Miracle-dz/UniFAR-FTUs huggingface dataset:
Nanoscale binding site localization by molecular distance estimation on native cell surfaces using topological image averaging

Antibody binding to cell surface proteins plays a crucial role in immunity, and the location of an epitope can altogether determine the immunological outcome of a host-target interaction. Techniques available today for epitope identification are costly, time-consuming, and unsuited for high-throughput analysis. Fast and efficient screening of epitope location can be useful for the development of therapeutic monoclonal antibodies and vaccines. Cellular morphology typically varies, and antibodies often bind heterogeneously across a cell surface, making traditional particle-averaging strategies challenging for accurate native antibody localization. In the present work, we have developed a method, SiteLoc, for imaging-based molecular localization on cellular surface proteins. Nanometer-scale resolution is achieved through localization in one dimension, namely, the distance from a bound ligand to a reference surface. This is done by using topological image averaging. Our results show that this method is well suited for antibody binding site measurements on native cell surface morphology and that it can be applied to other molecular distance estimations as well.
Effect of paeonol against bacterial growth, biofilm formation and dispersal of Staphylococcus aureus and Listeria monocytogenes in vitro

Abstract Previous studies have demonstrated the antibacterial activity of paeonol against bacterial pathogens, but its anti-biofilm activities against Staphylococcus aureus and Listeria monocytogenes remain largely unexplored. Here, the antibacterial and anti-biofilm activities of paeonol against S. aureus and L. monocytogenes were examined using the crystal violet staining assay (CVSA), field emission scanning electron microscopy (FESEM), and confocal laser scanning microscopy (CLSM) analysis. Paeonol effectively inhibited the growth of S. aureus and L. monocytogenes with a minimum inhibitory concentration (MIC) of 500 and 125 μg ml−1, respectively, and disrupted the integrity of cell membranes. Moreover, sub-MIC paeonol exhibited an inhibitory effect on the attachment of S. aureus and L. monocytogenes to the abiotic surface and biofilm formation. Further, paeonol effectively destroyed cell membranes within biofilms, and dispersed mature biofilms of both strains. The results indicate that paeonol might be a promising antibacterial and anti-biofilm agent for combating infections caused by S. aureus and L. monocytogenes.
A multi center real world observation to evaluate the efficacy of cryotherapy versus local hyperthermia for the treatment of plane warts

Most plane warts are recalcitrant to treatment. Both cryotherapy and local hyperthermia have been applied to treat plane warts. However, no direct comparative study on their respective efficacy and safety has ever been performed. To assess the efficacy and safety of local hyperthermia at 43 ± 1°C versus liquid nitrogen cryotherapy for plane warts. Sequential patients with plane warts entered the study, either receiving cryotherapy or local hyperthermia therapy at the discretion of the patients and the recommendations of consultants. Cryotherapy with liquid nitrogen was delivered in two sessions 2 weeks apart, while local hyperthermia was delivered on three consecutive days, plus two similar treatments 10 ± 3 days later. The temperature over the treated skin surface was set at 43 ± 1°C for 30 min in each session. The primary outcome was the clearance rates of the lesions 6 months after treatment. Among the 194 participants enrolled, 183 were included in the analysis at 6 months. Local hyperthermia and cryotherapy achieved clearance rates of 35.56% (48/135) and 31.25% (15/48), respectively (p = 0.724); recurrence rates of 16.67% (8/48) and 53.33% (8/15) (p = 0.01); and adverse events rates of 20.74% (28/135) and 83.33% (40/48), respectively (p < 0.001). Cryotherapy had a higher pain score (p < 0.001) and a longer healing time (p < 0.001). Local hyperthermia at 43°C and cryotherapy had similar efficacy for plane warts. Local hyperthermia had a safer profile than cryotherapy but it required more treatment visits during a treatment course. More patients preferred local hyperthermia due to its treatment friendly nature.
Case Report of Small Cell Carcinoma of the Ovary, Hypercalcemic Type (Ovarian Rhabdoid Tumor) with SMARCB1 Mutation: A Literature Review of a Rare and Aggressive Condition

