CENsible: Interpretable Insights into Small-Molecule Binding with Context Explanation Networks.

We present a novel and interpretable approach for assessing small-molecule binding using context explanation networks. Given the specific structure of a protein/ligand complex, our CENsible scoring function uses a deep convolutional neural network to predict the contributions of precalculated terms to the overall binding affinity. We show that CENsible can effectively distinguish active vs inactive compounds for many systems. Its primary benefit over related machine-learning scoring functions, however, is that it retains interpretability, allowing researchers to identify the contribution of each precalculated term to the final affinity prediction, with implications for subsequent lead optimization.

Development of an inhibitor of the mutagenic SOS response that suppresses the evolution of quinolone antibiotic resistance.

Antimicrobial resistance (AMR) is a growing threat to health globally, with the potential to render numerous medical procedures so dangerous as to be impractical. There is therefore an urgent need for new molecules that function through novel mechanisms of action to combat AMR. The bacterial DNA-repair and SOS-response pathways promote survival of pathogens in infection settings and also activate hypermutation and resistance mechanisms, making these pathways attractive targets for new therapeutics. Small molecules, such as IMP-1700, potentiate DNA damage and inhibit the SOS response in methicillin-resistant S. aureus; however, understanding of the structure-activity relationship (SAR) of this series is lacking. We report here the first comprehensive SAR study of the IMP-1700 scaffold, identifying key pharmacophoric groups and delivering the most potent analogue reported to date, OXF-077. Furthermore, we demonstrate that as a potent inhibitor of the mutagenic SOS response, OXF-077 suppresses the rate of ciprofloxacin resistance emergence in S. aureus. This work supports SOS-response inhibitors as a novel means to combat AMR, and delivers OXF-077 as a tool molecule for future development.

Breaking Binaries: The Critical Need for Feminist Bioethics in Pediatric Gender-Affirming Care.

This commentary responds to Moti Gorin's article "What Is the Aim of Pediatric 'Gender-Affirming' Care?" We argue that Gorin's case against pediatric gender-affirming care rests upon numerous false conceptual binaries: female/male, public/private, objective/subjective, and medically necessary/elective. Drawing on feminist bioethics, we show how such dichotomous thinking is both inaccurate and marginalizing of gender minorities.

Comparing Intubation Rates in Patients Receiving Parenteral Olanzapine With and Without a Parenteral Benzodiazepine in the Emergency Department.

STUDY OBJECTIVE: United States prescribing information recommends against coadministration of injectable olanzapine with injectable benzodiazepines due to a risk of cardiorespiratory depression, whereas European prescribing information recommends the 2 drugs not be administered within 60 minutes of each other. In contrast, a recently published American College of Emergency Physicians clinical policy recommends injectable olanzapine and benzodiazepines be coadministered for treating severe agitation. We sought to compare injectable olanzapine with and without injectable benzodiazepines for evidence of cardiorespiratory depression. METHODS: We performed a retrospective study of patients in an urban emergency department from January 2017 through November 2019 who received parenteral olanzapine with or without parenteral benzodiazepines. We included patients receiving 2 total medication doses, either olanzapine+benzodiazepine or 2 doses of olanzapine, coadministered within 60 minutes. The primary outcome was tracheal intubation in the emergency department. Secondary outcomes included hypotension (systolic blood pressure less than 90 mmHg) and hypoxemia (SpO2 less than 90%). RESULTS: We identified 693 patients (median [alcohol]=210 mg/dL, median age=37 years [IQR 29 to 49]). In total, 549 received 2 doses of olanzapine, and 144 patients received olanzapine and a benzodiazepine. We found no difference in intubation rates between the olanzapine-only group (21/549, 3.8%) and the olanzapine+benzodiazepine group (5/144, 3.5%; difference=0.3%, 95% confidence interval -3.0% to 3.7%). Rates of hypoxemia (2% olanzapine-only and 3% olanzapine+benzodiazepine) and hypotension (9% both groups) also were not different between groups. CONCLUSION: We found no difference in cardiorespiratory depression between patients receiving only olanzapine versus olanzapine plus a benzodiazepine.

