Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity.

Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated metabolic gene across human cancers. Mutant IDH1 (mIDH1) generates the oncometabolite (R)-2-hydroxyglutarate, disrupting enzymes involved in epigenetics and other processes. A hallmark of IDH1-mutant solid tumors is T cell exclusion, whereas mIDH1 inhibition in preclinical models restores antitumor immunity. Here, we define a cell-autonomous mechanism of mIDH1-driven immune evasion. IDH1-mutant solid tumors show selective hypermethylation and silencing of the cytoplasmic double-stranded DNA (dsDNA) sensor CGAS, compromising innate immune signaling. mIDH1 inhibition restores DNA demethylation, derepressing CGAS and transposable element (TE) subclasses. dsDNA produced by TE-reverse transcriptase (TE-RT) activates cGAS, triggering viral mimicry and stimulating antitumor immunity. In summary, we demonstrate that mIDH1 epigenetically suppresses innate immunity and link endogenous RT activity to the mechanism of action of a US Food and Drug Administration-approved oncology drug.

Comparing opioid utilization and costs for surgical management of single-level spondylolisthesis: A national claims database analysis.

Introduction: The rise in degenerative lumbar spondylolisthesis (DLS) cases has led to a significant increase in fusion surgeries, which incur substantial hospitalization costs and often necessitate chronic opioid use for pain management. Recent evidence suggests that single-level low-grade DLS outcomes are comparable whether a fusion procedure or decompression alone is performed, sparking debate over the cost-effectiveness of these procedures, particularly with the advent of minimally invasive techniques reducing the morbidity of fusion. This study aims to compare chronic opioid utilization and associated costs between decompression alone and decompression with instrumented fusion for single-level degenerative lumbar spondylolisthesis. Material and methods: Using data from the PearlDiver database, a retrospective database analysis was conducted. We analyzed records of Medicare and Medicaid patients undergoing lumbar fusion or decompression from 2010 to 2022. Patient cohorts were divided into decompression alone (DA) and decompression with instrumented fusion (DIF). Chronic opioid use, pain clinic visits, and total costs were compared between the two groups at 90 days, 1 year, and 2 years post-surgery. Theory: Does DIF offer a more cost-effective approach to managing DLS in terms of chronic opioid use in single-level DLS patients. Results: The study revealed comparable chronic opioid use and pain clinic visits between DA and DIF groups at 90 days and 1 year. However, total costs associated with opioid prescriptions as well as surgical aftercare were significantly higher in the DIF group at 90 days (p < 0.05), 1 year (p < 0.05), and 2 years (p < 0.05) post-surgery compared to the DA group. Conclusions: This study highlights the higher costs associated with DIF up to 2 years post-surgery despite comparable symptom improvement when compared to DA and DIF at the 1-year interval. DA emerges as a more financially favorable option, challenging the notion of fusion's cost-offsetting benefits. While further investigation is needed to understand underlying cost drivers and optimize outcomes, our findings emphasize the necessity of integrating clinical and economic factors in the management of single-level DLS.

A Comparison of Rosuvastatin Monotherapy and Rosuvastatin Plus Ezetimibe Combination Therapy in Patients With Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials.

Type 2 diabetes mellitus is a metabolic condition where vascular inflammation and oxidative stress contribute to disease progression and associated complications. Although statins are recommended for managing dyslipidemia in diabetes, additional therapies are often required to achieve target lipid levels. This meta-analysis aimed to evaluate the efficacy of rosuvastatin monotherapy versus combination therapy with ezetimibe in patients with type 2 diabetes. A systematic literature search was conducted across multiple databases until April 2024, identifying six randomized controlled trials meeting the inclusion criteria. The meta-analysis revealed that the rosuvastatin plus ezetimibe combination resulted in significantly greater reductions in total cholesterol (mean difference, or MD: 19.49; 95% CI: 13.99 to 24.99), triglycerides (MD: 13.44; 95% CI: 2.04 to 24.85), and low-density lipoprotein cholesterol (MD: -17.68; 95% CI: 12.85 to 22.51) compared to rosuvastatin monotherapy. Conversely, rosuvastatin monotherapy achieved a greater reduction in HbA1c levels (MD: -0.11; 95% CI: -0.17 to -0.04). Subgroup analysis demonstrated that using the same dose of rosuvastatin in both groups led to more significant improvements in lipid parameters with lower heterogeneity. The findings suggest that the rosuvastatin-ezetimibe combination may be a more effective lipid-lowering strategy for patients with type 2 diabetes, though larger studies are needed to assess long-term safety and optimal dosing. Additionally, while rosuvastatin monotherapy provided modest HbA1c reductions, the clinical relevance remains uncertain, and potential risks with high-dose statins should be considered.