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive condition that is associated with the SMARCA4 mutation and has a dismal prognosis. It is generally diagnosed in young women. Here, we report a case of a young woman with SCCOHT harboring a rare molecular finding with a highly aggressive biological behavior. The patient had a somatic SMARCB1 mutation instead of an expected SMARCA4 alteration. Even though the patient was treated with high-dose chemotherapy followed by stem cell transplantation, she evolved with disease progression and died 11 months after her first symptoms appeared. We present a literature review of this rare disease and discuss the findings in the present patient in comparison to expected molecular alterations and options for SCCOHT treatment.
Cervical vestibular evoked myogenic potentials and video head impulse test studies: alternative methods for detecting brainstem involvement in multiple sclerosis

Abstract Background Brainstem involvement (BSI) has been reported as a major predictive factor for future disability in Multiple Sclerosis (MS). Aims/Objectives To evaluate whether Cervical Vestibular Evoked Myogenic Potentials (cVEMPs) and Video Head Impulse Test (vHIT) can be used to detect demyelinating lesions in vestibular pathways in MS. Material and Methods Fifty three people with MS and 40 controls were evaluated with Dizziness Handicap Inventory (DHI), vHIT and cVEMP. Results The median value of DHI in MS group was significantly higher than controls (p<.001). According to vHIT results, while the results of horizontal canal vestibulo-ocular reflex gain in group with brain stem involvement (gBSI (+)) were significantly different from both controls and group without brain stem involvement (gBSI (−)) (p= .036 and .024, respectively), results of gBSI (−) were similar with controls (p= .858). When cVEMP results were examined, mean P1 wave latency in gBSI (+) was significantly longer than controls (p= .002), but difference between gBSI (−) and controls and gBSI (+) was not statistically significant (p= .104 and .279, respectively). Conclusions and Significance vHIT and cVEMP can be used in diagnosis and follow-up of people with MS without demyelinating brainstem lesions on MRI.
Regulation of influenza A virus infection by Lnc‐PINK1‐2:5

Influenza virus causes approximately 291,000 to 646,000 human deaths worldwide annually. It is also a disease of zoonotic importance, affecting animals such as pigs, horses, and birds. Even though vaccination is being used to prevent influenza virus infection, there are limited options available to treat the disease. Long noncoding RNAs (lncRNAs) are RNA molecules with more than 200 nucleotides that do not translate into proteins. They play important roles in the physiological and pathological processes. In this study, we identified a novel transcript, Lnc‐PINK1‐2:5 that was upregulated by influenza virus. This lncRNA was predominantly located in the nucleus and was not affected by type I interferons. Overexpression of Lnc‐PINK1‐2:5 reduced the influenza viral mRNA and protein levels in cells as well as titres in culture media. Knockdown of Lnc‐PINK1‐2:5 using CRISPR interference enhanced the virus replication. Antiviral activity of Lnc‐PINK1‐2:5 was independent of influenza virus strains. RNA sequencing analysis revealed that Lnc‐PINK1‐2:5 upregulated thioredoxin interacting protein (TXNIP) during influenza virus infection. Overexpression of TXNIP reduced influenza virus infection, suggesting that TXNIP is an antiviral gene. Knockdown of TXNIP abolished the Lnc‐PINK1‐2:5‐mediated increase in influenza virus infection. In conclusion, the newly identified Lnc‐PINK1‐2:5 isoform is an anti‐influenza lncRNA acting through the upregulation of TXNIP gene expression.
Disentangled Representation Learning for Recommendation

There exist complex interactions among a large number of latent factors behind the decision making processes of different individuals, which drive the various user behavior patterns in recommender systems. These factors hidden in those diverse behaviors demonstrate highly entangled patterns, covering from high-level user intentions to low-level individual preferences. Uncovering the disentanglement of these latent factors can benefit in enhanced robustness, interpretability, and controllability during representation learning for recommendation. However, the large degree of entanglement within latent factors poses great challenges for learning representations that disentangle them, and remains largely unexplored. In this paper, we present the SEMantic MACRo-mIcro Disentangled Variational Auto-Encoder (SEM-MacridVAE) model for learning disentangled representations from user behaviors, taking item semantic information into account. Our SEM-MacridVAE model achieves macro disentanglement by inferring the high-level concepts associated with user intentions through a prototype routing mechanism, and guarantees the micro disentanglement through a micro-disentanglement regularizer stemming from an information-theoretic interpretation of VAEs, which forces each dimension of the representations to independently reflect an isolated low-level factor. The semantic information extracted from candidate items is utilized to further boost the recommendation performances. Empirical experiments demonstrate that our proposed approach is able to achieve significant improvement over the state-of-the-art baselines.
A Systematic Review of the Sport Psychology Mixed Martial Arts Literature: Replication and Extension

