CRISPR-GPT: An LLM Agent for Automated Design of Gene-Editing Experiments.

The introduction of genome engineering technology has transformed biomedical research, making it possible to make precise changes to genetic information. However, creating an efficient gene-editing system requires a deep understanding of CRISPR technology, and the complex experimental systems under investigation. While Large Language Models (LLMs) have shown promise in various tasks, they often lack specific knowledge and struggle to accurately solve biological design problems.

Direct Photobiomodulation Therapy on the Sciatic Nerve Significantly Attenuates Acute Nociceptive Sensitivity Without Affecting Motor Output.

Objectives: Pharmacologic pain treatments lack specific targeting and often produce unwanted side effects (eg, addiction, additional hyperalgesia). We previously established that the direct application of laser irradiation (direct photobiomodulation [PBM]) of the sural nerve reduces thermal hypersensitivity in a rodent model of chronic pain, but not mechanical hypersensitivity. These observations were consistent with a selective reduction in the small-diameter fiber contribution to electrophysiologically measured evoked response after direct PBM of a sensory nerve (saphenous).

Computational Approaches to Drug Repurposing: Methods, Challenges, and Opportunities.

Drug repurposing refers to the inference of therapeutic relationships between a clinical indication and existing compounds. As an emerging paradigm in drug development, drug repurposing enables more efficient treatment of rare diseases, stratified patient populations, and urgent threats to public health. However, prioritizing well-suited drug candidates from among a nearly infinite number of repurposing options continues to represent a significant challenge in drug development.

Genetic Correlations Among Corneal Biophysical Parameters and Anthropometric Traits.

Purpose: The genetic architecture of corneal dysfunction remains poorly understood. Epidemiological and clinical evidence suggests a relationship between corneal structural features and anthropometric measures. We used global and local genetic similarity analysis to identify genomic features that may underlie structural corneal dysfunction.

Integrative analysis of functional genomic screening and clinical data identifies a protective role for spironolactone in severe COVID-19.

We demonstrate that integrative analysis of CRISPR screening datasets enables network-based prioritization of prescription drugs modulating viral entry in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by developing a network-based approach called Rapid proXimity Guidance for Repurposing Investigational Drugs (RxGRID). We use our results to guide a propensity-score-matched, retrospective cohort study of 64,349 COVID-19 patients, showing that a top candidate drug, spironolactone, is associated with improved clinical prognosis, measured by intensive care unit (ICU) admission and mechanical ventilation rates. Finally, we show that spironolactone exerts a dose-dependent inhibitory effect on viral entry in human lung epithelial cells.

Deep Learning for Localized Detection of Optic Disc Hemorrhages.

Purpose: To develop an automated deep learning system for detecting the presence and location of disc hemorrhages in optic disc photographs.

Design: Development and testing of a deep learning algorithm.

Methods: Optic disc photos (597 images with at least 1 disc hemorrhage and 1075 images without any disc hemorrhage from 1562 eyes) from 5 institutions were classified by expert graders based on the presence or absence of disc hemorrhage.

Assessment of Team Dynamics and Operative Efficiency in Hip and Knee Arthroplasty.

Importance: Surgical team communication is a critical component of operative efficiency. The factors underlying optimal communication, including team turnover, role composition, and mutual familiarity, remain underinvestigated in the operating room.

Objective: To assess staff turnover, trainee involvement, and surgeon staff preferences in terms of intraoperative efficiency.

Association between spironolactone use and COVID-19 outcomes in population-scale claims data: a retrospective cohort study.

Background: Spironolactone has been proposed as a potential modulator of SARS-CoV-2 cellular entry. We aimed to measure the effect of spironolactone use on the risk of adverse outcomes following COVID-19 hospitalization.

Methods: We performed a retrospective cohort study of COVID-19 outcomes for patients with or without exposure to spironolactone, using population-scale claims data from the Komodo Healthcare Map.

Gene set proximity analysis: expanding gene set enrichment analysis through learned geometric embeddings, with drug-repurposing applications in COVID-19.

Motivation: Gene set analysis methods rely on knowledge-based representations of genetic interactions in the form of both gene set collections and protein-protein interaction (PPI) networks. However, explicit representations of genetic interactions often fail to capture complex interdependencies among genes, limiting the analytic power of such methods.

Results: We propose an extension of gene set enrichment analysis to a latent embedding space reflecting PPI network topology, called gene set proximity analysis (GSPA).

Wastewater treatment plant operators report high capacity to support wastewater surveillance for COVID-19 across New York State, USA.

Wastewater surveillance for infectious disease expanded greatly during the COVID-19 pandemic. As a collaboration between sanitation engineers and scientists, the most cost-effective deployment of wastewater surveillance routinely tests wastewater samples from wastewater treatment plants. To evaluate the capacity of treatment plants of different sizes and characteristics to participate in surveillance efforts, we developed and distributed a survey to New York State municipal treatment plant supervisors in the summer and fall of 2021.

Influence of team composition on turnover and efficiency of total hip and knee arthroplasty.

Aims: Surgical costs are a major component of healthcare expenditures in the USA. Intraoperative communication is a key factor contributing to patient outcomes. However, the effectiveness of communication is only partially determined by the surgeon, and understanding how non-surgeon personnel affect intraoperative communication is critical for the development of safe and cost-effective staffing guidelines.

Regional Infoveillance of COVID-19 Case Rates: Analysis of Search-Engine Query Patterns.

