Miracle-dz/UniFAR-FTUs huggingface dataset:
Bayesian-estimated hierarchical HMMs enable robust analysis of single-molecule kinetic heterogeneity

Single-molecule kinetic experiments allow the reaction trajectories of individual biomolecules to be directly observed, eliminating the effects of population averaging and providing a powerful approach for elucidating the kinetic mechanisms of biomolecular processes. A major challenge to the analysis and interpretation of these experiments, however, is the kinetic heterogeneity that almost universally complicates the recorded single-molecule signal versus time trajectories (i.e., signal trajectories). Such heterogeneity manifests as changes and/or differences in the transition rates that are observed within individual signal trajectories or across a population of signal trajectories. Although characterizing kinetic heterogeneity can provide critical mechanistic information, there are currently no computational methods available that effectively and/or comprehensively enable such analysis. To address this gap, we have developed a computational algorithm and software program, hFRET, that uses the variational approximation for Bayesian inference to estimate the parameters of a hierarchical hidden Markov model, thereby enabling robust identification and characterization of kinetic heterogeneity. Using simulated signal trajectories, we demonstrate the ability of hFRET to accurately and precisely characterize kinetic heterogeneity. In addition, we use hFRET to analyze experimentally recorded signal trajectories reporting on the conformational dynamics of ribosomal pre-translocation (PRE) complexes. The results of our analyses demonstrate that PRE complexes exhibit kinetic heterogeneity, reveal the physical origins of this heterogeneity, and allow us to expand the current model of PRE complex dynamics. The methods described here can be applied to signal trajectories generated using any type of signal and can be easily extended to the analysis of signal trajectories exhibiting more complex kinetic behaviors. Moreover, variations of our approach can be easily developed to integrate kinetic data obtained from different experimental constructs and/or from molecular dynamics simulations of a biomolecule of interest. The hFRET source code, graphical user interface, and user manual can be downloaded as freeware at https://github.com/GonzalezBiophysicsLab/hFRET.
Influence of the Urban Exposome on Birth Weight

Background: The exposome is defined as the totality of environmental exposures from conception onwards. It calls for providing a holistic view of environmental exposures and their effects on human health by evaluating multiple environmental exposures simultaneously during critical periods of life. Objective: We evaluated the association of the urban exposome with birth weight. Methods: We estimated exposure to the urban exposome, including the built environment, air pollution, road traffic noise, meteorology, natural space, and road traffic (corresponding to 24 environmental indicators and 60 exposures) for nearly 32,000 pregnant women from six European birth cohorts. To evaluate associations with either continuous birth weight or term low birth weight (TLBW) risk, we primarily relied on the Deletion-Substitution-Addition (DSA) algorithm, which is an extension of the stepwise variable selection method. Second, we used an exposure-by-exposure exposome-wide association studies (ExWAS) method accounting for multiple hypotheses testing to report associations not adjusted for coexposures. Results: The most consistent statistically significant associations were observed between increasing green space exposure estimated as Normalized Difference Vegetation Index (NDVI) and increased birth weight and decreased TLBW risk. Furthermore, we observed statistically significant associations among presence of public bus line, land use Shannon's Evenness Index, and traffic density and birth weight in our DSA analysis. Conclusion: This investigation is the first large urban exposome study of birth weight that tests many environmental urban exposures. It confirmed previously reported associations for NDVI and generated new hypotheses for a number of built-environment exposures. https://doi.org/10.1289/EHP3971
Relationship between Photosynthetic CO2 Assimilation and Chlorophyll Fluorescence for Winter Wheat under Water Stress