MMA is a global sport with a growing body of psychological literature. Our main objective was to replicate and extend a past review concerning the sport psychology literature with MMA participants. We conducted our electronic search in EBSCO with the following databases: SPORTDiscus, PsycINFO, ERIC, and Psychology and Behavioral Sciences Collection. Our eligibility criteria were research articles (a) found in academic journals, (b) with MMA participants, and (c) at least one topic found in sport psychology literature. After conducting a PRISMA-guided search, 16 studies met our inclusion criteria. The studies spanned from 2011 to 2021, with 795 MMA participants from the USA (n = 7), Brazil (n = 4), and one study each from Czechia, Poland, Spain, Sweden, and the United Kingdom. From studies reporting mean ages, MMA participants were in their mid-20s (M = 26.55 ± 2.38 years of age). The results section includes risk of bias ratings across five areas (i.e., subject selection, sample’s MMA background, participant anonymity, data collection procedures, and questionnaire or qualitative theme reporting). More risk of bias concerns resulted with the quantitative than qualitative articles. To best represent the studies, we presented separate results tables with many specifics for both the quantitative (i.e., topic, main analysis, time frame, summary of results, and meaningfulness) and qualitative studies (topic, main analysis, time frame, and main themes). The included studies covered a variety of historic and meta-analyzed topics such as confidence, mood, motivations, and social facilitation. Based on our review, we discussed the literature strengths and limitations, and suggested future research directions. Last, we provided practical points for both MMA participants and their trainers.
Population genetics and microevolution of clinical Candida glabrata reveals recombinant sequence types and hyper-variation within mitochondrial genomes, virulence genes, and drug targets

Abstract Candida glabrata is the second most common etiological cause of worldwide systemic candidiasis in adult patients. Genome analysis of 68 isolates from 8 hospitals across Scotland, together with 83 global isolates, revealed insights into the population genetics and evolution of C. glabrata. Clinical isolates of C. glabrata from across Scotland are highly genetically diverse, including at least 19 separate sequence types that have been recovered previously in globally diverse locations, and 1 newly discovered sequence type. Several sequence types had evidence for ancestral recombination, suggesting transmission between distinct geographical regions has coincided with genetic exchange arising in new clades. Three isolates were missing MATα1, potentially representing a second mating type. Signatures of positive selection were identified in every sequence type including enrichment for epithelial adhesins thought to facilitate fungal adhesin to human epithelial cells. In patent microevolution was identified from 7 sets of recurrent cases of candidiasis, revealing an enrichment for nonsynonymous and frameshift indels in cell surface proteins. Microevolution within patients also affected epithelial adhesins genes, and several genes involved in drug resistance including the ergosterol synthesis gene ERG4 and the echinocandin target FKS1/2, the latter coinciding with a marked drop in fluconazole minimum inhibitory concentration. In addition to nuclear genome diversity, the C. glabrata mitochondrial genome was particularly diverse, with reduced conserved sequence and conserved protein-encoding genes in all nonreference ST15 isolates. Together, this study highlights the genetic diversity within the C. glabrata population that may impact virulence and drug resistance, and 2 major mechanisms generating this diversity: microevolution and genetic exchange/recombination.
Analysis of eGFR index category and annual eGFR slope association with adverse clinical outcomes using real-world Japanese data: a retrospective database study

