Effects of two wintering practices on behavioral and physiological indicators of welfare of non-lactating, pregnant dairy cattle in a pasture-based system.

In countries with pasture-based dairy systems and relatively cold winters, such as New Zealand, it is common to manage pregnant, nonlactating cows on forage crop paddocks rather than pasture due to slow pasture growth rates. Wintering dairy cattle on grazed crops can compromise welfare if wet and muddy underfoot conditions occur, which can reduce lying. This study investigated behavioral and physiological indicators of welfare of cows under 2 wintering practices: cows managed on and grazed kale crop (Brassica oleracea), and cows managed on pasture with baled hay. Following dry-off (d 0), 80 cows were randomly assigned to one of the 2 wintering practices (40 cows/practice) and monitored between d 4 and d 32 (phase 1). During this period, lying and stepping behavior was continuously recorded using leg-based accelerometers. Blood samples were obtained at d 0 and 32 for measurements of thyroxine (T4), nonesterified fatty acids (NEFA), white blood cells (WBC), and red blood cells (RBC). All data for phase 1 were presented descriptively due to the lack of treatment replication. Daily mean air temperature during this period was 5.2°C (range: 0.0 to 10.7°C), and rainfall was 1.1mm/d (range: 0 to 5.6mm/d). Between d 4 and 32, cows in both groups spent similar amounts of time lying (pasture with hay cows: 8.9h/24h ± 2.57, kale crop cows: 8.7h/24h ± 3.06, mean ± SEM). Both groups reduced their lying on wet and cold days and there was evidence of rebound lying once unfavorable weather conditions stopped. Cows on kale crop had numerically higher NEFA and lower WBC compared with cows managed on pasture, although most physiological values were within normal ranges. In a second phase of the study (d 34 and 35), cows were managed under controlled, replicated conditions in the 2 wintering practices using typical on-farm stocking rates (2 or 4 cows per group in the pasture with hay and kale crop treatments, respectively; n = 10 groups/treatment). During this period, cow behavior, skin and surface temperatures, hygiene scores, feed intakes and ground conditions were measured. Weather conditions during the 48-h exposure were mostly cold and dry (mean air temperature: 7.8°C, range: -2.2 to 20.5°C). Cows managed on pasture with hay spent more time lying down on the first day of exposure, however, this was likely due to less space being available to kale cows on this day. Cows managed on pasture with hay ruminated more than cows on kale crop on both days of observations (Day 1: 37.9% vs 30.9% of observations, Day 2: 36.8% vs 28.7% of observations for pasture with hay and kale crop groups, respectively) and were lying more often in postures indicative of greater thermal comfort. Cows managed on pasture with hay had higher skin and surface temperatures compared with cows on kale crop, whereas cows on kale crop had dirtier coats. Results suggest that opportunities for thermal comfort were greater for cows managed on pasture with hay bales, which may be due to increased rumination activities and more insulated lying areas.

Investigating the role of nicotinic acetylcholine receptors in menthol's effects in mice.

The use of menthol in tobacco products has been linked to an increased likelihood of developing nicotine dependence. The widespread use of menthol can be attributed to its unique sensory characteristics; however, emerging evidence suggests that menthol also alters sensitivity to nicotine through modulation of nicotinic acetylcholine receptors (nAChRs). Nicotinic subunits, such as ß2 and α5, are of interest due to their implications in nicotine reward, reinforcement, intake regulation, and aversion. This study, therefore, examined the in vivo relevance of ß2 and α5 nicotinic subunits on the pharmacological and behavioral effects of menthol. Data suggests that the α5 nicotinic subunit modulates menthol intake in mice. Overall, deletion or a reduction in function of the α5 subunit lessened aversion to menthol. α5 KO mice and mice possessing the humanized α5 SNP, a variant that confers a nicotine dependence phenotype in humans, demonstrated increased menthol intake compared to their WT counterparts and in a sex-related fashion for α5 SNP mice. We further reported that the modulatory effects of the α5 subunit do not extend to other aversive tastants like quinine, suggesting that deficits in α5* nAChR signaling may not abolish general sensitivity to the aversive effects of other noxious chemicals. Further probing into the role of α5 in other pharmacological properties of menthol revealed that the α5 subunit does not modulate the antinociceptive properties of menthol in mice and suggests that the in vivo differences observed are likely not due to the direct effects of menthol on α5-containing nAChRs in vitro.

