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Patterning the Mutual Human-Environment Process for Wellbecoming of All Living Beings and the Planet: A Unitary Conceptualization
No full textPatterning the mutual human-environment process for wellbecoming of all living beings and the planet is a unitary conceptualization proposed by Rogerian scholar, Dr. Violet M. Malinski. In this scholarly dialogue column, she and her colleague, nurse scholar Dr. Donna J. Perry, discuss why this conceptualization is important to them, the theoretical, philosophical, and research underpinnings, and other related human-environment topics.No embarg
Modular integration of neural connectomics, dynamics and biomechanics for identification of behavioral sensorimotor pathways in Caenorhabditis elegans [preprint]
No full textThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.Computational approaches which emulate in-vivo nervous system are needed to investigate mechanisms of the brain to orchestrate behavior. Such approaches must integrate a series of biophysical models encompassing the nervous system, muscles, biomechanics to allow observing the system in its entirety while supporting model variations. Here we develop modWorm: a modular modeling framework for the nematode C. elegans. modWorm allows for construction of a model as an integrated series of configurable, exchangeable modules each describing specific biophysical processes across different modalities. Utilizing modWorm, we propose a base neuro-mechanical model for C. elegans built upon the complete connectome. The model integrates a series of 7 modules: i) intra-cellular dynamics, ii) electrical and iii) chemical extra-cellular neural dynamics, iv) translation of neural activity to muscle calcium dynamics, v) muscle calcium dynamics to muscle forces, vi) muscle forces to body postures and vii) proprioceptive feedback. We validate the base model by in-silico injection of constant currents into neurons known to be associated with locomotion behaviors and by applying external forces to the body. Applications of in-silico neural stimuli experimentally known to modulate locomotion show that the model can recapitulate natural behavioral responses such as forward and backward locomotion as well as mid-locomotion responses such as avoidance and turns. Furthermore, through in-silico ablation surveys, the model can infer novel neural circuits involved in sensorimotor behaviors. To further dissect mechanisms of locomotion, we utilize modWorm to introduce empirical based model variations and model optimizations to elucidate their effects on simulated locomotion. Our results show that modWorm can be utilized to identify neural circuits which control, mediate and generate natural behavior.No embarg
Perceptions of sources of transmission among hospital employees infected with severe acute respiratory coronavirus 2 (SARS-CoV-2) in an urban tertiary care hospital: a qualitative study to inform future pandemic management
Get PDFObjective: Hospital employees are at risk of severe acute respiratory coronavirus 2 (SARS-CoV-2) infection from patient, coworker, and community interactions. Understanding employees' perspectives on transmission risks may inform hospital pandemic management strategies.
Design: Qualitative interviews were conducted with 23 employees to assess factors contributing to perceived transmission risks during patient, coworker, and community interactions and to elicit recommendations. Using a deductive approach, transcripts were coded to identify recurring themes.
Setting: Tertiary hospital in Boston, Massachusetts.
Participants: Employees with a positive SARS-CoV-2 PCR test between March 2020 and January 2021, a period before widespread vaccine availability.
Results: Employees generally reported low concern about transmission risks during patient care. Most patient-related risks, including limited inpatient testing and personal protective equipment availability, were only reported during the early weeks of the pandemic, except for suboptimal masking adherence by patients. Participants reported greater perceived transmission risks from coworkers, due to limited breakroom space, suboptimal coworker masking, and perceptions of inadequate contact tracing. Perceived community risks were related to social gatherings and to household members who also had high SARS-CoV-2 infection risk because they were essential workers. Recommendations included increasing well-ventilated workspaces and breakrooms, increasing support for sick employees, and stronger hospital communication about risks from non-patient-care activities, including the importance of masking adherence with coworkers and in the community.
Conclusions: To reduce transmission during future pandemics, hospitals may consider improving communication on risk reduction during coworker and community interactions. Societal investments are needed to improve hospital infrastructure (eg, better ventilation and breakroom space) and increase support for sick employees.No embarg
Understanding piRNA-guided Gene Regulation with Massively Parallel Cellular Assays
No full textRegulatory small RNAs, including microRNAs (miRNAs), Piwi-interacting RNAs (piRNAs), and endogenous siRNAs (endo-siRNAs), are ubiquitously found across various life forms. piRNAs mainly exist in the gonads and early embryos of animals, ranging from humans to sponges. Disrupting piRNA pathway genes or piRNA-producing genomic loci causes sterility. Despite the prevalence of piRNAs, our knowledge about the regulatory capacity of individual piRNAs is limited. Cell line models suitable for piRNA study are rare. I use moth cell lines by developing automated dual-luciferase-fluorescence reporter assays and massively parallel reporter assays to examine the effect of tens of thousands of designed small RNA target variants at single-nucleotide resolution. I also pave the way for pooled CRISPR-Cas9 screening to identify unknown genes in the small-RNA pathways.
