1 (range 1–2) day in the control group (progesterone and placebo vs. control p < 0.001). The rate of preterm birth before 34 weeks was 32% after progesterone and 37 % after placebo (p = 0.32) compared to 100 % in the control group (p < 0.001, respectively). The composite neonatal morbidity (p = 0.65) and neonatal intensive care unit admission (p = 0.12) were comparable between the progesterone and placebo groups and lower in these groups compared with neonates in the control group (p < 0.001, respectively). Conclusions: Progesterone gel and placebo were equally effective in prolonging pregnancy among women with early preterm labor, and both treatments were more effective than standard intravenous tocolysis alone. We hypothesize that the acidic placebo gel reinforced the biochemical barrier at the uterine cervix, which counteracts ascending pathogen invasion and subsequent inflammation, and thereby prevented preterm labor.
Haemagglutinin substitutions N125D, D127E, D222G and R223Q improve replicative fitness and vaccine effectiveness of an A/H1N1pdm09 live attenuated influenza vaccine virus by enhancing α-2,6 receptor binding

During 2013–14 and 2015–16, A/H1N1pdm09 live attenuated influenza vaccine (LAIV) viruses replicated inefficiently in primary human nasal epithelial cells (hNEC). This led to reduced vaccine effectiveness (VE) in quadrivalent formulations, mediated by inter-strain competition. By mutating the haemagglutinin (HA) protein, we aimed to enhance hNEC replication of a novel A/H1N1pdm09 vaccine strain to overcome competition and improve VE. Combinations of N125D, D127E, D222G and R223Q substitutions were introduced to the HA protein of A/Slovenia/2903/2015 (A/SLOV15). A/SLOV15 S13, containing all four HA substitutions, produced approximately 1000-fold more virus than parental V1 during hNEC infection. Immunogenicity in ferrets was increased by approximately 10-fold, without compromising yield in eggs or antigenic match to wild-type (wt) reference strains. Despite S13 and V1 being antigenically similar, only S13 protected ferrets from wt virus shedding and fever post-challenge. Crucially, these data suggested that enhanced fitness allowed S13 to overcome inter-strain competition in quadrivalent LAIV (QLAIV). This improved efficacy was later validated by real-world VE data. S13 displayed increased binding avidity to a mammalian-like α-2,6 receptor analogue (6-SLN), relative to V1, while maintaining avian-like 3-SLN avidity. In silico modelling of the HA receptor binding site revealed additional interactions in the S13:6-SLN binding network and a mild increase in 6-SLN binding energy, indicating a possible mechanism for increased α-2,6 receptor-binding avidity. These data confirm that rational HA mutagenesis can be used to optimise hNEC replication and VE for A/H1N1pdm09 LAIV viruses.
A broad v. focused digital intervention for recurrent binge eating: a randomized controlled non-inferiority trial

Abstract Background Empirically validated digital interventions for recurrent binge eating typically target numerous hypothesized change mechanisms via the delivery of different modules, skills, and techniques. Emerging evidence suggests that interventions designed to target and isolate one key change mechanism may also produce meaningful change in core symptoms. Although both ‘broad’ and ‘focused’ digital programs have demonstrated efficacy, no study has performed a direct, head-to-head comparison of the two approaches. We addressed this through a randomized non-inferiority trial. Method Participants with recurrent binge eating were randomly assigned to a broad (n = 199) or focused digital intervention (n = 199), or a waitlist (n = 202). The broad program targeted dietary restraint, mood intolerance, and body image disturbances, while the focused program exclusively targeted dietary restraint. Primary outcomes were eating disorder psychopathology and binge eating frequency. Results In intention-to-treat analyses, both intervention groups reported greater improvements in primary and secondary outcomes than the waitlist, which were sustained at an 8-week follow-up. The focused intervention was not inferior to the broad intervention on all but one outcome, but was associated with higher rates of attrition and non-compliance. Conclusion Focused digital interventions that are designed to target one key change mechanism may produce comparable symptom improvements to broader digital interventions, but appear to be associated with lower engagement.
Combined Exposure to Multiple Mycotoxins: An Example of Using a Tiered Approach in a Mixture Risk Assessment

Abstract Humans are exposed to mycotoxins on a regular basis. Exposure to a mixture of mycotoxins may, therefore, result in a combination of adverse effects, or trigger the same effects. This should be accounted for when assessing the combined risk of multiple mycotoxins. Here, we show the outcome of using different approaches in assessing the risks related to the combined exposure to mycotoxins. We performed a tiered approach using assessment groups with a common target organ (kidney, liver and haematologic system), or a common adverse effect (phenomenon) (reduced white blood cell count), to combine the exposure to mycotoxins. The combined exposure was calculated for the individuals in this assessment, using the Monte Carlo Risk Assessment (MCRA) tool. The risk related to this combined exposure was assessed using toxicological reference values, e.g., health based guidance values. We show that estimating the combined risk by adding the single compounds’ risk distributions slightly overestimates the combined risk in the 95th percentile, as compared to combining the exposures at an individual level. We also show that relative potency factors can be used to refine the mixture risk assessment, as compared to ratios of toxicological reference values with different effect sizes and assessment factors.