Bacterial cholesterol-dependent cytolysins and their interaction with the human immune response.

PURPOSE OF REVIEW: Many cholesterol-dependent cytolysin (CDC)-producing pathogens pose a significant threat to human health. Herein, we review the pore-dependent and -independent properties CDCs possess to assist pathogens in evading the host immune response. RECENT FINDINGS: Within the last 5 years, exciting new research suggests CDCs can act to inhibit important immune functions, disrupt critical cell signaling pathways, and have tissue-specific effects. Additionally, recent studies have identified a key region of CDCs that generates robust immunity, providing resources for the development of CDC-based vaccines. SUMMARY: This review provides new information on how CDCs alter host immune responses to aid bacteria in pathogenesis. These studies can assist in the design of more efficient vaccines and therapeutics against CDCs that will enhance the immune response to CDC-producing pathogens while mitigating the dampening effects CDCs have on the host immune response.

BioVDB: biological vector database for high-throughput gene expression meta-analysis.

High-throughput sequencing has created an exponential increase in the amount of gene expression data, much of which is freely, publicly available in repositories such as NCBI's Gene Expression Omnibus (GEO). Querying this data for patterns such as similarity and distance, however, becomes increasingly challenging as the total amount of data increases. Furthermore, vectorization of the data is commonly required in Artificial Intelligence and Machine Learning (AI/ML) approaches. We present BioVDB, a vector database for storage and analysis of gene expression data, which enhances the potential for integrating biological studies with AI/ML tools. We used a previously developed approach called Automatic Label Extraction (ALE) to extract sample labels from metadata, including age, sex, and tissue/cell-line. BioVDB stores 438,562 samples from eight microarray GEO platforms. We show that it allows for efficient querying of data using similarity search, which can also be useful for identifying and inferring missing labels of samples, and for rapid similarity analysis.

Association of glucose metabolism and insulin resistance with feed efficiency and production traits of finishing beef steers.

Increasing nutrient utilization efficiency is an important component of enhancing the sustainability of beef cattle production. The objective of this experiment was to determine the association of glucose metabolism and insulin resistance with dry matter intake (DMI), average daily gain (ADG), gain:feed ratio (G:F), and residual feed intake (RFI). Steers (n = 54; initial body weight = 518 ±â€…27.0 kg) were subjected to an intravenous glucose tolerance test (IVGTT) where glucose was dosed through a jugular catheter and serial blood samples were collected. Three days after the last group's IVGTT, steers began a 63-d DMI and ADG test. Body weight was measured on days 0, 1, 21, 42, 62, and 63, and DMI was measured using an Insentec Roughage Intake Control system (Hokofarm Group, Emmeloord, the Netherlands). To examine relationships between DMI, ADG, G:F, and RFI with IVGTT measurements, Pearson correlations were calculated using Proc Corr of SAS 9.4 (SAS Inst. Inc., Cary, NC). Additionally, cattle were classified based on DMI, ADG, RFI, and G:F, where the medium classification was set as mean ±â€…0.5 SD, the low classification was < 0.5 SD from the mean, and the high classification was > 0.5 SD from the mean. No associations between DMI and IVGTT parameters were observed, and no differences were detected when classifying cattle as having low, medium, or high DMI. Peak insulin concentration in response to the IVGTT tended to be correlated with ADG (r = 0.28; P = 0.07), indicating cattle with greater ADG tend to have a greater insulin release in response to glucose. Glucose nadir concentrations tended to be positively correlated with ADG (r = 0.26; P = 0.10). Additionally, the glucose nadir was greater in high-ADG steers (P = 0.003). The association of greater glucose nadir with high-ADG could indicate that high-ADG steers do not clear glucose as efficiently as low-ADG steers, potentially indicating increased insulin resistance. Further, RFI was not correlated with IVGTT measurements, but low RFI steers had a greater peak glucose concentration (P = 0.040) and tended to have a greater glucose area under the curve (P = 0.09). G:F was correlated with glucose area under the curve (r = 0.33; P = 0.050), glucose nadir (r = 0.35; P = 0.011), and insulin time to peak (r = 0.39; P = 0.010). These results indicate that glucose metabolism and insulin signaling are associated with growth and efficiency, but the molecular mechanisms that drive these effects need to be elucidated.