My findings highlight some characteristics of ~27 nucleotide piRNAs: Unlike piRNAs in fruit flies, piRNAs in moth cells do not guide repressive histone mark deposition. piRNAs silence their targets even with mismatches within the 5′ end “seed” region. While base pairings at the very 3′ ends of piRNAs have a minimum contribution to silencing, pairing before the 15th nucleotide of piRNA helps. A single 27nt piRNA target site in mRNAs is enough to reduce the target mRNA and protein level more than fourfold. Furthermore, I found that thousands of different piRNAs are equally effective as tens of miRNAs with high cellular concentrations. In contrast, most endo-siRNA cannot regulate mRNAs with one target site. Overall, my results reveal the unexpected potential of piRNAs to silence both endogenous and exogenous transcripts. These large-scale datasets can be leveraged to build models to predict gene expression in germ cells and design synthetic components for recombinant protein production, where moth cell lines are commonly used.Interdisciplinary Graduate Program1 year2026-07-1
Septic and Aseptic Iliopsoas Bursitis - A Systematic Review of the Literature
No full textIliopsoas bursitis (IB) is a rare entity and usually presents with ambiguous clinical presentation similar to other musculoskeletal conditions in the anatomic area. In septic IB, patients usually present with vague complaints of hip pain and fever.To better understand this vague clinical entity, a systematic review of cases of iliopsoas bursitis published in the open literature was performed to better characterize the clinical presentation, demographics and clinical outcome in patients with IB. An analysis of 50 articles and 54 patients including our index case revealed that hip pain was the most common presenting complaint in 74% of the patients, followed by lower limb edema (16.7% of patients). Common etiologies were total hip arthroplasty (16.7%) and infection (14.8%). The mortality rate calculated in the reported cases of septic IB was high. Therefore, knowledge of this entity is important as delay in diagnosis and management, especially in septic IB, can result in fatal outcome.No embarg
Suppression of binge alcohol drinking by an inhibitory neuronal ensemble in the mouse medial orbitofrontal cortex
No full textAlcohol consumption remains a significant global health challenge, directly and indirectly causing millions of deaths annually. Alcohol abuse causes dysregulated activity of the prefrontal cortex, yet effects on specific prefrontal circuits remain to be elucidated. Here, we identify a discrete GABAergic neuronal ensemble in the mouse medial orbitofrontal cortex (mOFC) that is selectively recruited in response to binge alcohol drinking and limits further drinking behavior. Optogenetic silencing of this population, or its ablation, results in uncontrolled binge alcohol consumption. This neuronal ensemble is specific to alcohol and is not recruited by other rewarding substances. Neurons in this ensemble project widely throughout the brain, but projections specifically to the mediodorsal thalamus regulate binge alcohol drinking. Together, these results identify a brain circuit in the mOFC that serves to protect against binge drinking by reducing alcohol intake, which may offer avenues for the development of mOFC neuronal ensemble-targeted interventions.No embarg
Plasma fibronectin is a prognostic biomarker of disability in Parkinson's disease: a prospective, multicenter cohort study
Get PDFIn a prospective longitudinal study with 218 Parkinson's disease (PD) patients in the discovery cohort and 84 in the validation cohort, we aimed to identify novel blood biomarkers predicting disability milestones in PD. Through Least Absolute Shrinkage and Selection Operator-Cox (Lasso-Cox) regression, developed nomogram predictive model and Linear mixed-effects models, we identified low level of plasma fibronectin (pFN) as one of the best-performing risk markers in predicting disability milestones. A low level of pFN was associated with a short milestone-free survival period in PD. Longitudinal analysis showed an annual decline in the rate of pFN was significantly associated with the annual elevation rate in the Hoehn-Yahr stage. Moreover, pFN level was negatively correlated with phosphorylated α-synuclein, and a low level of pFN was associated with BBB disruption in the striatum on neuroimaging, providing evidence for pFN's role in PD progression. We finally identified pFN as a novel blood biomarker that predicted first-milestone disability in PD.No embarg
Dual-vector rAAVrh8 gene therapy for GM2 gangliosidosis: a phase 1/2 trial