Tumor immunogenicity regulates host immune responses, and conventional dendritic cell type 2 uptakes the majority of tumor antigens in an orthotopic lung cancer model.

Human lung cancer carries high genetic alterations, expressing high tumor-specific neoantigens. Although orthotopic murine lung cancer models recapitulate many characteristics of human lung cancers, genetically engineered mouse models have fewer somatic mutations than human lung cancer, resulting in scarce immune cell infiltration and deficient immune responses. The endogenous mouse lung cancer model driven by Kras mutation and Trp53 deletion (KP model) has minimal immune infiltration because of a scarcity of neoantigens. Fine-tuning tumor antigenicity to trigger the appropriate level of antitumor immunity would be key to investigating immune responses against human lung cancer. We engineered the KP model to express antigens of OVA peptides (minOVA) as neoantigens along with ZsGreen, a traceable fluorescent conjugate. The KP model expressing minOVA exhibited stronger immunogenicity with higher immune cell infiltration comprised of CD8+ T cells and CD11c+ dendritic cells (DCs). Consequentially, the KP model expressing minOVA exhibits suppressed tumor growth compared to its origin. We further analyzed tumor-infiltrated DCs. The majority of ZsGreen conjugated with minOVA was observed in the conventional type 2 DCs (cDC2), where cDC1 has minimal. These data indicate that tumor immunogenicity regulates host immune responses, and tumor neoantigen is mostly recognized by cDC2 cells, which may play a critical role in initiating anti-tumor immune responses in an orthotopic murine lung cancer model.

Experimental evidence that dung beetles benefit from reduced ivermectin in targeted treatment of livestock parasites.

Anthelmintic residues in livestock dung can adversely affect beneficial organisms. Targeted selective treatment (TST) of a reduced proportion of livestock with anthelmintics can slow resistance development in gastrointestinal nematodes by providing residue-free dung which could also benefit non-target organisms. We tested effects of TST on survival and reproduction of the dung beetle Onthophagus taurus (Scarabaeidae) in a factorial glasshouse experiment (Experimental treatments: five TST levels, 0.00, 0.25, 0.50, 0.75, 1.00 x four ivermectin concentrations, 125, 250, 375, 500 ppb). Each mesocosm comprised a 60 L bin containing sand, four dung pats and six pairs of adult beetles (F0 generation). No effects of TST level and ivermectin concentration on mortality of F0 adults after one week were observed. F0 adult brood ball production was affected by TST level, particularly at high ivermectin concentrations. Brood ball production increased as more untreated pats became available, with greater increases at higher ivermectin concentrations. We tested for evidence of a reported attraction of dung beetles to ivermectin-treated dung using a novel glitter-marker to trace the origin of dung used in brood balls. Where mesocosms contained both dung types, the proportion of brood balls created from untreated dung showed no statistical difference from the null expectation based on untreated dung availability in the mesocosm. Emergence of F1 adults was affected by the increase in TST, with this effect dependent on concentration. Treatments with concentrations of 250-500 ppb had the lowest emergence rates (ca. 5-20 % in mesocosms where all dung pats were treated) but emergence rates increased with TST level, reaching 68-88 % emergence where no dung pats were treated with ivermectin. Ivermectin-induced mortality occurred predominantly at egg and first instar stages. TST can provide refuges for dung beetles offering a strategy for livestock producers to maintain livestock welfare whilst benefiting from ecosystem services provided by important insects.

Prior fragility fractures are associated with a higher risk of 8-year complications following total shoulder arthroplasty.