Effect of Pulmonary Hypertension on Survival Outcomes in Patients With Transcatheter Aortic Valve Replacement: A Systematic Review and Meta-Analysis.

The aim of this meta-analysis was to determine the effect of pulmonary hypertension (PH) on survival in patients undergoing transcatheter aortic valve replacement (TAVR). The present study was conducted according to the guidelines of Preferred Reporting of Systematic Review and Meta-Analysis (PRISMA). We conducted a comprehensive search of electronic databases including PubMed/MEDLINE, Embase, Cochrane Library, and Web of Science from January 1, 2015, to March 10, 2024. Outcomes assessed in this meta-analysis included early and late all-cause mortality and cardiovascular mortality. Total 15 studies were integrated into the pooled analysis to assess the impact of PH on outcomes among patients undergoing TAVR, comprising a total sample size of 35,732 individuals. The pooled prevalence of PH stood at 52.57% (n=18,767). Predominantly, the studies were conducted in the United States (n=6), followed by Germany (n=3), with one study each from Japan, Italy, Switzerland, Brazil, Poland, and Australia. Pooled analysis showed that risk of short-term mortality was greater in patients with PH compared to patients without PH (risk ratio (RR): 1.46, 95% CI: 1.19 to 1.80). Risk of long-term mortality was greater in patients with PH (RR: 1.42, 95% CI: 1.29 to 1.55). Risk of cardiovascular mortality was also greater in patients with PH compared to patients without PH (RR: 1.66, 95% CI: 1.36 to 2.02). We advocate for further research to address gaps in understanding different types of PH and their impacts on mortality and cardiovascular outcomes.

Trends in Pediatric Attention-Deficit Hyperactive Disorder Diagnoses and Prescription Utilization: 2016 to 2019.

OBJECTIVE: Attention-deficit hyperactive disorder (ADHD) is one of the most common psychiatric disorders among children, with estimated prevalence of 7% to 15% worldwide. The aim of this analysis was to update and summarize trends in diagnosis, demographics, and drug utilization of pediatric patients with ADHD. METHODS: We used the Agency for Health care Research and Quality Medical Expenditure Panel Survey (MEPS), a survey of US individuals, families, their medical providers, and employers, using datasets from 2016 to 2019. The data sources from the MEPS database included the full-year consolidated files, medical conditions files, prescribed-medicines files, and condition-event link files for each year. We summarized trends in the proportion of children, ages 17 years and younger, with a diagnosis of ADHD, demographic information and a prescription for medication known to treat ADHD. In addition, we further stratified ADHD medication use by stimulant/nonstimulant categories. RESULTS: There was a 1.6% and 4.7% absolute increase in children with an ADHD diagnosis and those prescribed ADHD medications, respectively, from 2016 to 2019. Most of these children were male, non-Hispanic, and on public insurance. Of the children prescribed an ADHD medication and concomitant behavioral medications, stimulants-only use was the highest (60%-67%), followed by stimulants/nonstimulants (13%-15%), stimulant/antidepressants (6%-9%), and nonstimulants only (5%-9%). The proportion of patients with ADHD in the high-income and near-poor categories increased by 4% from 2016 to 2019. CONCLUSION: Diagnosis of ADHD among children is trending upward in the United States. Central nervous system stimulants, especially methylphenidate formulations, are the most prescribed ADHD medications for children 17 years and younger.

