A Data-Driven Approach to Estimate Human Center of Mass State During Perturbed Locomotion Using Simulated Wearable Sensors.

Center of mass (COM) state, specifically in a local reference frame (i.e., relative to center of pressure), is an important variable for controlling and quantifying bipedal locomotion. However, this metric is not easily attainable in real time during human locomotion experiments. This information could be valuable when controlling wearable robotic exoskeletons, specifically for stability augmentation where knowledge of COM state could enable step placement planners similar to bipedal robots. Here, we explored the ability of simulated wearable sensor-driven models to rapidly estimate COM state during steady state and perturbed walking, spanning delayed estimates (i.e., estimating past state) to anticipated estimates (i.e., estimating future state). We used various simulated inertial measurement unit (IMU) sensor configurations typically found on lower limb exoskeletons and a temporal convolutional network (TCN) model throughout this analysis. We found comparable COM estimation capabilities across hip, knee, and ankle exoskeleton sensor configurations, where device type did not significantly influence error. We also found that anticipating COM state during perturbations induced a significant increase in error proportional to anticipation time. Delaying COM state estimates significantly increased accuracy for velocity estimates but not position estimates. All tested conditions resulted in models with R2 > 0.85, with a majority resulting in R2 > 0.95, emphasizing the viability of this approach. Broadly, this preliminary work using simulated IMUs supports the efficacy of wearable sensor-driven deep learning approaches to provide real-time COM state estimates for lower limb exoskeleton control or other wearable sensor-based applications, such as mobile data collection or use in real-time biofeedback.

Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders on a disease spectrum that are characterized by the cytoplasmic mislocalization and aberrant phase transitions of prion-like RNA-binding proteins (RBPs). The common accumulation of TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), and other nuclear RBPs in detergent-insoluble aggregates in the cytoplasm of degenerating neurons in ALS/FTD is connected to nuclear pore dysfunction and other defects in the nucleocytoplasmic transport machinery. Recent advances suggest that beyond their canonical role in the nuclear import of protein cargoes, nuclear-import receptors (NIRs) can prevent and reverse aberrant phase transitions of TDP-43, FUS, and related prion-like RBPs and restore their nuclear localization and function. Here, we showcase the NIR family and how they recognize cargo, drive nuclear import, and chaperone prion-like RBPs linked to ALS/FTD. We also discuss the promise of enhancing NIR levels and developing potentiated NIR variants as therapeutic strategies for ALS/FTD and related neurodegenerative proteinopathies.

Perturbational phenotyping of human blood cells reveals genetically determined latent traits associated with subsets of common diseases.

Although genome-wide association studies (GWAS) have successfully linked genetic risk loci to various disorders, identifying underlying cellular biological mechanisms remains challenging due to the complex nature of common diseases. We established a framework using human peripheral blood cells, physical, chemical and pharmacological perturbations, and flow cytometry-based functional readouts to reveal latent cellular processes and performed GWAS based on these evoked traits in up to 2,600 individuals. We identified 119 genomic loci implicating 96 genes associated with these cellular responses and discovered associations between evoked blood phenotypes and subsets of common diseases. We found a population of pro-inflammatory anti-apoptotic neutrophils prevalent in individuals with specific subsets of cardiometabolic disease. Multigenic models based on this trait predicted the risk of developing chronic kidney disease in type 2 diabetes patients. By expanding the phenotypic space for human genetic studies, we could identify variants associated with large effect response differences, stratify patients and efficiently characterize the underlying biology.

Transcriptomics and chromatin accessibility in multiple African population samples.

Mapping the functional human genome and impact of genetic variants is often limited to European-descendent population samples. To aid in overcoming this limitation, we measured gene expression using RNA sequencing in lymphoblastoid cell lines (LCLs) from 599 individuals from six African populations to identify novel transcripts including those not represented in the hg38 reference genome. We used whole genomes from the 1000 Genomes Project and 164 Maasai individuals to identify 8,881 expression and 6,949 splicing quantitative trait loci (eQTLs/sQTLs), and 2,611 structural variants associated with gene expression (SV-eQTLs). We further profiled chromatin accessibility using ATAC-Seq in a subset of 100 representative individuals, to identity chromatin accessibility quantitative trait loci (caQTLs) and allele-specific chromatin accessibility, and provide predictions for the functional effect of 78.9 million variants on chromatin accessibility. Using this map of eQTLs and caQTLs we fine-mapped GWAS signals for a range of complex diseases. Combined, this work expands global functional genomic data to identify novel transcripts, functional elements and variants, understand population genetic history of molecular quantitative trait loci, and further resolve the genetic basis of multiple human traits and disease.