Solar-induced chlorophyll fluorescence (SIF) has a high correlation with Gross Primary Production (GPP). However, studies focusing on the impact of drought on the SIF-GPP relationship have had mixed results at various scales, and the mechanisms controlling the dynamics between photosynthesis and fluorescence emission under water stress are not well understood. We developed a leaf-scale measurement system to perform concurrent measurements of active and passive fluorescence, and gas-exchange rates for winter wheat experiencing a one-month progressive drought. Our results confirmed that: (1) shifts in light energy allocation towards decreasing photochemistry (the quantum yields of photochemical quenching in PSII decreased from 0.42 to 0.21 under intermediate light conditions) and increasing fluorescence emissions (the quantum yields of fluorescence increased to 0.062 from 0.024) as drought progressed enhance the degree of nonlinearity of the SIF-GPP relationship, and (2) SIF alone has a limited capacity to track changes in the photosynthetic status of plants under drought conditions. However, by incorporating the water stress factor into a SIF-based mechanistic photosynthesis model, we show that drought-induced variations in a variety of key photosynthetic parameters, including stomatal conductance and photosynthetic CO2 assimilation, can be accurately estimated using measurements of SIF, photosynthetically active radiation, air temperature, and soil moisture as inputs. Our findings provide the experimental and theoretical foundations necessary for employing SIF mechanistically to estimate plant photosynthetic activity during periods of drought stress.
Single-Cell Lymphocyte Heterogeneity in Advanced Cutaneous T-cell Lymphoma Skin Tumors

Purpose: The heterogeneity of tumor cells presents a major challenge to cancer diagnosis and therapy. Cutaneous T-cell lymphomas (CTCL) are a group of T lymphocyte malignancies that primarily affect skin. Lack of highly specific markers for malignant lymphocytes prevents early diagnosis, while only limited treatment options are available for patients with advanced stage CTCL. Droplet-based single-cell transcriptome analysis of CTCL skin biopsies opens avenues for dissecting patient-specific T lymphocyte heterogeneity, providing a basis for identifying specific markers for diagnosis and cure of CTCL. Experimental Design: Single-cell RNA-sequencing was performed by Droplet-based sequencing (10X Genomics), focusing on 14,056 CD3+ lymphocytes (448 cells from normal and 13,608 cells from CTCL skin samples) from skin biopsies of 5 patients with advanced-stage CTCL and 4 healthy donors. Protein expression of identified genes was validated in advanced stage CTCL skin tumors by immunohistochemistry and confocal immunofluorescence microscopy. Results: Our analysis revealed a large inter- and intratumor gene expression heterogeneity in the T lymphocyte subset, as well as a common gene expression signature in highly proliferating lymphocytes that was validated in multiple advanced-stage skin tumors. In addition, we established the immunologic state of reactive lymphocytes and found heterogeneity in effector and exhaustion programs across patient samples. Conclusions: Single-cell analysis of CTCL skin tumor samples reveals patient-specific landscapes of malignant and reactive lymphocytes within the local microenvironment of each tumor, giving an unprecedented view of lymphocyte heterogeneity and identifying tumor-specific molecular signatures, with important implications for diagnosis and personalized disease treatment.
Examining Arm Vascular Function and Blood Flow Regulation in Row-trained Males.

Vascular function and blood flow responses to upper limb exercise are differentially altered in response to different exercise training modalities. Rowing is a unique exercise modality that incorporates the upper limbs and can significantly augment upper limb endurance, strength, and power capacity. PURPOSE This study sought to determine if vascular function and blood flow regulation during handgrip exercise is altered in row-trained males. METHODS Nine young row-trained males (ROW: 20±1 yrs; VO2peak = 51±2 ml.kg.min) and fourteen recreationally active male controls (C: 22±1 yrs; VO2peak = 37±2 ml.kg.min) were recruited for this study. Subjects performed multiple bouts of progressive rhythmic handgrip exercise. Brachial artery (BA) diameter, blood flow, shear rate, and mean arterial pressure (MAP) were measured at rest and during the last minute of each exercise workload. RESULTS Resting values for BA diameter, blood flow, shear rate, and MAP were not different between groups. During handgrip exercise, the ROW group reported significantly lower BA blood flow [ROW vs C; 4 kg (146±21 vs 243±13); 8 kg (248±29 vs 375±17); 12 kg (352±43 vs 490±22 ml.min)] across all workloads when compared to controls. The examination of BA dilation, when controlled for the shear rate stimulus and evaluated across all workloads, was revealed to be significantly greater in ROW group vs controls. CONCLUSION This study revealed that vascular function and blood flow regulation was significantly different in row-trained males when compared to untrained controls evidenced by greater shear-induced brachial artery dilation and lower arm blood flow during progressive handgrip exercise.
Music Training Positively Influences the Preattentive Perception of Voice Onset Time in Children with Dyslexia: A Longitudinal Study