Get PDFThe dual rAAVrh8-HEXA and rAAVrh8-HEXB vector can restore central nervous system hexosaminidase (Hex) enzyme activity, decrease GM2 levels in cerebrospinal fluid and rescue phenotypic consequences of GM2 gangliosidosis, Tay-Sachs and Sandhoff diseases in animal models following simultaneous bi-thalamic (BiT) injections. Following up on an n = 2 expanded access trial, we initiated a phase 1/2, single-dose, dose-escalation of combined BiT, intra-cisterna magna and intrathecal infusion in children with Tay-Sachs and Sandhoff diseases (six infantile, three juvenile). The BiT injection volume and vector dose were doubled between four cohorts, with the lowest dose matching the earlier expanded access trial. Cerebrospinal fluid HexA enzyme activity, serum total Hex activity and GM2 levels showed a dose-dependent biochemical correction of the disease. Serum Hex activity surpassed 40 nmol h ml, two times the lower limit of normal, and neuroimaging demonstrated increased fiber tracts. Correction was greatest at 12 weeks, but in decline by 24 weeks postdosing. Infantile patients experienced global clinical stabilization and prolonged oral feeding without aspiration until 3-3.5 years. Seizures had a later onset, were less frequent, less severe and more responsive to anti-convulsant medication. Adverse events were rare in infantile patients, but worsening dystonia was observed in juvenile patients, who were excluded from ongoing enrollment. ClinicalTrials.gov registration: NCT04669535 and NCT06614569 .No embarg
BAMBI integrates biostatistical and artificial intelligence methods to improve RNA biomarker discovery
Get PDFRNA biomarkers enable early and precise disease diagnosis, monitoring, and prognosis, facilitating personalized medicine and targeted therapeutic strategies. However, identification of RNA biomarkers is hindered by the challenge of analyzing relatively small yet high-dimensional transcriptomics datasets, typically comprising fewer than 1000 biospecimens but encompassing hundreds of thousands of RNAs, especially noncoding RNAs. This complexity leads to several limitations in existing methods, such as poor reproducibility on independent datasets, inability to directly process omics data, and difficulty in identifying noncoding RNAs as biomarkers. Additionally, these methods often yield results that lack biological interpretation and clinical utility. To overcome these challenges, we present BAMBI (Biostatistical and Artificial-intelligence Methods for Biomarker Identification), a computational tool integrating biostatistical approaches and machine-learning algorithms. By initially reducing high dimensionality through biologically informed statistical methods followed by machine learning-based feature selection, BAMBI significantly enhances the accuracy and clinical utility of identified RNA biomarkers and also includes noncoding RNA biomarkers that existing methods may overlook. BAMBI outperformed existing methods on both real and simulated datasets by identifying individual and panel biomarkers with fewer RNAs while still ensuring superior prediction accuracy. BAMBI was benchmarked on multiple transcriptomics datasets across diseases, including breast cancer, psoriasis, and leukemia. The prognostic biomarkers for acute myeloid leukemia discovered by BAMBI showed significant correlations with patient survival rates in an independent cohort, highlighting its potential for enhancing clinical outcomes. The software is available on GitHub (https://github.com/CZhouLab/BAMBI).No embarg
The Mechanism of Cell Lethality Following Transcriptional Inhibition
No full textPol II-mediated transcription is essential for eukaryotic life. While loss of transcription is thought to be universally lethal, the associated mechanisms promoting cell death are not yet known. Here, we show that death following loss of Pol II activity does not result from dysregulated gene expression. Instead, death occurs in response to loss of the hypo-phosphorylated form of Rbp1 (also called Pol IIA). Loss of Pol IIA exclusively activates apoptosis, and expression of a transcriptionally inactive version of Rpb1 rescues cell viability. Using functional genomics, we identify the mechanisms driving lethality following loss of Pol IIA, which we call the Pol II Degradation-dependent Apoptotic Response (PDAR). Using the genetic dependencies of PDAR, we identify clinically used drugs that owe their lethality to a PDAR-dependent mechanism. Our findings unveil an apoptotic signaling response that contributes to the efficacy of a wide array of anti-cancer therapies.Biochemistry and Molecular Biotechnology6 months2026-02-1