Objectives Real-world clinical outcome data of patients with an above-normal estimated glomerular filtration rate (eGFR) and increasing eGFR over time (eGFR slope) are scarce. Although eGFR is commonly recorded, eGFR slopes are rarely used for adverse outcome risk categorisation in clinical practice. We investigated the association of above-normal/below-normal eGFR ranges and increasing/declining eGFR slopes with clinical outcomes in Japan. Design Observational cohort study. Setting Primary and acute care hospitals; 423 centres. Participants 57 452 patients aged ≥16 years with ≥3 eGFR values (latest available January 2013–December 2016) from the Japanese Medical Data Vision database were stratified into six index eGFR and six eGFR slope groups (slopes calculated using a linear mixed model). Primary and secondary outcome measures Time-to-event analyses of cardiovascular mortality, all-cause mortality (ACM), all-cause hospitalisation (ACH) and cardiovascular and major kidney events. eGFR and slope groups were analysed by Cox proportional hazard models with multivariable adjustment, using normal eGFR/little-to-no slope groups as reference. Results Higher risk of clinical outcomes was observed with declining eGFR slope groups versus the reference group; the HR (95% CI) for slope ≤−5 mL/min/1.73 m2/year: cardiovascular events 1.8 (1.4 to 2.2), ACH 1.8 (1.5 to 2.1), and ACM 2.8 (1.9 to 4.2) and was non-significant for kidney events 1.5 (0.9 to 2.5). A similar, but non-significant, pattern was observed with increasing slope groups (slope >3 mL/min/1.73 m2/year HR (95% CI): cardiovascular events 1.2 (0.9 to 1.5), ACH 1.1 (0.9 to 1.4) and ACM 1.5 (0.9 to 2.3)). Above-normal and below-normal eGFR groups were associated with poorer outcomes versus the reference group, but kidney events were associated with below-normal eGFR only. Conclusion Poorer clinical outcomes were observed not only for below-normal eGFR and declining eGFR slope groups but also for certain above-normal eGFR and increasing slope groups. eGFR and eGFR slope may, therefore, be useful for identifying patients at high risk of adverse clinical outcomes.
Special Section on Pharmacokinetics and ADME of Biological Therapeutics – Minireview Mathematical Models to Characterize the Absorption, Distribution, Metabolism, and Excretion of Protein Therapeutics

Therapeutic proteins (TPs) have ranked among the most important and fastest-growing classes of drugs in the clinic, yet the development of successful TPs is often limited by unsatisfactory efficacy. Understanding pharmacokinetic (PK) characteristics of TPs is key to achieving sufficient and prolonged exposure at the site of action, which is a prerequisite for eliciting desired pharmacological effects. PK modeling represents a powerful tool to investigate factors governing in vivo disposition of TPs. In this mini-review, we discuss many state-of-the-art models that recapitulate critical processes in each of the absorption, distribution, metabolism/catabo-lism, and excretion pathways of TPs, which can be integrated into the physiologically-based pharmacokinetic framework. Addition-ally, we provide our perspectives on current opportunities and challenges for evolving the PK models to accelerate the discovery and development of safe and efficacious TPs. This minireview provides an overview of mechanistic pharmacokinetic (PK) models developed to characterize absorption, distribution, metabolism, and elimination (ADME) properties of therapeutic proteins (TPs), which can support model-informed discovery and development of TPs. As the next-generation of TPs with diverse physicochemical properties and mechanism-of-action are being developed rapidly, there is an urgent need to better understand the determinants for the ADME of TPs and evolveexistingplatformPKmodelstofacilitatesuccessfulbench-to-bed-sidetranslationofthesepromisingdrugmolecules.
Digitally Supported Lifestyle Intervention to Prevent Type 2 Diabetes Through Healthy Habits: Secondary Analysis of Long-Term User Engagement Trajectories in a Randomized Controlled Trial