Patients who sustain fragility fractures prior to total shoulder arthroplasty have significantly higher risk for bone health-related complications within 8 years of procedure. Identification of these high-risk patients with an emphasis on preoperative, intraoperative, and postoperative bone health optimization may help minimize these preventable complications. PURPOSE: As the population ages, more patients with osteoporosis are undergoing total shoulder arthroplasty (TSA), including those who have sustained a prior fragility fracture. Sustaining a fragility fracture before TSA has been associated with increased risk of short-term revision rates, periprosthetic fracture (PPF), and secondary fragility fractures but long-term implant survivorship in this patient population is unknown. Therefore, the purpose of this study was to characterize the association of prior fragility fractures with 8-year risks of revision TSA, periprosthetic fracture, and secondary fragility fracture. METHODS: Patients aged 50 years and older who underwent TSA were identified in a large national database. Patients were stratified based on whether they sustained a fragility fracture within 3 years prior to TSA. Patients who had a prior fragility fracture (7631) were matched 1:1 to patients who did not based on age, gender, Charlson Comorbidity Index (CCI), smoking, obesity, diabetes mellitus, and alcohol use. Kaplan-Meier and Cox Proportional Hazards analyses were used to observe the cumulative incidences of all-cause revision, periprosthetic fracture, and secondary fragility fracture within 8 years of index surgery. RESULTS: The 8-year cumulative incidence of revision TSA (5.7% vs. 4.1%), periprosthetic fracture (3.8% vs. 1.4%), and secondary fragility fracture (46.5% vs. 10.1%) were significantly higher for those who had a prior fragility fracture when compared to those who did not. On multivariable analysis, a prior fragility fracture was associated with higher risks of revision (hazard ratio [HR], 1.48; 95% confidence interval [CI], 1.24-1.74; p < 0.001), periprosthetic fracture (HR, 2.98; 95% CI, 2.18-4.07; p < 0.001) and secondary fragility fracture (HR, 8.39; 95% CI, 7.62-9.24; p < 0.001). CONCLUSIONS: Prior fragility fracture was a significant risk factor for revision, periprosthetic fracture, and secondary fragility fracture within 8 years of primary TSA. Identification of these high-risk patients with an emphasis on preoperative and postoperative bone health optimization may help minimize these complications. LEVEL OF EVIDENCE: III.

Response to von Schmalensee et al.

Von Schmalensee et al. present two concerns about our study. While the first stems from a general disagreement about our simulation methodology, the second is a useful observation of a modelling choice we made that affected simulation outcomes, but in ways that do not invalidate our original conclusions.

IgG Testing, Immunoglobulin Replacement Therapy, and Infection Outcomes in Patients with CLL or NHL: Real-World Evidence.

Patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) can develop hypogammaglobulinemia, a form of secondary immune deficiency (SID), from the disease and treatments. Patients with hypogammaglobulinemia with recurrent infections may benefit from immunoglobulin replacement therapy (IgRT). This study evaluated patterns of IgG testing and the effectiveness of IgRT in real-world patients with CLL or NHL. A retrospective, longitudinal study was conducted among adult patients diagnosed with CLL or NHL. Clinical data from the Massachusetts General Brigham Research Patient Data Registry were used. IgG testing, infections, and antimicrobial use were compared before vs. 3, 6, and 12 months after IgRT initiation. Generalized estimating equation logistic regression models were used to estimate odds ratios (OR), 95% Confidence Intervals (CIs), and P-values. The study population included 17,192 patients (CLL: N=3,960; median age, 68 years; NHL: N=13,232; median age, 64 years). In the CLL and NHL cohorts, 67% and 51.2% had IgG testing and 6.5% and 4.7% received IgRT, respectively. Following IgRT initiation, the proportion of patients with hypogammaglobulinemia, the odds of infections or severe infections, and associated antimicrobial use, decreased significantly. Increased frequency of IgG testing was associated with a significantly lower likelihood of severe infection. In conclusion, in real-world patients with CLL or NHL, IgRT was associated with significant reductions in hypogammaglobulinemia, infections, severe infections, and associated antimicrobials. Optimizing IgG testing and IgRT are warranted for the comprehensive management of SID in patients with CLL or NHL.