Background: Timely allocation of medical resources for coronavirus disease (COVID-19) requires early detection of regional outbreaks. Internet browsing data may predict case outbreaks in local populations that are yet to be confirmed.

Objective: We investigated whether search-engine query patterns can help to predict COVID-19 case rates at the state and metropolitan area levels in the United States.

Nailfold Capillary Morphology in Alzheimer's Disease Dementia.

Background: Cerebrovascular disease (CVD) is highly comorbid with Alzheimer's disease (AD), yet its role is not entirely understood. Nailfold video capillaroscopy (NVC) is a noninvasive method of live imaging the capillaries near the fingernail's cuticle and may help to describe further vascular contributions to AD.

Objective: To examine finger nailfold capillary morphology using NVC in subjects with AD dementia, mild cognitive impairment (MCI), and normal cognition (NC).

Toward Precision Medicine for Neurological and Neuropsychiatric Disorders.

The genetic complexity, clinical variability, and inaccessibility of affected tissue in neurodegenerative and neuropsychiatric disorders have largely prevented the development of effective disease-modifying therapeutics. A precision medicine approach that integrates genomics, deep clinical phenotyping, and patient stem cell models may facilitate identification of underlying biological drivers and targeted drug development.

Role for Wnt Signaling in Retinal Neuropil Development: Analysis via RNA-Seq and In Vivo Somatic CRISPR Mutagenesis.

Screens for genes that orchestrate neural circuit formation in mammals have been hindered by practical constraints of germline mutagenesis. To overcome these limitations, we combined RNA-seq with somatic CRISPR mutagenesis to study synapse development in the mouse retina. Here synapses occur between cellular layers, forming two multilayered neuropils.

Electrical coupling between the myenteric interstitial cells of Cajal and adjacent muscle layers in the guinea-pig gastric antrum.

Intracellular recordings were made from short segments of the muscular wall of the guinea-pig gastric antrum. Preparations were impaled using two independent microelectrodes, one positioned in the circular layer and the other either in the longitudinal layer, in the network of myenteric interstitial cells of Cajal (ICCMY) or in the circular layer. Cells in each layer displayed characteristic patterns of rhythmical activity, with the largest signals being generated by ICCMY.

Parallel metabotropic pathways in the heart of the toad, Bufo marinus.

This study examined the transduction pathways activated by epinephrine in the pacemaker region of the toad heart. Recordings of membrane potential, force, and intracellular Ca(2+) concentration ([Ca(2+)](i)) were made from arrested toad sinus venosus. Sympathetic nerve stimulation activated non-alpha-, non-beta-adrenoceptors to evoke a membrane depolarization and a transient increase in [Ca(2+)](i).

Predominant distribution of nifedipine-insensitive, high voltage-activated Ca2+ channels in the terminal mesenteric artery of guinea pig.

We have found nifedipine-insensitive (NI), rapidly inactivating, voltage-dependent Ca2+ channels (current, NI-I(Ca)) with unique biophysical and pharmacological properties in the terminal branches of guinea pig mesenteric artery, by using a whole-cell mode of the patch-clamp technique. The fraction of NI-I(Ca) appeared to increase dramatically along the lower branches of mesenteric artery, amounting to almost 100% of global I(Ca) in its periphery. With 5 mmol/L Ba2+ as the charge carrier, NI-I(Ca) was activated with a threshold of -50 mV, peaked at -10 mV, and was half-activated and inactivated at -11 and -52 mV, respectively, generating a potential range of constant activation near the resting membrane potential.

Effects of sympathetic nerve stimulation on membrane potential, [Ca2+]i, and force in the toad sinus venosus.

The effects of sympathetic nerve stimulation on beat rate, force, intracellular Ca2+ concentration ([Ca2+]i) measured using fura 2, and membrane potential were recorded from the spontaneously beating toad sinus venosus. Short trains of stimuli evoked an increase in the beat rate and force. During this tachycardia the amplitude of pacemaker action potentials was not changed, but there was an increase in the basal level of [Ca2+]i with little change in peak [Ca2+]i measured during each action potential.

Effects of sympathetic nerve stimulation on membrane potential, [Ca2+]i and force in the arrested sinus venosus of the toad, Bufo marinus.

1. The effects of sympathetic nerve stimulation on membrane potential and on the intracellular concentration of calcium ions, [Ca2+]i, were recorded concurrently from the sinus venosus of the toad, Bufo marinus, in preparations where beating had been abolished by adding an organic calcium antagonist to the physiological saline. In a separate set of experiments the effects of sympathetic nerve stimulation on force production were examined.

Neuronally released and applied acetylcholine on the longitudinal muscle of the guinea-pig ileum.

Brief transmural stimuli, which selectively excited cholinergic fibres, initiated contractions and excitatory junction potentials in preparations of longitudinal muscle isolated from the guinea-pig ileum: these responses were associated with an increase in the internal concentration of calcium ions. When muscle voltage-dependent calcium channels were blocked using the organic calcium antagonist nifedipine, brief stimuli continued to initiate contractions, evoke excitatory junction potentials and cause an increase in the intracellular calcium concentration. Ionophoretically applied acetylcholine caused depolarizations which resembled the excitatory junction potentials evoked by cholinergic nerve stimulation.

Cholinergic neuromuscular transmission in the longitudinal muscle of the guinea-pig ileum.

1. Brief transmural stimuli, 0.5-1 ms, initiated contractions of the longitudinal muscle taken from the guinea-pig ileum that were recorded isometrically.