Feed efficiency is an important component of improving the sustainability of beef production. There is a need to understand how metabolism influences feed efficiency. This experiment aimed to explore the association of glucose metabolism and insulin resistance with feed intake, growth, and efficiency of finishing beef cattle. The results indicate that there is a relationship between insulin resistance and improved efficiency measured as the ratio of growth to feed intake. The findings of this experiment are novel as they show a relationship between insulin resistance and feed efficiency and indicate further research is needed to determine the mechanisms of insulin resistance in ruminants that contribute to improved feed efficiency.

The Cochlear Implant "Seatbelt" Technique for Receiver/Stimulator Fixation.

Receiver/stimulator migration and extrusion are among the most commonly reported complications of cochlear implantation. Current techniques implement either a tight subperiosteal pocket or postauricular bone well. Here we describe a safe and effective technique to secure a cochlear implant receiver/stimulator with a Mersilene cervical cerclage tape "seatbelt." Laryngoscope, 2024.

Renal Neuroendocrine Tumor: A Case Report with Evaluation of Grading Criteria and Relationship with Carbonic Anhydrase 9 Immunoreactivity.

Neuroendocrine tumors (NETs) are only exceptionally primary to the kidney. At present, scant information is known regarding the behavior and prognosis of renal NETs, especially according to the assessment of grading parameters used for NETs originating from other more commonplace sites such as the pancreas and lungs. There are only rare reports of grade assessment in renal NETs, with most of these reports relying upon now antiquated World Health Organization gastroenteropancreatic and lung/thymus criteria. As an additional prognostic factor, positive CA9 staining in NETs may correlate with elevated grade, stage and risk of metastasis while serving as a potential target of chemotherapy and immunotherapy and indicator of Von Hippel-Lindau Syndrome. Rarer still are descriptions of renal NETs presenting with renal cell carcinoma in the ipsilateral or contralateral kidney. Thus, we present a patient with a primary renal NET of the right kidney with regional lymphovascular invasion and distant metastasis with an emphasis on grading criteria concordant with the World Health Organization 2022 gastroenteropancreatic and lung/thymus systems. In addition, we discuss unusual staining for CA9 in the patient's tumor and a concomitant left kidney clear cell renal cell carcinoma that may act as a clinicopathologic mimic of Von Hippel-Lindau Syndrome.

Grass-Fed and Non-Grass-Fed Whey Protein Consumption Do Not Attenuate Exercise-Induced Muscle Damage and Soreness in Resistance-Trained Individuals: A Randomized, Placebo-Controlled Trial.

Eccentric muscle contractions can cause structural damage to muscle cells resulting in temporarily decreased muscle force production and soreness. Prior work indicates pasture-raised dairy products from grass-fed cows have greater anti-inflammatory and antioxidant properties compared to grain-fed counterparts. However, limited research has evaluated the utility of whey protein from pasture-raised, grass-fed cows to enhance recovery compared to whey protein from non-grass-fed cows. Therefore, using a randomized, placebo-controlled design, we compared the effect of whey protein from pasture-raised, grass-fed cows (PRWP) to conventional whey protein (CWP) supplementation on indirect markers of muscle damage in response to eccentric exercise-induced muscle damage (EIMD) in resistance-trained individuals. Thirty-nine subjects (PRWP, n = 14; CWP, n = 12) completed an eccentric squat protocol to induce EIMD with measurements performed at 24, 48, and 72 h of recovery. Dependent variables included: delayed onset muscle soreness (DOMS), urinary titin, maximal isometric voluntary contraction (MIVC), potentiated quadriceps twitch force, countermovement jump (CMJ), and barbell back squat velocity (BBSV). Between-condition comparisons did not reveal any significant differences (p ≤ 0.05) in markers of EIMD via DOMS, urinary titin, MIVC, potentiated quadriceps twitch force, CMJ, or BBSV. In conclusion, neither PRWP nor CWP attenuate indirect markers of muscle damage and soreness following eccentric exercise in resistance-trained individuals.