Gastrointestinal Stromal Tumour of the Appendix: A Very Rare Entity.

A 74-year-old man who presented with upper abdominal pain was found to have an incidental appendiceal mass on cross-sectional imaging. He underwent a laparoscopic appendicectomy with histopathological examination confirming a completely resected appendiceal gastrointestinal stromal tumour (GIST). Appendiceal GISTs are rare. Therefore, there is limited evidence to guide risk stratification and management with extrapolation of prognosis from data on GISTs at other sites. This paper highlights the rarity of these tumours and presents another case which correlates well with the existing but limited literature. There is a need to maintain a registry of this rare disease entity with the maintenance of longer-term follow-up data.

Effects of telemetry collars on two free-roaming feral equid species.

There are two species of free-roaming feral equids in North America: horses (Equus caballus) and donkeys or "burros" (E. asinus). Both species were introduced as domestic animals to North America in the early 1500s and currently inhabit rangelands across the western United States, Canada, and all continents except Antarctica. Despite their global distribution, little is known about their fine scale spatial ecology. Contemporary research tools to assess space use include global positioning system (GPS) tracking collars, but older models were problematic due to stiff collar belting causing poor fit. We tested modern designs of GPS collars on n = 105 horses and n = 60 burros for 4 years in five populations (3 horse, 2 burro) across the western United States, to assess whether collars posed welfare risks to horses or burros. We found no difference in survival of collared versus uncollared mares and jennies, and no difference in survival of their foals. In 4036 of 4307 observations for horses (93.7%) and 2115 of 2258 observations for burros (93.6%), collars were observed symmetrical, maintaining proper fit on the neck. Fur effects from collars (sweaty neck, indented fur, broken fur) were seen in 3% of horse observations and 25% of burro observations. Superficial effects (chafes and marks on skin surface) were seen in 2% of horse observations and 11% of burro observations; no severe effects from collars were seen. Body condition was not affected by collars; mean body condition of collared horses was 4.70 ± 0.54 (mean ± s.d) and 4.71 ± 0.65 for collared burros. Behavior results indicated minimal effects; collared horses stood slightly more than uncollared, and collared burros stood and foraged more in one population, but not in the other. For 6.3% of observations of horses and 6.4% of observations of burros, we found an effect of time wearing a collar on the cumulative sum of fur effects which increased over time (burros: rs = 0.87, P = <0.0001; horses: rs = 0.31, P = 0.002). Burros also showed an increase over time in the number of superficial effects, but horses did not. Collars occasionally moved into the wrong position, shifting forward over the ears; we observed this on 19 horses and 1 burro. Of those, most collars went over the ears in summer (n = 12). All collars were equipped with a remote release mechanism as well as a timed-release mechanism for redundancy, thus removed when observed in wrong position to avoid rubbing or discomfort. Our finding of no consequential physical effects in 98% of horse observations, and 89% of burro observations suggests the consequences of collars on free-roaming equid welfare and survival is biologically insignificant, although collars should be monitored regularly and continue to be equipped with a remote release mechanism to remove a collar if needed. With frequent welfare-driven, visual monitoring, collaring of free-roaming equids can be a safe and useful tool to increase our understanding of their spatial ecology, demography, habitat use, behavior, and interactions with other wildlife.

Epidemiology of physical activity and sedentary behavior levels among patients entering treatment for substance use disorder in the United States: a descriptive study.