Strategies and outcomes of extracorporeal membrane oxygenation use in peripartum patients: a single institution experience.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) use in peripartum patients is rare, and there is a gap in the literature on the outcomes and guidance on using ECMO in peripartum patients. This study describes ECMO strategies our institution uses for peripartum patients and reports outcomes of ECMO use in peripartum patients with respiratory and/or cardiac failure. METHODS: A case series of all peripartum patients, defined as pregnant or up to 6 weeks after delivery of an infant >20 weeks gestation, from 2018 to 2023 from a single center requiring ECMO support. Patients were included if ECMO was initiated in the setting of cardiac, pulmonary, or combined failure. Patient demographics, operative details, ECMO data, and adverse outcomes for maternal, fetus, and neonates were all collected. RESULTS: Eighteen patients met the inclusion criteria. The cohort had a mean maternal age of 30.7 years old and was racially diverse. A majority of this cohort tested positive for COVID-19 (n = 10, 55%). ECMO was a bridge to recovery for all patients, of whom 14 (78%) were discharged out of the hospital alive. No patients received transplantation or a durable mechanical device. The most common complications were infection (25%) and postpartum hemorrhage (22%). CONCLUSIONS: ECMO use in peripartum patients in a single tertiary center was associated with a high survival rate. Furthermore, a strong multidisciplinary team, careful reevaluation of clinical trajectory, and consideration of complications and risks associated with using ECMO in peripartum patients are possible frameworks to use when challenged with critically ill peripartum patients.

Anti-Ha Antisynthetase Syndrome: A Case Report.

Anti-synthetase syndrome (ASyS) is a rare systemic autoimmune myopathy characterized by the involvement of muscles, lungs, and joints, in addition to Raynaud's phenomenon, "mechanics' hand," and fever. Laboratory ASyS is defined by the positivity of anti-aminoacyl-tRNA synthetase autoantibodies, of which anti-Jo-1 is the most common. Herein, we reported an ASyS defined by an anti-Ha autoantibody, which has rarely been described in the literature. Moreover, to the best of our knowledge, we reported the first case of anti-Ha ASyS in Brazil.

An analysis of ChatGPT recommendations for the diagnosis and treatment of cervical radiculopathy.

OBJECTIVE: The objective of this study was to assess the safety and accuracy of ChatGPT recommendations in comparison to the evidence-based guidelines from the North American Spine Society (NASS) for the diagnosis and treatment of cervical radiculopathy. METHODS: ChatGPT was prompted with questions from the 2011 NASS clinical guidelines for cervical radiculopathy and evaluated for concordance. Selected key phrases within the NASS guidelines were identified. Completeness was measured as the number of overlapping key phrases between ChatGPT responses and NASS guidelines divided by the total number of key phrases. A senior spine surgeon evaluated the ChatGPT responses for safety and accuracy. ChatGPT responses were further evaluated on their readability, similarity, and consistency. Flesch Reading Ease scores and Flesch-Kincaid reading levels were measured to assess readability. The Jaccard Similarity Index was used to assess agreement between ChatGPT responses and NASS clinical guidelines. RESULTS: A total of 100 key phrases were identified across 14 NASS clinical guidelines. The mean completeness of ChatGPT-4 was 46%. ChatGPT-3.5 yielded a completeness of 34%. ChatGPT-4 outperformed ChatGPT-3.5 by a margin of 12%. ChatGPT-4.0 outputs had a mean Flesch reading score of 15.24, which is very difficult to read, requiring a college graduate education to understand. ChatGPT-3.5 outputs had a lower mean Flesch reading score of 8.73, indicating that they are even more difficult to read and require a professional education level to do so. However, both versions of ChatGPT were more accessible than NASS guidelines, which had a mean Flesch reading score of 4.58. Furthermore, with NASS guidelines as a reference, ChatGPT-3.5 registered a mean ± SD Jaccard Similarity Index score of 0.20 ± 0.078 while ChatGPT-4 had a mean of 0.18 ± 0.068. Based on physician evaluation, outputs from ChatGPT-3.5 and ChatGPT-4.0 were safe 100% of the time. Thirteen of 14 (92.8%) ChatGPT-3.5 responses and 14 of 14 (100%) ChatGPT-4.0 responses were in agreement with current best clinical practices for cervical radiculopathy according to a senior spine surgeon. CONCLUSIONS: ChatGPT models were able to provide safe and accurate but incomplete responses to NASS clinical guideline questions about cervical radiculopathy. Although the authors' results suggest that improvements are required before ChatGPT can be reliably deployed in a clinical setting, future versions of the LLM hold promise as an updated reference for guidelines on cervical radiculopathy. Future versions must prioritize accessibility and comprehensibility for a diverse audience.

Genome-wide association study for yield and quality of granulated cassava processed product.