New avenue of diagnostic stewardship: procedural stewardship for recurrent urinary tract infections in female patients.

Introduction: Societal guidelines offer a weak recommendation to perform cystoscopy for female patients with recurrent urinary tract infections (rUTI) of advanced age and/or with high-risk features. These guidelines lack the support of robust data and are instead based on expert opinion. In this retrospective cohort study, we aim to determine the utility of cystoscopy in patients with and without high-risk features for rUTI. Materials and methods: We identified 476 women who underwent cystoscopy for the evaluation of rUTI at a single tertiary academic medical center from May 1, 2015 and March 15, 2021. Patients were excluded if they had a competing indication for cystoscopy. Risk factors, demographic information, cystoscopic findings, and patient outcomes were analyzed. Results: 192 (41.1%) were classified as having complicated UTI. We identified six patients (1.3%) with findings that prompted management to significantly impact patient outcomes. All six patients had high-risk features. 14 patients (3.0%) were found to have mucosal abnormalities prompting biopsy, three of which required general anesthesia. All 14 biopsies were ultimately benign. Conclusions: Our findings demonstrate a low diagnostic yield and increased risk exposure for women undergoing cystoscopy for the evaluation of complicated rUTI. Additionally, our observations support prior studies indicating that cystoscopy has limited utility in the evaluation of rUTI without high-risk features.

Pulmonary hypertension in adults completing tuberculosis treatment.

Background: Pulmonary hypertension (PH) after tuberculosis (TB) is typically not included among the chronic lung diseases causing PH (group 3 PH), with few data available to support the inclusion. Objectives: To determine the prevalence of PH in an adult population completing TB treatment. Methods: This single-centre, cross-sectional study only included patients with their first documented episode of TB, and who were in the second half of treatment or had recently completed treatment. PH was assessed using transthoracic echocardiography. Questionnaires were completed, and spirometry and a 6-minute walk test were performed. Results: One hundred patients were enrolled, with a mean age of 37.1 years, of whom 58% were male and 46% HIV positive. The median time since initiation of TB treatment was 22 weeks. The mean (standard deviation) measured right ventricular systolic pressure (RVSP) was 23.6 (6.24) mmHg. One participant had PH (defined as RVSP ≥40 mmHg; 95% confidence interval (CI) 0.0 - 3.0) and a further 3 had possible PH (RVSP ≥35 and <40 mmHg), with a combined PH prevalence of 4% (95% CI 0.2 - 7.8). Airflow obstruction on spirometry was found in 13.3% of 98 patients, while 25.5% had a reduced forced vital capacity. There was no association between RVSP or PH/possible PH and sex, age, HIV status, systemic hypertension, spirometry measurements or 6-minute walking distance. Smoking status was associated with RVSP, but not with the presence of PH/possible PH. Conclusion: There was a significant prevalence of PH in this preliminary study of predominantly young patients completing treatment for a first episode of TB. Larger and more detailed studies are warranted. Study synopsis: What the study adds. Of 100 adult patients with their first episode of tuberculosis (TB) who underwent echocardiograms near the end of treatment completion to determine the prevalence of pulmonary hypertension (PH), 1 (1%) had PH and a further 3 (3%) had possible PH. There was no association between sex, age, HIV status, lung function or 6-minute walking distance and the presence of PH. The study adds to the growing awareness of the association of TB with pulmonary vascular disease. It shows that even in a young population with a first episode of TB treated in an ambulatory setting, there is a significant prevalence of PH on treatment completion.Implications of the findings. Given that 10.6 million people acquire TB annually, the absolute global burden of cases with PH is likely to be high, but is underappreciated to date. Further work is urgently needed in this field.