Introduction: Little is known about physical activity behaviors among people with SUD. This study aimed to (a) describe self-reported moderate-to-vigorous physical activity (MVPA) and sedentary (SED) behaviors of adults with SUD initiating treatment (b), determine the potential contributions of drug of choice (DOC) on these behaviors, and (c) determine the potential contributions of level of care and demographic variables on these behaviors. Methods: Secondary data that was collected via surveys including demographic information, psychological health, drug of choice, MVPA (categorized as inactive, insufficiently active, meets guidelines, exceeds guidelines) and SED (<4 h/day, 4-<6 h/day, 6-8 h/day, >8 h/day) were analyzed from 1,293 patients in inpatient/outpatient treatment facilities across the United States. Results: On average, over half (51%) of patients entering treatment reported not meeting guidelines, but sitting time was generally low (median= 360 min/day). MVPA levels differed based on level of care (p<0.001) with 48% of patients in detox facilities reporting inactivity compared to 37% in residential and 29% in outpatient programs. MVPA and SED levels differed by sex with women less likely to report sitting <4 h/day (27.9% vs. 38.2%, p<0.001) and more likely to report sitting for >8 h/day (31.5% vs. 21.8%, p<0.001) compared to men. SED differed by race (p=0.01), with 54% of Black patients reporting <4 h/day compared to 33% of White patients. Discussion: Understanding activity behavior patterns among individuals entering SUD treatment provides opportunities for identifying the extent of lifestyle behavior needs and opportunities to develop personalized treatment strategies.

Deliberately introduced dung beetles in Australia: 12 years of occurrence and abundance records from 2001 to 2022.

Since 1968, the Australian Dung Beetle Project has carried out field releases of 43 deliberately introduced dung beetle species for the biological control of livestock dung and dung-breeding pests. Of these, 23 species are known to have become established. For most of these species, sufficient time has elapsed for population expansion to fill the extent of their potential geographic range through both natural and human-assisted dispersal. Consequently, over the last 20 years, extensive efforts have been made to quantify the current distribution of these introduced dung beetles, as well as the seasonal and spatial variation in their activity levels. Much of these data and their associated metadata have remained unpublished, and they have not previously been synthesized into a cohesive dataset. Here, we collate and report data from the three largest dung beetle monitoring projects from 2001 to 2022. Together, these projects encompass data collected from across Australia, and include records for all 23 species of established dung beetles introduced for biocontrol purposes. In total, these data include 22,718 presence records and 213,538 absence records collected during 10,272 sampling events at 546 locations. Most presence records (97%) include abundance data. In total, 1,752,807 dung beetles were identified as part of these data. The distributional occurrence and abundance data can be used to explore questions such as factors influencing dung beetle species distributions, dung beetle biocontrol, and insect-mediated ecosystem services. These data are provided under a CC-BY-NC 4.0 license and users are encouraged to cite this data paper when using the data.

MolModa: accessible and secure molecular docking in a web browser.

Molecular docking advances early-stage drug discovery by predicting the geometries and affinities of small-molecule compounds bound to drug-target receptors, predictions that researchers can leverage in prioritizing drug candidates for experimental testing. Unfortunately, existing docking tools often suffer from poor usability, data security, and maintainability, limiting broader adoption. Additionally, the complexity of the docking process, which requires users to execute a series of specialized steps, often poses a substantial barrier for non-expert users. Here, we introduce MolModa, a secure, accessible environment where users can perform molecular docking entirely in their web browsers. We provide two case studies that illustrate how MolModa provides valuable biological insights. We further compare MolModa to other docking tools to highlight its strengths and limitations. MolModa is available free of charge for academic and commercial use, without login or registration, at https://durrantlab.com/molmoda.

The chaperone PrsA2 regulates the secretion, stability, and folding of listeriolysin O during Listeria monocytogenes infection.