Glycoproteomic landscape and structural dynamics of TIM family immune checkpoints enabled by mucinase SmE.

Mucin-domain glycoproteins are densely O-glycosylated and play critical roles in a host of biological functions. In particular, the T cell immunoglobulin and mucin-domain containing family of proteins (TIM-1, -3, -4) decorate immune cells and act as key regulators in cellular immunity. However, their dense O-glycosylation remains enigmatic, primarily due to the challenges associated with studying mucin domains. Here, we demonstrate that the mucinase SmE has a unique ability to cleave at residues bearing very complex glycans. SmE enables improved mass spectrometric analysis of several mucins, including the entire TIM family. With this information in-hand, we perform molecular dynamics (MD) simulations of TIM-3 and -4 to understand how glycosylation affects structural features of these proteins. Finally, we use these models to investigate the functional relevance of glycosylation for TIM-3 function and ligand binding. Overall, we present a powerful workflow to better understand the detailed molecular structures and functions of the mucinome.

Across-Agency Partnerships and Within-Agency Capacities Facilitate Holistic, Tailored Approaches to Addressing Food Insecurity: A Qualitative Study.

BACKGROUND: Capacity-oriented approaches have the potential to reduce food insecurity (FI) and promote nutrition and health equity in low-resource settings. OBJECTIVE: The objective of this study was to identify multilevel capacities in San Diego County, CA that key informants from diverse food- and nutrition-related stakeholder agencies perceived to be helping to address FI. DESIGN: Trained qualitative interviewers conducted face-to-face, semi-structured interviews (30-60 minutes) with key informants. The Socioecological Model and a capacity-oriented approach informed interview guides. PARTICIPANTS/SETTING: Participants were key informants (n = 23) from diverse purposively sampled stakeholder agencies (n = 16) providing food or nutrition services and programs across San Diego County. Interviews were conducted between April 2019 and December 2021. ANALYSES PERFORMED: Interviews were audio-recorded, transcribed verbatim, and checked for accuracy. The research team conducted thematic content analysis to identify themes. RESULTS: Two interrelated themes, within-agency capacities and across-agency partnerships, collectively appeared to influence each individual agency's ability to provide tailored, holistic care to their clients and, thus, expand each agency's reach and impact to address the 4 domains of food security (ie, quantity, quality, psychological, and social). Multilevel (ie, individual, interpersonal, organizational, and macro) within-agency human, social, and cultural capital (eg, volunteers, staff-client relationships, and cultural competency) positively influenced the reach and impact of the individual agencies by enabling them to provide clients with personalized, holistic care. Alongside within-agency capacities, multilevel (ie, interpersonal, organizational, community, and macro levels) across-agency partnerships allowed individual agencies to address FI more effectively and holistically by connecting clients to other services (eg, housing and mental health) related to the circumstances of FI. CONCLUSIONS: In San Diego County, multilevel capacities in the form of within-agency capacities and across-agency partnerships collectively influenced the effectiveness of stakeholder agencies in addressing the 4 domains of FI among at-risk households. Future research should consider how to evaluate the impact of these existing capacities on FI.

Fermenting a place in history: The first outbreak of Escherichia coli O157 associated with kimchi in Canada.