The starchy storage roots of cassava are commonly processed into a variety of products, including cassava granulated processed products (gari). The commercial value of cassava roots depends on the yield and quality of processed products, directly influencing the acceptance of new varieties by farmers, processors, and consumers. This study aims to estimate genetic advance through phenotypic selection and identify genomic regions associated and candidate genes linked with gari yield and quality. Higher single nucleotide polymorphism (SNP)-based heritability estimates compared to broad-sense heritability estimates were observed for most traits highlighting the influence of genetic factors on observed variation. Using genome-wide association analysis of 188 clones, genotyped using 53,150 genome-wide SNPs, nine SNPs located on seven chromosomes were significantly associated with peel loss, gari yield, color parameters for gari and eba, bulk density, swelling index, and textural properties of eba. Future research will focus on validating and understanding the functions of identified genes and their influence on gari yield and quality traits.

Design of Inhibitors That Target the Menin-Mixed-Lineage Leukemia Interaction.

The prognosis of mixed-lineage leukemia (MLL) has remained a significant health concern, especially for infants. The minimal treatments available for this aggressive type of leukemia has been an ongoing problem. Chromosomal translocations of the KMT2A gene are known as MLL, which expresses MLL fusion proteins. A protein called menin is an important oncogenic cofactor for these MLL fusion proteins, thus providing a new avenue for treatments against this subset of acute leukemias. In this study, we report results using the structure-based drug design (SBDD) approach to discover potential novel MLL-mediated leukemia inhibitors from natural products against menin. The three-dimensional (3D) protein model was derived from Protein Databank (Protein ID: 4GQ4), and EasyModeller 4.0 and I-TASSER were used to fix missing residues during rebuilding. Out of the ten protein models generated (five from EasyModeller and I-TASSER each), one model was selected. The selected model demonstrated the most reasonable quality and had 75.5% of residues in the most favored regions, 18.3% of residues in additionally allowed regions, 3.3% of residues in generously allowed regions, and 2.9% of residues in disallowed regions. A ligand library containing 25,131 ligands from a Chinese database was virtually screened using AutoDock Vina, in addition to three known menin inhibitors. The top 10 compounds including ZINC000103526876, ZINC000095913861, ZINC000095912705, ZINC000085530497, ZINC000095912718, ZINC000070451048, ZINC000085530488, ZINC000095912706, ZINC000103580868, and ZINC000103584057 had binding energies of -11.0, -10.7, -10.6, -10.2, -10.2, -9.9, -9.9, -9.9, -9.9, and -9.9 kcal/mol, respectively. To confirm the stability of the menin-ligand complexes and the binding mechanisms, molecular dynamics simulations including molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) computations were performed. The amino acid residues that were found to be potentially crucial in ligand binding included Phe243, Met283, Cys246, Tyr281, Ala247, Ser160, Asn287, Asp185, Ser183, Tyr328, Asn249, His186, Leu182, Ile248, and Pro250. MI-2-2 and PubChem CIDs 71777742 and 36294 were shown to possess anti-menin properties; thus, this justifies a need to experimentally determine the activity of the identified compounds. The compounds identified herein were found to have good pharmacological profiles and had negligible toxicity. Additionally, these compounds were predicted as antileukemic, antineoplastic, chemopreventive, and apoptotic agents. The 10 natural compounds can be further explored as potential novel agents for the effective treatment of MLL-mediated leukemia.

Fertility and pregnancy outcomes in primary hyperparathyroidism: Observations from a large insured population.

CONTEXT: Primary hyperparathyroidism (PHPT) has initially been implicated in adverse maternal and neonatal outcomes, while subsequent population studies have failed to show an association. OBJECTIVE: To compare maternal, pregnancy, and neonatal outcomes in patients with and without PHPT. DESIGN: Retrospective matched-cohort study (2005-2020). SETTING: An integrated healthcare delivery system in Southern California. PATIENTS: Women aged 18-44 years were included. Patients with biochemical diagnosis of PHPT were matched 1:3 with eucalcemic controls (non-PHPT). MAIN OUTCOME MEASURES: Achievement of pregnancy, pregnancy outcomes (including rates of abortion, maternal complications), and neonatal outcomes (including hypocalcemia, need for intensive care). RESULTS: The cohort comprised 386 women with PHPT and 1158 age-matched controls. Pregnancy rates between PHPT and control groups were similar (10.6% vs 12.8%). The adjusted rate ratio of pregnancy was 0.89 (95% CI: 0.64-1.24) (PHPT vs non-PHPT). Twenty-nine pregnancies occurred in women with co-existing PHPT and 191 pregnancies occurred in controls, resulting in 23 (79.3%) and 168 (88.0%) live births, respectively (p=0.023). Neonatal outcomes were similar. Live birth rates were similar (86.4%, 80%, 79.2%) for those undergoing parathyroidectomy prior (n=22), during (n=5), or after pregnancy/never (n=24). Among patients who underwent parathyroidectomy during pregnancy, no spontaneous abortions occurred in women entering pregnancy with peak calcium <11.5 mg/dL [2.9 mmol/L]. CONCLUSIONS: We observed no difference in pregnancy rates between women with or without PHPT. Performing parathyroidectomy before pregnancy or during the second trimester appears to be a safe and successful strategy, and adherence to this strategy may be most critical for patients with higher calcium levels (≥11.5 mg/dL [2.9 mmol/L]).