Electrocardiographic Findings in Genotype-Positive and Non-sarcomeric Children with Definite Hypertrophic Cardiomyopathy and Subclinical Variant Carriers.

In children with hypertrophic cardiomyopathy (HCM), the genotype-phenotype association of abnormal electrocardiographic (ECG) features in the backdrop of gene positivity has not been well described. This study aimed to describe the abnormal ECG findings in children with HCM harboring who have genetic variants and determine the association with major adverse cardiac events (MACE). We retrospectively analyzed 81 variants-positive, phenotype-positive (V+P+), 66 variant-positive, phenotype-negative (V+P-), and 85 non-sarcomeric subjects. We analyzed ECG findings and clinical outcomes in the three groups of subjects. Repolarization abnormalities (ST and T wave changes) and pathologic Q waves were the most common abnormalities in variant and non-sarcomeric subjects. The V+P+ group showed higher occurrence of ST segment changes and T wave abnormalities compared to V+P- group. Independent predictors of MACE included ST segment changes (OR 3.54, CI 1.20-10.47, p = 0.022). T wave changes alone did not predict outcome (OR 2.13, CI 0.75-6.07, p = 0.157), but combined repolarization abnormalities (ST+T changes) were strong predictors of MACE (OR 5.84, CI 1.43-23.7, p = 0.014) than ST segment changes alone. Maximal wall z score by echocardiography was a predictor of MACE (OR 1.21, CI 1.07-1.37, p = 0.002). Despite the presence of significant myocardial hypertrophy (z score > 4.7), voltage criteria for LVH were much less predictive. In the non-sarcomeric group, RVH was significantly associated with MACE (OR 3.85, CI 1.08-13.73, p = 0.038). These abnormal ECG findings described on the platform of known genetic status and known myocardial hypertrophy may add incremental value to the diagnosis and surveillance of disease progression in children with HCM. Select ECG findings, particularly repolarization abnormalities, may serve as predictors of MACE in children.

Monitoring environmental microbiomes: Alignment of microbiology and computational biology competencies within a culturally integrated curriculum and research framework.

We have developed a flexible undergraduate curriculum that leverages the place-based research of environmental microbiomes to increase the number of Indigenous researchers in microbiology, data science and scientific computing. Monitoring Environmental Microbiomes (MEM) provides a curriculum and research framework designed to integrate an Indigenous approach when conducting authentic scientific research and to build interest and confidence at the undergraduate level. MEM has been successfully implemented as a short summer workshop to introduce computing practices in microbiome analysis. Based on self-assessed student knowledge of topics and skills, increased scientific confidence and interest in genomics careers were observed. We propose MEM be incorporated in a scalable course-based research experience for undergraduate institutions, including tribal colleges and universities, community colleges and other minority serving institutions. This coupled curricular and research framework explicitly considers cultural perspectives, access and equity to train a diverse future workforce that is more informed to engage in microbiome research and to translate microbiome science to benefit community and environmental health.

Translabyrinthine Craniotomy Is Associated with Higher Risk of Asymptomatic Dural Venous Sinus Thrombosis in Vestibular Schwannoma Resection.