Previous results showed a positive influence of music training on linguistic abilities at both attentive and preattentive levels. Here, we investigate whether six months of active music training is more efficient than painting training to improve the preattentive processing of phonological parameters based on durations that are often impaired in children with developmental dyslexia (DD). Results were also compared to a control group of Typically Developing (TD) children matched on reading age. We used a Test–Training–Retest procedure and analysed the Mismatch Negativity (MMN) and the N1 and N250 components of the Event-Related Potentials to syllables that differed in Voice Onset Time (VOT), vowel duration, and vowel frequency. Results were clear-cut in showing a normalization of the preattentive processing of VOT in children with DD after music training but not after painting training. They also revealed increased N250 amplitude to duration deviant stimuli in children with DD after music but not painting training, and no training effect on the preattentive processing of frequency. These findings are discussed in view of recent theories of dyslexia pointing to deficits in processing the temporal structure of speech. They clearly encourage the use of active music training for the rehabilitation of children with language impairments.
GIP and GLP-1: Stepsiblings Rather Than Monozygotic Twins Within the Incretin Family

The importance of the incretin effect for the postprandial augmentation of insulin released has long been recognized (1). However, there has been a long-standing controversy as to the relative importance of the various gastrointestinal hormones in mediating this effect. While earlier studies suggested a contribution of gastrin, secretin, and cholecystokinin (2), it later became obvious that in humans, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are the predominant incretin hormones (1). Which of the two incretins is the most relevant one is still a matter of debate. Gasbjerg et al. (3) performed studies in healthy human subjects receiving oral glucose loads of 75 g in the fasting state on four different days. The known incretin hormones, GIP and GLP-1, which are secreted in response to glucose administration/absorption, were antagonized with the established peptide receptor antagonist exendin(9-39), blocking the stimulation of GLP-1 receptors, or with the novel GIP receptor antagonist, GIP(3-30)amide, a naturally occurring fragment of intact GIP (full sequence 1–42), which has recently been characterized as a specific GIP receptor antagonist for use in human studies (4). A similar GIP receptor antagonist, GIP(7-30)amide, had previously been used in animal studies but had not been validated for human experiments (5). These incretin receptor antagonists were compared with placebo and used alone and in combination. The result was a slight rise in postload glucose concentrations and a minor reduction in insulin secretory responses, when the GLP-1 receptor was blocked, and a substantial rise in glycemic excursions after the glucose load and a more pronounced reduction in insulin secretory responses, when the recently validated GIP antagonist GIP(3-30)amide was administered at an approximately 1,000-fold excess (∼60 nmol/L) over endogenous peak GIP concentrations (∼60 pmol/L). The combination of exendin(9-39) and GIP(3-30)amide further raised plasma glucose and reduced insulin secretory responses over and above …
Effect of including n-3/n-6 fatty acid feed sources in diet on fertility and hatchability of broiler breeders and post-hatch performance and carcass parameters of progeny