Pathogenic bacteria rely on secreted virulence factors to cause disease in susceptible hosts. However, in Gram-positive bacteria, the mechanisms underlying secreted protein activation and regulation post-membrane translocation remain largely unknown. Using proteomics, we identified several proteins that are dependent on the secreted chaperone PrsA2. We followed with phenotypic, biochemical, and biophysical assays and computational analyses to examine the regulation of a detected key secreted virulence factor, listeriolysin O (LLO), and its interaction with PrsA2 from the bacterial pathogen Listeria monocytogenes (Lm). Critical to Lm virulence is internalization by host cells and the subsequent action of the cholesterol-dependent pore-forming toxin, LLO, which enables bacterial escape from the host cell phagosome. Since Lm is a Gram-positive organism, the space between the cell membrane and wall is solvent exposed. Therefore, we hypothesized that the drop from neutral to acidic pH as the pathogen is internalized into a phagosome is critical to regulating the interaction of PrsA2 with LLO. Here, we demonstrate that PrsA2 directly interacts with LLO in a pH-dependent manner. We show that PrsA2 protects and sequesters LLO under neutral pH conditions where LLO can be observed to aggregate. In addition, we identify molecular features of PrsA2 that are required for interaction and ultimately the folding and activity of LLO. Moreover, protein-complex modeling suggests that PrsA2 interacts with LLO via its cholesterol-binding domain. These findings highlight a mechanism by which a Gram-positive secretion chaperone regulates the secretion, stability, and folding of a pore-forming toxin under conditions relevant to host cell infection. IMPORTANCE: Lm is a ubiquitous food-borne pathogen that can cause severe disease to vulnerable populations. During infection, Lm relies on a wide repertoire of secreted virulence factors including the LLO that enables the bacterium to invade the host and spread from cell to cell. After membrane translocation, secreted factors must become active in the challenging bacterial cell membrane-wall interface. However, the mechanisms required for secreted protein folding and function are largely unknown. Lm encodes a chaperone, PrsA2, that is critical for the activity of secreted factors. Here, we show that PrsA2 directly associates and protects the major Lm virulence factor, LLO, under conditions corresponding to the host cytosol, where LLO undergoes irreversible denaturation. Additionally, we identify molecular features of PrsA2 that enable its interaction with LLO. Together, our results suggest that Lm and perhaps other Gram-positive bacteria utilize secreted chaperones to regulate the activity of pore-forming toxins during infection.

Treatment with dextroamphetamine decreases the reacquisition of cocaine self-administration: Consistency across social contexts.

RATIONALE: A return to cocaine use following abstinence frequently occurs in a social context, and the presence of other individuals using cocaine may contribute to the likelihood of use. Previous studies have reported that chronic d-amphetamine treatment decreases cocaine self-administration in laboratory animals and reduces a return to cocaine use following abstinence in humans. OBJECTIVE: The purpose of this study was to examine the effects of chronic d-amphetamine treatment on the reacquisition of cocaine use in rats self-administering cocaine in different social contexts. METHODS: Male and female rats were implanted with intravenous catheters and trained to self-administer cocaine during daily 6-hr sessions. After 14 days, cocaine self-administration was extinguished by substituting saline for the cocaine stimulus. At this time, rats were randomized to receive chronic treatment with either d-amphetamine or saline. After 9 days of extinction, cocaine was again made available during daily 6-hr sessions. At this time, rats were further randomized into three social conditions: (1) rats continued self-administering cocaine in isolation, (2) rats self-administered cocaine in the presence of a same-sex partner that also self-administered cocaine, or (3) rats self-administered cocaine in the presence of a same-sex partner that did not have access to cocaine. Daily treatment with d-amphetamine or saline continued for the duration of reacquisition testing. RESULTS: Chronic treatment with d-amphetamine decreased cocaine intake during reacquisition, but these effects were not influenced by the social context. No sex differences were observed. CONCLUSION: These data support previous studies reporting that d-amphetamine decreases cocaine intake and demonstrate its efficacy across social contexts.

Heat exhaustion and heat stroke among active component members of the U.S. Armed Forces, 2019-2023.