OBJECTIVE: Characterize the incidence, risk factors, and patient outcomes of dural venous sinus thrombosis identified on postoperative imaging after retrosigmoid or translabyrinthine craniotomy for vestibular schwannoma resection. STUDY DESIGN: Retrospective cohort study. SETTING: Single tertiary academic referral center. PATIENTS: Eighty-one patients 19 to 82 years of age with vestibular schwannomas, 58% female. INTERVENTIONS: Retrosigmoid or translabyrinthine craniotomy with postoperative magnetic resonance imaging/magnetic resonance venography. MAIN OUTCOME MEASURES: Association between operative approach, age, sex, body mass index, tumor size, dominant sinus, operative time, laterality, and perioperative cerebrospinal fluid (CSF) leaks with rate of thrombosis. RESULTS: Translabyrinthine craniotomy was associated with the highest relative risk of thrombosis (odds ratios [OR] = 19.82, 95% confidence interval [CI] = 1.75-224, p = 0.007), followed by male sex (OR = 5.53, 95% CI = 1.63-18.8, p = 0.035). Other patient and demographic risk factors were not associated with increased rates of dural venous thrombosis, nor was there an association with postoperative CSF leak. 81% (25/31) of thrombi had resolved within 3 years of surgery. CONCLUSIONS: Translabyrinthine approach and male sex most strongly predicted postoperative dural venous thrombosis after postauricular craniotomy for vestibular schwannoma resection. PROFESSIONAL PRACTICE GAP AND EDUCATIONAL NEED: Better understanding of risk factors and management of dural venous thrombosis after vestibular schwannoma surgery. LEARNING OBJECTIVE: Characterize clinically significant risk factors for dural venous thrombosis in vestibular schwannoma surgery. DESIRED RESULT: Identification of patient and operative risk factors for dural venous thrombosis. LEVEL OF EVIDENCE: III. INDICATE IRB OR IACUC: Exempt.

A Change in Scope: Endoscopic Retrograde Cholangiopancreatography via a Gastroscope in Billroth II Gastrojejunostomy.

Previous gastric procedures often make endoscopic interventions challenging. Our case study focuses specifically on performing an endoscopic retrograde cholangiopancreatography (ERCP) through a gastroscope (EVIS EXERA III GIF-HQ190, Olympus, Center Valley, USA) in a patient with a history of Billroth II gastrojejunostomy. Successful ERCP in Billroth II using a gastroscope with traditional ERCP instrumentation has been very rarely reported in case reports in the literature review. This case study provides an alternative method of access to the common bile duct (CBD) and treatment of obstruction to prevent the risk of morbidities from an open CBD exploration. The primary diagnosis for this patient was choledocholithiasis. He initially underwent a standard ERCP with a side-viewing duodenoscope (EVIS EXERA II, TJF-Q190V, Olympus, Center Valley, USA); however, due to the difficult anatomy from his previous Billroth II reconstruction, the CBD was very difficult to access. A gastroscope was then used instead to perform the ERCP, providing an innovative endoscopic therapy. Given the patient's multiple comorbidities, he was at high risk for morbidity and mortality with an open CBD exploration. Hence, this case report provides insight into an innovative endoscopic approach to CBD exploration with difficult anatomy.

Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer's disease.

BACKGROUND: Microglia, the brain's principal immune cells, have been implicated in the pathogenesis of Alzheimer's disease (AD), a condition shown to affect more females than males. Although sex differences in microglial function and transcriptomic programming have been described across development and in disease models of AD, no studies have comprehensively identified the sex divergences that emerge in the aging mouse hippocampus. Further, existing models of AD generally develop pathology (amyloid plaques and tau tangles) early in life and fail to recapitulate the aged brain environment associated with late-onset AD. Here, we examined and compared transcriptomic and translatomic sex effects in young and old murine hippocampal microglia. METHODS: Hippocampal tissue from C57BL6/N and microglial NuTRAP mice of both sexes were collected at young (5-6 month-old [mo]) and old (22-25 mo) ages. Cell sorting and affinity purification techniques were used to isolate the microglial transcriptome and translatome for RNA-sequencing and differential expression analyses. Flow cytometry, qPCR, and imaging approaches were used to confirm the transcriptomic and translatomic findings. RESULTS: There were marginal sex differences identified in the young hippocampal microglia, with most differentially expressed genes (DEGs) restricted to the sex chromosomes. Both sex chromosomally and autosomally encoded sex differences emerged with aging. These sex DEGs identified at old age were primarily female-biased and enriched in senescent and disease-associated microglial signatures. Normalized gene expression values can be accessed through a searchable web interface ( https://neuroepigenomics.omrf.org/ ). Pathway analyses identified upstream regulators induced to a greater extent in females than in males, including inflammatory mediators IFNG, TNF, and IL1B, as well as AD-risk genes TREM2 and APP. CONCLUSIONS: These data suggest that female microglia adopt disease-associated and senescent phenotypes in the aging mouse hippocampus, even in the absence of disease pathology, to a greater extent than males. This sexually divergent microglial phenotype may explain the difference in susceptibility and disease progression in the case of AD pathology. Future studies will need to explore sex differences in microglial heterogeneity in response to AD pathology and determine how sex-specific regulators (i.e., sex chromosomal or hormonal) elicit these sex effects.