Genomic tailoring of autogenous poultry vaccines to reduce Campylobacter from farm to fork.

Campylobacter is a leading cause of food-borne gastroenteritis worldwide, linked to the consumption of contaminated poultry meat. Targeting this pathogen at source, vaccines for poultry can provide short-term caecal reductions in Campylobacter numbers in the chicken intestine. However, this approach is unlikely to reduce Campylobacter in the food chain or human incidence. This is likely as vaccines typically target only a subset of the high genomic strain diversity circulating among chicken flocks, and rapid evolution diminishes vaccine efficacy over time. To address this, we used a genomic approach to develop a whole-cell autogenous vaccine targeting isolates harbouring genes linked to survival outside of the host. We hyper-immunised a whole major UK breeder farm to passively target offspring colonisation using maternally-derived antibody. Monitoring progeny, broiler flocks revealed a near-complete shift in the post-vaccination Campylobacter population with an ~50% reduction in isolates harbouring extra-intestinal survival genes and a significant reduction of Campylobacter cells surviving on the surface of meat. Based on these findings, we developed a logistic regression model that predicted that vaccine efficacy could be extended to target 65% of a population of clinically relevant strains. Immuno-manipulation of poultry microbiomes towards less harmful commensal isolates by competitive exclusion, has major potential for reducing pathogens in the food production chain.

Evaluation of the EMA log kow trigger for fish BCF testing based on data for several human pharmaceuticals.

In the European Medicines Agency (EMA) "Guideline for Environmental Risk Assessment of Medicinal Products for Human Use," a fish bioconcentration factor (BCF) study is triggered in Phase I for pharmaceuticals having log Kow >4.5, to support Persistence, Bioaccumulation and Toxicity (PBT) screening, and in Phase II to assess secondary poisoning and bioaccumulation ('B') potential when log Kow ≥3. The standard sampling schedule outlined in OECD Test Guideline 305 (TG305) may require assessment of approximately 200 fish following exposure to low- and high-test concentrations and a negative control. We report experimental log Kow and BCF values for 64 human pharmaceuticals that were used to evaluate the current BCF testing trigger of log Kow ≥3, and whether a single BCF exposure concentration allows accurate classification of bioaccumulation potential. Our data support raising the BCF testing trigger to log Kow ≥4, and use of a single test concentration. The resulting reduction in the use of fish is consistent with the 3 R s principle and did not adversely affect classification accuracy. An assessment of potential risk of secondary poisoning was also conducted for three drugs classified as either B or vB, and no risks were identified.

Efficacy of Sodium-Glucose Cotransporter 2 Inhibitors in Preventing Heart Failure in Patients Receiving Anthracycline-Based Cancer Therapy: A Systematic Review and Meta-Analysis.

Anthracyclines are effective chemotherapeutic agents widely used to treat various cancers, but their use is limited by the risk of cardiotoxicity and heart failure. While strategies like dose reduction have been explored, there are no well-established therapies to mitigate this risk. Emerging evidence suggests sodium-glucose cotransporter 2 inhibitors (SGLT2i) may have cardioprotective effects, providing a rationale for investigating their potential utility in anthracycline-treated patients. We conducted a systematic review and meta-analysis to synthesize available evidence on the efficacy of SGLT2i in reducing heart failure incidence and mortality in patients undergoing anthracycline-based cancer therapy. Relevant studies were identified through comprehensive database searches and screened based on predefined criteria. Data extraction and quality assessment were performed independently by two reviewers. Four observational studies, encompassing 5,590 patients, were included. The pooled analysis showed a higher but non-significant risk of developing heart failure in the non-SGLT2i group compared to the SGLT2i group (RR = 0.67, 95% CI: 0.40-1.41). The risk of all-cause mortality was significantly lower in patients receiving SGLT2i (RR = 0.55, 95% CI: 0.39-0.77). This meta-analysis suggests SGLT2i are associated with a lower risk of mortality and heart failure incidence in anthracycline-treated patients, although larger studies are needed to confirm these findings. The mechanisms underlying these potential benefits require further elucidation. Despite limitations, this analysis highlights the promising role of SGLT2i as a cardioprotective strategy in this high-risk population.