Background Digital health interventions may offer a scalable way to prevent type 2 diabetes (T2D) with minimal burden on health care systems by providing early support for healthy behaviors among adults at increased risk for T2D. However, ensuring continued engagement with digital solutions is a challenge impacting the expected effectiveness. Objective We aimed to investigate the longitudinal usage patterns of a digital healthy habit formation intervention, BitHabit, and the associations with changes in T2D risk factors. Methods This is a secondary analysis of the StopDia (Stop Diabetes) study, an unblinded parallel 1-year randomized controlled trial evaluating the effectiveness of the BitHabit app alone or together with face-to-face group coaching in comparison with routine care in Finland in 2017-2019 among community-dwelling adults (aged 18 to 74 years) at an increased risk of T2D. We used longitudinal data on usage from 1926 participants randomized to the digital intervention arms. Latent class growth models were applied to identify user engagement trajectories with the app during the study. Predictors for trajectory membership were examined with multinomial logistic regression models. Analysis of covariance was used to investigate the association between trajectories and 12-month changes in T2D risk factors. Results More than half (1022/1926, 53.1%) of the participants continued to use the app throughout the 12-month intervention. The following 4 user engagement trajectories were identified: terminated usage (904/1926, 46.9%), weekly usage (731/1926, 38.0%), twice weekly usage (208/1926, 10.8%), and daily usage (83/1926, 4.3%). Active app use during the first month, higher net promoter score after the first 1 to 2 months of use, older age, and better quality of diet at baseline increased the odds of belonging to the continued usage trajectories. Compared with other trajectories, daily usage was associated with a higher increase in diet quality and a more pronounced decrease in BMI and waist circumference at 12 months. Conclusions Distinct long-term usage trajectories of the BitHabit app were identified, and individual predictors for belonging to different trajectory groups were found. These findings highlight the need for being able to identify individuals likely to disengage from interventions early on, and could be used to inform the development of future adaptive interventions. Trial Registration ClinicalTrials.gov NCT03156478; https://clinicaltrials.gov/ct2/show/NCT03156478 International Registered Report Identifier (IRRID) RR2-10.1186/s12889-019-6574-y
Association of Clonal Hematopoiesis of Indeterminate Potential with Worse Kidney Function and Anemia in Two Cohorts of Patients with Advanced Chronic Kidney Disease

Significance Statement Clonal hematopoiesis of indeterminate potential (CHIP), a premalignant expansion of clonal leukocytes caused by acquired somatic mutations in myeloid stem/progenitor cells, occurs in 10%–15% of the general population aged 65 years or older. This proinflammatory condition appears causally associated with cardiovascular disease and death. The authors found that 43 of 172 (25%) individuals with advanced CKD had CHIP. Those with CHIP had a 2.2-fold greater risk of kidney failure over 5 years of follow-up and were more likely to have complications of CKD (including anemia) compared with those without CHIP. More research, including studies in animal models, is needed to understand the relationship between CHIP and CKD. CHIP-related inflammation might offer a novel therapeutic target for those with CHIP and CKD. Visual Abstract Background Clonal hematopoiesis of indeterminate potential (CHIP) is an inflammatory premalignant disorder resulting from acquired genetic mutations in hematopoietic stem cells. This condition is common in aging populations and associated with cardiovascular morbidity and overall mortality, but its role in CKD is unknown. Methods We performed targeted sequencing to detect CHIP mutations in two independent cohorts of 87 and 85 adults with an eGFR<60 ml/min per 1.73m2. We also assessed kidney function, hematologic, and mineral bone disease parameters cross-sectionally at baseline, and collected creatinine measurements over the following 5-year period. Results At baseline, CHIP was detected in 18 of 87 (21%) and 25 of 85 (29%) cohort participants. Participants with CHIP were at higher risk of kidney failure, as predicted by the Kidney Failure Risk Equation (KFRE), compared with those without CHIP. Individuals with CHIP manifested a 2.2-fold increased risk of a 50% decline in eGFR or ESKD over 5 years of follow-up (hazard ratio 2.2; 95% confidence interval, 1.2 to 3.8) in a Cox proportional hazard model adjusted for age, sex, and baseline eGFR. The addition of CHIP to 2-year and 5-year calibrated KFRE risk models improved ESKD predictions. Those with CHIP also had lower hemoglobin, higher ferritin, and higher red blood cell mean corpuscular volume versus those without CHIP. Conclusions In this exploratory analysis of individuals with preexisting CKD, CHIP was associated with higher baseline KFRE scores, greater progression of CKD, and anemia. Further research is needed to define the nature of the relationship between CHIP and kidney disease progression.