A Canadian outbreak investigation was initiated in January 2022 after a cluster of cases of Shiga-toxin-producing Escherichia coli (STEC) O157 was identified through whole genome sequencing (WGS). Exposure information was collected through case interviews. Traceback investigations were conducted, and samples from case homes, retail, and the manufacturer were tested for STEC O157. Fourteen cases were identified in two provinces in Western Canada, with isolates related by 0-5 whole genome multi-locus sequence typing allele differences. Symptom onset dates ranged from 11 December 2021 to 7 January 2022. The median age of cases was 29.5 (range 0-61); 64% were female. No hospitalisations or deaths were reported. Of 11 cases with information available on fermented vegetable exposures, 91% (10/11) reported consuming Kimchi Brand A during their exposure period. The traceback investigation identified Manufacturer A in Western Canada as the producer. One open and one closed sample of Kimchi Brand A tested positive for STEC O157, with isolates considered genetically related by WGS to the outbreak strain. Napa cabbage within the kimchi product was hypothesised as the most likely source of contamination. This paper summarises the investigation into this STEC O157 outbreak associated with kimchi, the first reported outside of East Asia.

Circulating tumor DNA reveals mechanisms of lorlatinib resistance in patients with relapsed/refractory ALK-driven neuroblastoma.

Activating point mutations in Anaplastic Lymphoma Kinase (ALK) have positioned ALK as the only mutated oncogene tractable for targeted therapy in neuroblastoma. Cells with these mutations respond to lorlatinib in pre-clinical studies, providing the rationale for a first-in-child Phase 1 trial (NCT03107988) in patients with ALK-driven neuroblastoma. To track evolutionary dynamics and heterogeneity of tumors, and to detect early emergence of lorlatinib resistance, we collected serial circulating tumor DNA samples from patients enrolled on this trial. Here we report the discovery of off-target resistance mutations in 11 patients (27%), predominantly in the RAS-MAPK pathway. We also identify newly acquired secondary compound ALK mutations in 6 (15%) patients, all acquired at disease progression. Functional cellular and biochemical assays and computational studies elucidate lorlatinib resistance mechanisms. Our results establish the clinical utility of serial circulating tumor DNA sampling to track response and progression and to discover acquired resistance mechanisms that can be leveraged to develop therapeutic strategies to overcome lorlatinib resistance.

Factors of transurethral incision effectiveness for ureteroceles in pediatric patients: A 28-year, single-institution retrospective review.

BACKGROUND: As a congenital anomaly, ureteroceles occur in 1 in 4000 children, and are usually diagnosed prenatally. However, there remains a lack of definite consensus on the optimal management of congenital ureteroceles. OBJECTIVE: We evaluated factors associated with success of primary transurethral incision (TUI) in ureterocele pediatric patients. METHODS: Demographic and clinical information for 120 pediatric patients who were diagnosed with congenital ureterocele between 1993 and 2021 at our institution were obtained through retrospective chart review. Data were analyzed using Fisher's exact tests, t-tests, and logistic regression with a significance threshold of p < 0.05. The primary outcome of ureterocele management was TUI effectiveness, defined by no need for further surgical intervention. RESULTS: Of the 120 patients (39 boys, 81 girls) with ureteroceles, 75 patients (22 boys, 53 girls) met our inclusion criteria of undergoing initial TUI ureterocele. Initial TUI was effective in 51/75 patients (68.0%). We analyzed possible correlative factors for TUI efficacy. Simplex system was a significant predictor of primary TUI efficacy (85% effective in simplex systems, 62% in duplex systems). Prior urinary tract infection, prenatal diagnosis, and electrocautery technique were all associated with an increased risk of needing additional surgeries after primary TUI. DISCUSSION: The most significant predictors of effective primary TUI were simplex system and the absence of preoperative vesicoureteral reflux. Prenatal diagnosis, preoperative febrile urinary tract infection, higher preoperative hydronephrosis grade, and the use of electrocautery were all associated with decreased primary TUI efficacy. Study limitations include that it was a retrospective chart review, and cohort size was limited by incomplete urology follow-up and operative records. CONCLUSIONS: Initial TUI was an effective procedure for the majority of our pediatric ureterocele patients, a higher success rate compared to other cohorts. Patients with a simplex system were more likely to have an effective first TUI than patients with duplex systems, as were patients without preoperative reflux. Although not statistically significant, our data suggest prior UTI, prenatal diagnosis, higher preoperative hydronephrosis grade, and the use of electrocautery may be associated with having additional surgeries.