Liposome-encapsulated cytochrome P450 and gibberellic acid biosynthesis in Priestia megaterium RP1.

This study explores the potential of liposome encapsulated silica immobilized cytochrome P450 monooxygenase (LSICY) for bioremediation of mercury (Hg2+). Current limitations in Hg2+ reduction, including sensitivity to factors like pH and cost, necessitate alternative methods. We propose LSICY as a solution, leveraging the enzymatic activities of cytochrome P450 monooxygenase (CYPM) for Hg2+ reduction through hydroxylation and oxygenation. Our investigation employs LSICY to assess its efficacy in mitigating Hg2+ toxicity in Oryza sativa (rice) plants. Gas chromatography confirmed gibberellic acid (GA) presence in the Hg2+ reducing bacteria Priestia megaterium RP1 (PMRP1), highlighting a potential link between CYP450 activity and plant health. This study demonstrates the promise of LSICY as a sustainable and effective approach for Hg2+ bioremediation, promoting a safer soil environment.

A Peptide Derived from Sorting Nexin 1 Inhibits HPV16 Entry, Retrograde Trafficking, and L2 Membrane Spanning.

High risk human papillomavirus (HPV) infection is responsible for 99% of cervical cancers and 5% of all human cancers worldwide. HPV infection requires the viral genome (vDNA) to gain access to nuclei of basal keratinocytes of epithelium. After virion endocytosis, the minor capsid protein L2 dictates the subcellular retrograde trafficking and nuclear localization of the vDNA during mitosis. Prior work identified a cell-permeable peptide termed SNX1.3, derived from the BAR domain of sorting nexin 1 (SNX1), that potently blocks the retrograde and nuclear trafficking of EGFR in triple negative breast cancer cells. Given the importance of EGFR and retrograde trafficking pathways in HPV16 infection, we set forth to study the effects of SNX1.3 within this context. SNX1.3 inhibited HPV16 infection by both delaying virion endocytosis, as well as potently blocking virion retrograde trafficking and Golgi localization. SNX1.3 had no effect on cell proliferation, nor did it affect post-Golgi trafficking of HPV16. Looking more directly at L2 function, SNX1.3 was found to impair membrane spanning of the minor capsid protein. Future work will focus on mechanistic studies of SNX1.3 inhibition, and the role of EGFR signaling and SNX1- mediated endosomal tubulation, cargo sorting, and retrograde trafficking in HPV infection.

A peptide derived from sorting nexin 1 inhibits HPV16 entry, retrograde trafficking, and L2 membrane spanning.

High risk human papillomavirus (HPV) infection is responsible for 99 % of cervical cancers and 5 % of all human cancers worldwide. HPV infection requires the viral genome (vDNA) to gain access to nuclei of basal keratinocytes of epithelium. After virion endocytosis, the minor capsid protein L2 dictates the subcellular retrograde trafficking and nuclear localization of the vDNA during mitosis. Prior work identified a cell-permeable peptide termed SNX1.3, derived from the BAR domain of sorting nexin 1 (SNX1), that potently blocks the retrograde and nuclear trafficking of EGFR in triple negative breast cancer cells. Given the importance of EGFR and retrograde trafficking pathways in HPV16 infection, we set forth to study the effects of SNX1.3 within this context. SNX1.3 inhibited HPV16 infection by both delaying virion endocytosis, as well as potently blocking virion retrograde trafficking and Golgi localization. SNX1.3 had no effect on cell proliferation, nor did it affect post-Golgi trafficking of HPV16. Looking more directly at L2 function, SNX1.3 was found to impair membrane spanning of the minor capsid protein. Future work will focus on mechanistic studies of SNX1.3 inhibition, and the role of EGFR signaling and SNX1-mediated endosomal tubulation, cargo sorting, and retrograde trafficking in HPV infection.

Detecting co-selection through excess linkage disequilibrium in bacterial genomes.