Objective The present trial was conducted to determine the influence of different dietary fatty acid (omega-3 and omega-6) sources on reproductive performance of female broiler breeders and growth performance and carcass traits of their progeny. Methods Two hundred and twenty, 25 weeks old Ross-308 male (20) and female (200) broiler breeders were used in the experiment for the period of 6 weeks. All birds were randomly divided into four dietary treatments (containing 2% soybean oil, 2% sunflower oil, 2% flaxseed oil, and 2% fish oil) each with five replicates of one male and ten females. Throughout this experiment hatching performance of broiler breeders, progeny growth performance and carcass parameters were recorded. Results The results showed that the inclusion of different fatty acid sources in female broiler breeders diet had no significant effects (p>0.05) on number of fertile eggs, post-hatch mortality, and fertility rate. The soybean oil supplemented group had significantly (p<0.05) higher late embryonic mortality compared to other three treatments. Conclusion It was concluded that inclusion of 2% of different sources of omega-3 and omega-6 fatty acids (especially 2% flax seed oil) in broiler breeders’ diet can reduce late embryonic mortality. The other reproductive characteristics of parents and growth and carcass characteristics of progeny remained unaltered by dietary sources of omega-3 and omega-6 fatty acids.
Reviewers' Comments: Reviewer #1: Remarks to the Author: In their study “Neural Substrates and Dynamics of Galvanic Vestibular Stimulation in the Behaving Primate” Kwan and colleagues investigate single vestibular afferent and eye movement responses to transmastoid galvanic vestibular stimulation (G

Reviewer #1: Remarks to the Author: In their study “Neural Substrates and Dynamics of Galvanic Vestibular Stimulation in the Behaving Primate” Kwan and colleagues investigate single vestibular afferent and eye movement responses to transmastoid galvanic vestibular stimulation (GVS) compared to actual head motion stimulation in three awake-behaving macaque monkeys. Their major findings are that (1) GVS activates both primary vestibular afferents in the semicircular canals and otolith organs, (2) irregular afferents exhibit a higher sensitivity to GVS compared to regular afferents, and response dynamics of vestibular afferents to GVS across different frequencies markedly differ from responses to natural motion stimulation. Experimental procedures are sound and the data analysis appears robust. The findings are important and of broad interest since they reveal in a non-human primate model the neural activation pattern of GVS, a method that has gained increasing interest in probing the human vestibular system in health and disease.
Cardiovascular disease risk factor burden and cognition: Implications of ethnic diversity within the Hispanic Community Health Study/Study of Latinos

Objective Hispanics/Latinos have some of the highest prevalence rates for cardiovascular disease risk factors, but stark differences exist by self-reported background. Cardiovascular disease risk factors negatively impact cognition in Hispanics/Latinos; less is known about these relationships by Hispanic/Latino backgrounds. We investigated cognitive associations with cardiovascular disease risk factor burden in a diverse cohort, the Hispanic Community Health Study/Study of Latinos. Methods Baseline data from this observational study of cardiovascular disease and its antecedents was collected from 2008–2011. We included 7,121 participants 45–74 years old from Central American, Cuban, Dominican, Mexican, Puerto Rican, or South American backgrounds. Dichotomous indicators for hypertension, diabetes, hypercholesterolemia, obesity, and smoking were evaluated and totaled, with participants grouped by lowest (0–2), middle (3) or highest (4–5) burden. Cognitive testing included the Brief Spanish English Verbal Learning Test, letter fluency, and digit symbol substitution. Results In separate fully-adjusted linear regression models, lower fluency and digit symbol substitution performance were restricted to the highest compared to the lowest burden group; whereas the middle burden group displayed impaired memory performance compared to the lowest burden group (p-values≤0.05). Background interacted with burden for learning and memory performance. That is, the association of burden level (i.e., lowest, middle, or highest) with cognitive performance was modified by background (e.g., Mexicans vs Cuban). Conclusions Hispanics/Latinos with higher levels of cardiovascular disease risk factor burden displayed lower levels of cognitive performance, with learning and memory performance modified by background.
Is marijuana identity associated with marijuana use and consequences? An examination of direct and interactive associations