Impact of the COVID-19 Pandemic on the Reported Incidence of Select Bacterial Enteric Diseases in Canada, 2020.

The aim of this study was to describe the impact of the COVID-19 pandemic on reported cases and clusters of select enteric diseases in Canada, for the period of March 2020 to December 2020. Weekly counts of laboratory confirmed cases of Salmonella, Shigella, Shiga toxin-producing Escherichia coli (STEC), and Listeria monocytogenes were obtained from laboratory surveillance data. These data were supplemented with epidemiological information on the suspected source of illness, collected for cases identified within whole genome sequencing clusters. Incidence rate ratios were calculated for each pathogen. All data were compared with a prepandemic reference period. Decreases in the number of reported cases in 2020 compared with the previous 5-year period were noted for Salmonella, Shigella, Escherichia coli O157, and non-O157 STEC. Reported number of cases for L. monocytogenes in 2020 remained similar to those of the previous 5-year period. There was a considerable decline (59.9%) in the number of cases associated with international travel compared with a 10% decline in the number of domestic cases. Comparison of reported incidence rates of clustered versus sporadic cases for each pathogen showed little variation. This study represents the first formal assessment of the impact of COVID-19 on reported enteric diseases in Canada. Reported case counts across several pathogens saw notable declines in 2020 compared with prepandemic levels, with restrictions on international travel playing a key role. Additional research is needed to understand how limitations on social gatherings, lock downs, and other public health measures have impacted enteric diseases.

Linking whole-body angular momentum and step placement during perturbed human walking.

Human locomotion is remarkably robust to environmental disturbances. Previous studies have thoroughly investigated how perturbations influence body dynamics and what recovery strategies are used to regain balance. Fewer studies have attempted to establish formal links between balance and the recovery strategies that are executed to regain stability. We hypothesized that there would be a strong relationship between the magnitude of imbalance and recovery strategy during perturbed walking. To test this hypothesis, we applied transient ground surface translations that varied in magnitude, direction and onset time while 11 healthy participants walked on a treadmill. We measured stability using integrated whole-body angular momentum (iWBAM) and recovery strategy using step placement. We found the strongest relationships between iWBAM and step placement in the frontal plane for earlier perturbation onset times in the perturbed step (R2=0.52, 0.50) and later perturbation onset times in the recovery step (R2=0.18, 0.25), while correlations were very weak in the sagittal plane (all R2≤0.13). These findings suggest that iWBAM influences step placement, particularly in the frontal plane, and that this influence is sensitive to perturbation onset time. Lastly, this investigation is accompanied by an open-source dataset to facilitate research on balance and recovery strategies in response to multifactorial ground surface perturbations, including 96 perturbation conditions spanning all combinations of three magnitudes, eight directions and four gait cycle onset times.

Commodity discounting: Obstacles and solutions.

Addictive behaviors involve patterns of impulsive choices. Discount functions are a useful means of describing the behavioral contingencies involved in those impulsive choices. Although monetary discounting tasks have proven useful, most impulsive behaviors of interest involve nonmonetary consequences. OBJECTIVE: Developing effective commodity discounting tasks is critical for assessing how delay (and other variables) influences choice with respect to meaningful real-world commodities (e.g., high-calorie foods, alcohol, opioids, and other drugs). METHOD: Identifying the obstacles specific to nonmonetary commodity discounting and evaluating solutions to those obstacles. RESULTS: Those obstacles include (1) real versus hypothetical commodities, (2) framing, (3) commodity indivisibility, (4) diminishing marginal utility, and (5) variations in economic context. CONCLUSIONS: Solutions are presented and evaluated for each of these five obstacles, including the following: (1) assessing relevant experiences and explicitly stipulating transportation and storage issues, (2) systematic analyses across various wordings and holding wording constant across commodities, (3) using an adjusting delay procedure with only whole commodities, (4) assessing value for different commodity amounts (without delay) and adopting quantitative models of discounting that include marginal utility, and (5) controlling for motivating operations, accounting for individual histories, and using closed economies. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A systematic review of social determinants of health in pediatric organ transplant outcomes.