Population genomics has revolutionized our ability to study bacterial evolution by enabling data-driven discovery of the genetic architecture of trait variation. Genome-wide association studies (GWAS) have more recently become accompanied by genome-wide epistasis and co-selection (GWES) analysis, which offers a phenotype-free approach to generating hypotheses about selective processes that simultaneously impact multiple loci across the genome. However, existing GWES methods only consider associations between distant pairs of loci within the genome due to the strong impact of linkage-disequilibrium (LD) over short distances. Based on the general functional organisation of genomes it is nevertheless expected that majority of co-selection and epistasis will act within relatively short genomic proximity, on co-variation occurring within genes and their promoter regions, and within operons. Here, we introduce LDWeaver, which enables an exhaustive GWES across both short- and long-range LD, to disentangle likely neutral co-variation from selection. We demonstrate the ability of LDWeaver to efficiently generate hypotheses about co-selection using large genomic surveys of multiple major human bacterial pathogen species and validate several findings using functional annotation and phenotypic measurements. Our approach will facilitate the study of bacterial evolution in the light of rapidly expanding population genomic data.

The Effect of Intraoperative Overdistraction on Subsidence Following Anterior Cervical Discectomy and Fusion.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: The purpose of this study was to evaluate the effect of overdistraction on interbody cage subsidence. BACKGROUND: Vertebral overdistraction due to the use of large intervertebral cage sizes may increase the risk of postoperative subsidence. METHODS: Patients who underwent anterior cervical discectomy and fusion between 2016 and 2021 were included. All measurements were performed using lateral cervical radiographs at 3 time points - preoperative, immediate postoperative, and final follow-up >6 months postoperatively. Anterior and posterior distraction were calculated by subtracting the preoperative disc height from the immediate postoperative disc height. Cage subsidence was calculated by subtracting the final follow-up postoperative disc height from the immediate postoperative disc height. Associations between anterior and posterior subsidence and distraction were determined using multivariable linear regression models. The analyses controlled for cage type, cervical level, sex, age, smoking status, and osteopenia. RESULTS: Sixty-eight patients and 125 fused levels were included in the study. Of the 68 fusions, 22 were single-level fusions, 35 were 2-level, and 11 were 3-level. The median final follow-up interval was 368 days (range: 181-1257 d). Anterior disc space subsidence was positively associated with anterior distraction (beta = 0.23; 95% CI: 0.08, 0.38; P = 0.004), and posterior disc space subsidence was positively associated with posterior distraction (beta = 0.29; 95% CI: 0.13, 0.45; P < 0.001). No significant associations between anterior distraction and posterior subsidence (beta = 0.07; 95% CI: -0.06, 0.20; P = 0.270) or posterior distraction and anterior subsidence (beta = 0.06; 95% CI: -0.14, 0.27; P = 0.541) were observed. CONCLUSIONS: We found that overdistraction of the disc space was associated with increased postoperative subsidence after anterior cervical discectomy and fusion. Surgeons should consider choosing a smaller cage size to avoid overdistraction and minimize postoperative subsidence.

Compound-specific stable isotope analyses of fatty acids indicate feeding zones of zooplankton across the water column of a subalpine lake.

Spatial and temporal zooplankton feeding dynamics across the water column of lakes are key for understanding site-specific acquisition of diet sources. During this 6-week lake study, we examined stable carbon (δ13C) and nitrogen (δ15N) isotopes and conducted compound-specific fatty acid (FA) stable isotope analysis (CSIA) of edible seston in the epi-, meta-, and hypolimnion, and zooplankton of Lake Lunz, Austria. We predicted that CSIA of essential FA can discern the foraging grounds of zooplankton more accurately than the commonly used bulk stable isotopes. The δ13C and δ15N values of seston from different lake strata were similar, whereas a dual CSIA approach using stable carbon and hydrogen isotopes of FA (δ13CFA and δ2HFA) provided sufficient isotopic difference in essential FA to discern different lake strata-specific diet sources throughout the study period. We present a CSIA model that suggests strata-specific foraging grounds for different zooplankton groups, indicating higher preference of cladocerans for feeding on epilimnetic diet sources, while calanoid copepods retained more hypolimnetic resources. The CSIA approach thus yields strata-specific information on foraging strategies of different zooplankton taxa and provides more details on the spatial and temporal trophodynamics of planktonic food webs than commonly used bulk stable isotopes.