The most serious types of heat illnesses, heat exhaustion and heat stroke, are occupational hazards associated with many of the military's training and operational environments. These illnesses can typically be prevented by appropriate situational awareness, risk management strategies, along with effective countermeasures. In 2023, the crude incidence of heat stroke and heat exhaustion were 31.7 and 172.7 cases per 100,000 person-years, respectively. The rates of incident heat stroke declined during the 2019 to 2023 surveillance period, but rates of incident heat exhaustion increased over the same period. In 2023, higher rates of heat stroke were observed among male service members compared to their female counterparts, and female service members experienced higher rates of heat exhaustion compared to male personnel. Heat illness rates were also higher among those younger than age 20, Marine Corps and Army service members, non-Hispanic Black service members, and recruits. Leaders, training cadres, and supporting medical and safety personnel must inform their subordinate and supported service members of heat illness risks, preventive measures, early signs and symptoms of illness, and appropriate interventions.

Predictability of B cell clonal persistence and immunosurveillance in breast cancer.

B cells and T cells are important components of the adaptive immune system and mediate anticancer immunity. The T cell landscape in cancer is well characterized, but the contribution of B cells to anticancer immunosurveillance is less well explored. Here we show an integrative analysis of the B cell and T cell receptor repertoire from individuals with metastatic breast cancer and individuals with early breast cancer during neoadjuvant therapy. Using immune receptor, RNA and whole-exome sequencing, we show that both B cell and T cell responses seem to coevolve with the metastatic cancer genomes and mirror tumor mutational and neoantigen architecture. B cell clones associated with metastatic immunosurveillance and temporal persistence were more expanded and distinct from site-specific clones. B cell clonal immunosurveillance and temporal persistence are predictable from the clonal structure, with higher-centrality B cell antigen receptors more likely to be detected across multiple metastases or across time. This predictability was generalizable across other immune-mediated disorders. This work lays a foundation for prioritizing antibody sequences for therapeutic targeting in cancer.

Genetic tuning of intrinsically photosensitive retinal ganglion cell subtype identity to drive visual behavior.

The melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs) comprise a subset of the ∼40 retinal ganglion cell types in the mouse retina and drive a diverse array of light-evoked behaviors from circadian photoentrainment to pupil constriction to contrast sensitivity for visual perception. Central to the ability of ipRGCs to control this diverse array of behaviors is the distinct complement of morphophysiological features and gene expression patterns found in the M1-M6 ipRGC subtypes. However, the genetic regulatory programs that give rise to subtypes of ipRGCs are unknown. Here, we identify the transcription factor Brn3b (Pou4f2) as a key genetic regulator that shapes the unique functions of ipRGC subtypes and their diverse downstream visual behaviors.

Engineering Memory T Cells as a platform for Long-Term Enzyme Replacement Therapy in Lysosomal Storage Disorders.

Enzymopathy disorders are the result of missing or defective enzymes. Amongst these enzymopathies, mucopolysaccharidosis type I, is a rare genetic lysosomal storage disorder caused by mutations in the gene encoding alpha-L-iduronidase (IDUA), ultimately causes toxic build-up of glycosaminoglycans (GAGs). There is currently no cure and standard treatments provide insufficient relief to the skeletal structure and central nervous system (CNS). Human memory T cells (Tm) migrate throughout the body's tissues and can persist for years, making them an attractive approach for cellular-based, systemic enzyme replacement therapy. Here, we tested genetically engineered, IDUA-expressing Tm as a cellular therapy in an immunodeficient mouse model of MPS I. Our results demonstrate that a single dose of engineered Tm leads to detectable IDUA enzyme levels in the blood for up to 22 weeks and reduced urinary GAG excretion. Furthermore, engineered Tm take up residence in nearly all tested tissues, producing IDUA and leading to metabolic correction of GAG levels in the heart, lung, liver, spleen, kidney, bone marrow, and the CNS. Our study indicates that genetically engineered Tm holds great promise as a platform for cellular-based enzyme replacement therapy for the treatment of mucopolysaccharidosis type I and potentially many other enzymopathies and protein deficiencies.