BACKGROUND: Equitable access to pediatric organ transplantation is critical, although risk factors negatively impacting pre- and post-transplant outcomes remain. No synthesis of the literature on SDoH within the pediatric organ transplant population has been conducted; thus, the current systematic review summarizes findings to date assessing SDoH in the evaluation, listing, and post-transplant periods. METHODS: Literature searches were conducted in Web of Science, Embase, PubMed, and Cumulative Index to Nursing and Allied Health Literature databases. RESULTS: Ninety-three studies were included based on pre-established criteria and were reviewed for main findings and study quality. Findings consistently demonstrated disparities in key transplant outcomes based on racial or ethnic identity, including timing and likelihood of transplant, and rates of rejection, graft failure, and mortality. Although less frequently assessed, variations in outcomes based on geography were also noted, while findings related to insurance or SES were inconsistent. CONCLUSION: This review underscores the persistence of SDoH and disparity in equitable transplant outcomes and discusses the importance of individual and systems-level change to reduce such disparities.

Nuclear import receptors are recruited by FG-nucleoporins to rescue hallmarks of TDP-43 proteinopathy.

BACKGROUND: Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) disease spectrum, causing both nuclear loss-of-function and cytoplasmic toxic gain-of-function phenotypes. While TDP-43 proteinopathy has been associated with defects in nucleocytoplasmic transport, this process is still poorly understood. Here we study the role of karyopherin-ß1 (KPNB1) and other nuclear import receptors in regulating TDP-43 pathology. METHODS: We used immunostaining, immunoprecipitation, biochemical and toxicity assays in cell lines, primary neuron and organotypic mouse brain slice cultures, to determine the impact of KPNB1 on the solubility, localization, and toxicity of pathological TDP-43 constructs. Postmortem patient brain and spinal cord tissue was stained to assess KPNB1 colocalization with TDP-43 inclusions. Turbidity assays were employed to study the dissolution and prevention of aggregation of recombinant TDP-43 fibrils in vitro. Fly models of TDP-43 proteinopathy were used to determine the effect of KPNB1 on their neurodegenerative phenotype in vivo. RESULTS: We discovered that several members of the nuclear import receptor protein family can reduce the formation of pathological TDP-43 aggregates. Using KPNB1 as a model, we found that its activity depends on the prion-like C-terminal region of TDP-43, which mediates the co-aggregation with phenylalanine and glycine-rich nucleoporins (FG-Nups) such as Nup62. KPNB1 is recruited into these co-aggregates where it acts as a molecular chaperone that reverses aberrant phase transition of Nup62 and TDP-43. These findings are supported by the discovery that Nup62 and KPNB1 are also sequestered into pathological TDP-43 aggregates in ALS/FTD postmortem CNS tissue, and by the identification of the fly ortholog of KPNB1 as a strong protective modifier in Drosophila models of TDP-43 proteinopathy. Our results show that KPNB1 can rescue all hallmarks of TDP-43 pathology, by restoring its solubility and nuclear localization, and reducing neurodegeneration in cellular and animal models of ALS/FTD. CONCLUSION: Our findings suggest a novel NLS-independent mechanism where, analogous to its canonical role in dissolving the diffusion barrier formed by FG-Nups in the nuclear pore, KPNB1 is recruited into TDP-43/FG-Nup co-aggregates present in TDP-43 proteinopathies and therapeutically reverses their deleterious phase transition and mislocalization, mitigating neurodegeneration.

Current treatments against mucormycosis and future directions.

Mucormycosis (previously called zygomycosis) is a serious but rare fungal infection caused by a group of fungi belonging to the order Mucorales. These molds exist throughout the environment and generally do not cause serious problems in humans. Mucormycosis mainly affects individuals who are immunocompromised. The clinical manifestations of mucormycosis are wide-ranging; they include sinusitis (pansinusitis, rhino-orbital, or rhino-cerebral) as well as cutaneous, gastrointestinal, pulmonary, and disseminate infections. Many uncertainties remain regarding how to control these infections despite the recent addition of triazoles to the antifungal arsenal for treating this infection. Currently, lipid formulations of amphotericin B have become the standard treatment for mucormycosis due to their efficiency. Moreover, a growing body of data supports the need for surgical excision of infected and/or necrosed tissue whenever practical. In this mini review, the current status of treatment options for mucormycosis and recent studies of novel therapeutic options will be presented.