Abstract Background: There is relatively little research examining the relationship between identity and marijuana-related outcomes (e.g., marijuana use and consequences). Identity may both directly help shape marijuana use behaviors and moderate the influence of other risk factors on marijuana outcomes. Objectives: The current study examines the relationship between marijuana identity and marijuana-related outcomes among emerging adults and explores whether identity moderates the relationships between nonidentity correlates (e.g., perceived norms and negative affect) of marijuana-related outcomes. Methods: College students who reported marijuana use in the past 12 months completed measures of marijuana identity, perceived norms, negative affect, frequency of marijuana use, and marijuana consequences. Conclusions/Importance: The results indicated that marijuana identity is associated with marijuana use frequency and moderates the relationship between perceived norms and marijuana consequences. The findings have implications for both identity-based and social norms-based interventions targeting problematic marijuana use among emerging adults.
Celiac Disease Prevalence Is Increased in Primary Sjögren’s Syndrome and Diffuse Systemic Sclerosis: Lessons from a Large Multi-Center Study

Association of celiac disease (CD) with systemic autoimmune diseases (ADs) remains controversial. Awareness of CD in these patients is important to prevent complications, including lymphoproliferative disorders. We evaluated previously diagnosed CD prevalence in systemic lupus erythematosus (SLE), primary Sjögren’s syndrome (pSS) and systemic sclerosis (SSc) patients in comparison to 14,298 matched controls. All patients were screened for subclinical CD. Data from 1458 unselected consecutive SLE (580), pSS (354) and SSc (524) patients were collected. Previously biopsy-proven CD diagnosis and both CD- and AD-specific features were registered. All patients without previous CD were tested for IgA transglutaminase (TG). Anti-endomysium were tested in positive/borderline IgA TG. Duodenal biopsy was performed in IgA TG/endomysium+ to confirm CD. CD prevalence in AD was compared to that observed in 14,298 unselected sex- and age-matched adults who acted as controls. CD was more prevalent in pSS vs controls (6.78% vs 0.64%, p < 0.0001). A trend towards higher prevalence was observed in SLE (1.38%, p = 0.058) and SSc (1.34%, p = 0.096). Higher CD prevalence was observed in diffuse cutaneous SSc (4.5%, p ≤ 0.002 vs controls). Subclinical CD was found in two SLE patients and one pSS patient. CD diagnosis usually preceded that of AD. Primary SS and SSc–CD patients were younger at AD diagnosis in comparison to non-celiac patients. Autoimmune thyroiditis was associated with pSS and CD. CD prevalence is clearly increased in pSS and diffuse SSc in comparison to the general population. The association of CD with diffuse but not limited SSc may suggest different immunopathogenic mechanisms characterizing the two subsets. CD screening may be considered in pSS and diffuse SSc in young patients, particularly at the time of diagnosis.
Does trauma-focused exposure therapy exacerbate symptoms among patients with comorbid PTSD and substance use disorders?

BACKGROUND Although exposure-based therapy is a well-established, effective treatment for post-traumatic stress disorder (PTSD), some practitioners report reluctance to implement it due to concerns that it may exacerbate symptoms of PTSD and commonly comorbid disorders, such as substance use disorders (SUD). AIM This study compared the exacerbation of psychological symptoms among participants with comorbid PTSD and SUD who received either SUD treatment alone or SUD treatment integrated with exposure therapy for PTSD. METHOD Participants (N = 71) were treatment-seeking, military Veterans with comorbid PTSD and SUD who were randomized to 12 individual sessions of either (1) an integrated, exposure-based treatment (Concurrent Treatment of PTSD and Substance Use Disorders using Prolonged Exposure; COPE); or (2) a non-exposure-based, SUD-only treatment (Relapse Prevention; RP). We examined between-group differences in the frequency of statistically reliable exacerbations of PTSD, SUD and depression symptoms experienced during treatment. RESULTS At each of the 12 sessions, symptom exacerbation was minimal and generally equally likely in either treatment group. However, an analysis of treatment completers suggests that RP participants experienced slightly more exacerbations of PTSD symptoms during the course of treatment. CONCLUSIONS This study is the first to investigate symptom exacerbation throughout trauma-focused exposure therapy for individuals with comorbid PTSD and SUD. Results add to a growing literature which suggests that trauma-focused, exposure-based therapy does not increase the risk of symptom exacerbation relative to non-exposure-based therapy.