Microglial MHC-I induction with aging and Alzheimer's is conserved in mouse models and humans.

Major histocompatibility complex I (MHC-I) CNS cellular localization and function is still being determined after previously being thought to be absent from the brain. MHC-I expression has been reported to increase with brain aging in mouse, rat, and human whole tissue analyses, but the cellular localization was undetermined. Neuronal MHC-I is proposed to regulate developmental synapse elimination and tau pathology in Alzheimer's disease (AD). Here, we report that across newly generated and publicly available ribosomal profiling, cell sorting, and single-cell data, microglia are the primary source of classical and non-classical MHC-I in mice and humans. Translating ribosome affinity purification-qPCR analysis of 3-6- and 18-22-month-old (m.o.) mice revealed significant age-related microglial induction of MHC-I pathway genes B2m, H2-D1, H2-K1, H2-M3, H2-Q6, and Tap1 but not in astrocytes and neurons. Across a timecourse (12-23 m.o.), microglial MHC-I gradually increased until 21 m.o. and then accelerated. MHC-I protein was enriched in microglia and increased with aging. Microglial expression, and absence in astrocytes and neurons, of MHC-I-binding leukocyte immunoglobulin-like (Lilrs) and paired immunoglobin-like type 2 (Pilrs) receptor families could enable cell -autonomous MHC-I signaling and increased with aging in mice and humans. Increased microglial MHC-I, Lilrs, and Pilrs were observed in multiple AD mouse models and human AD data across methods and studies. MHC-I expression correlated with p16INK4A, suggesting an association with cellular senescence. Conserved induction of MHC-I, Lilrs, and Pilrs with aging and AD opens the possibility of cell-autonomous MHC-I signaling to regulate microglial reactivation with aging and neurodegeneration.

Monoclonal antibodies against lipopolysaccharide protect against Pseudomonas aeruginosa challenge in mice.

Pseudomonas aeruginosa is a common cause of hospital-acquired infections, including central line-associated bloodstream infections and ventilator-associated pneumonia. Unfortunately, effective control of these infections can be difficult, in part due to the prevalence of multi-drug resistant strains of P. aeruginosa. There remains a need for novel therapeutic interventions against P. aeruginosa, and the use of monoclonal antibodies (mAb) is a promising alternative strategy to current standard of care treatments such as antibiotics. To develop mAbs against P. aeruginosa, we utilized ammonium metavanadate, which induces cell envelope stress responses and upregulates polysaccharide expression. Mice were immunized with P. aeruginosa grown with ammonium metavanadate and we developed two IgG2b mAbs, WVDC-0357 and WVDC-0496, directed against the O-antigen lipopolysaccharide of P. aeruginosa. Functional assays revealed that WVDC-0357 and WVDC-0496 directly reduced the viability of P. aeruginosa and mediated bacterial agglutination. In a lethal sepsis model of infection, prophylactic treatment of mice with WVDC-0357 and WVDC-0496 at doses as low as 15 mg/kg conferred 100% survival against challenge. In both sepsis and acute pneumonia models of infection, treatment with WVDC-0357 and WVDC-0496 significantly reduced bacterial burden and inflammatory cytokine production post-challenge. Furthermore, histopathological examination of the lungs revealed that WVDC-0357 and WVDC-0496 reduced inflammatory cell infiltration. Overall, our results indicate that mAbs directed against lipopolysaccharide are a promising therapy for the treatment and prevention of P. aeruginosa infections.