Integrative analysis of metabolite GWAS illuminates the molecular basis of pleiotropy and genetic correlation.

Pleiotropy and genetic correlation are widespread features in genome-wide association studies (GWAS), but they are often difficult to interpret at the molecular level. Here, we perform GWAS of 16 metabolites clustered at the intersection of amino acid catabolism, glycolysis, and ketone body metabolism in a subset of UK Biobank. We utilize the well-documented biochemistry jointly impacting these metabolites to analyze pleiotropic effects in the context of their pathways. Among the 213 lead GWAS hits, we find a strong enrichment for genes encoding pathway-relevant enzymes and transporters. We demonstrate that the effect directions of variants acting on biology between metabolite pairs often contrast with those of upstream or downstream variants as well as the polygenic background. Thus, we find that these outlier variants often reflect biology local to the traits. Finally, we explore the implications for interpreting disease GWAS, underscoring the potential of unifying biochemistry with dense metabolomics data to understand the molecular basis of pleiotropy in complex traits and diseases.

Short-Term Dairy Product Elimination and Reintroduction Minimally Perturbs the Gut Microbiota in Self-Reported Lactose-Intolerant Adults.

An outstanding question regarding the human gut microbiota is whether and how microbiota-directed interventions influence host phenotypic traits. Here, we employed a dietary intervention to probe this question in the context of lactose intolerance. To assess the effects of dietary dairy product elimination and (re)introduction on the microbiota and host phenotype, we studied 12 self-reported mildly lactose-intolerant adults with triweekly collection of fecal samples over a 12-week study period: 2 weeks of baseline diet, 4 weeks of dairy product elimination, and 6 weeks of gradual whole cow milk (re)introduction. Of the 12 subjects, 6 reported either no dairy or only lactose-free dairy product consumption. A clinical assay for lactose intolerance, the hydrogen breath test, was performed before and after each of these three study phases, and 16S rRNA gene amplicon sequencing was performed on all fecal samples. We found that none of the subjects showed change in a clinically defined measure of lactose tolerance. Similarly, fecal microbiota structure resisted modification. Although the mean fraction of the genus Bifidobacterium, a group known to metabolize lactose, increased slightly with milk (re)introduction (from 0.0125 to 0.0206; Wilcoxon P = 0.068), the overall structure of each subject's gut microbiota remained highly individualized and largely stable in the face of diet manipulation. IMPORTANCE Lactose intolerance is a gastrointestinal disorder diagnosed with a lactose hydrogen breath test. Lifestyle changes such as diet interventions can impact the gut microbiome; however, the role of the microbiome in lactose intolerance is unclear. Our study assessed the effects of a 12-week dietary dairy product elimination and (re)introduction on the microbiome and clinical lactose intolerance status in 12 adult self-reported lactose-intolerant individuals. We found each subject's gut microbiome remained highly individualized and largely stable in the face of this diet manipulation. We also report that none of the subjects showed change in a clinically defined measure of lactose tolerance.

The extant immunoglobulin superfamily, member 1 gene results from an ancestral gene duplication in eutherian mammals.

Immunoglobulin superfamily, member 1 (IGSF1) is a transmembrane glycoprotein with high expression in the mammalian pituitary gland. Mutations in the IGSF1 gene cause congenital central hypothyroidism in humans. The IGSF1 protein is co-translationally cleaved into N- and C-terminal domains (NTD and CTD), the latter of which is trafficked to the plasma membrane and appears to be the functional portion of the molecule. Though the IGSF1-NTD is retained in the endoplasmic reticulum and has no apparent function, it has a high degree of sequence identity with the IGSF1-CTD and is conserved across mammalian species. Based upon phylogenetic analyses, we propose that the ancestral IGSF1 gene encoded the IGSF1-CTD, which was duplicated and integrated immediately upstream of itself, yielding a larger protein encompassing the IGSF1-NTD and IGSF1-CTD. The selective pressures favoring the initial gene duplication and subsequent retention of a conserved IGSF1-NTD are unresolved.