A multifaceted ecological approach to explore links between environmental factors and the epidemiology of disorders of gut-brain interaction.

BACKGROUND: Disorders of gut-brain interaction (DGBI) are characterized by debilitating symptoms not explained by structural or biochemical abnormalities. While functional conditions present with complex, likely heterogeneous pathophysiology, we aimed to investigate if proxy measures of sociocultural and environmental factors are associated with the prevalence of various DGBI in populations across the world. METHODS: We performed an ecological study utilizing peer-reviewed published datasets reporting for 26 countries prevalence rates of DGBI (Rome Foundation Global Epidemiology Study, RFGES), with six independent variables: Helicobacter pylori prevalence and household size as proxy measures for orofecal infections, gross domestic product per capita (GDP), and median age as a proxy measures for socioeconomic development, density of fast food outlets (FFO) per 100,000 population as proxy measure for processed food exposure, and suicide mortality rate per 100,000 people, and world happiness scores were used as a proxy for psychological stress. The data were retrieved from publicly accessible datasets (United Nations, CIA World Factbook, World Bank, World Happiness Report, commercial/financial reports of a global FFO chain). We used linear regression to assess variables in univariate and multivariate analysis and report standardized ß coefficients with 95% confidence intervals (CI). KEY RESULTS: The regression model revealed that the overall prevalence of DGBI was inversely associated with both GDP per capita (ß = -0.57, 95% CI: -0.92, -0.22, p = 0.002) and happiness scores (ß = -0.433 95% CI: 0.821, -0.065, p = 0.023), while being positively associated with H. pylori prevalence (ß = 0.40, 95% CI: 0.008, 0.81, p = 0.046). The prevalence of functional constipation (FC) was also inversely associated with GDP per capita (ß = -0.50, 95% CI: -0.86, -0.13, p = 0.01) and happiness scores (ß = -0.497, 95% CI: -0.863, -0.132, p = 0.01), while being positively associated with H. pylori prevalence (ß = 0.53, 95% CI: 0.16, 0.91, p = 0.007). The Multivariate model analysis revealed that combining the factors of H. pylori prevalence, suicide rate, household size and happiness scores showed statistically significant association with FC (p = 0.039). Household size (ß = -0.43, 95% CI: -0.82, 0.038, p = 0.033) and suicide rates (ß = 0.55, 95% CI: 0.19, 0.90, p = 0.004) were statistically significantly associated with functional diarrhea. Irritable bowel syndrome (IBS) was associated with GDP per capita (ß = -0.40, 95% CI: -0.79, -0.014, p = 0.043) and happiness scores (ß = -0.390, 95% CI: -0.778, -0.003, p = 0.049). CONCLUSIONS & INFERENCES: Utilizing publicly available data, the prevalence of DGBI across diverse countries is linked to various socio-cultural and environmental factors. Collectively, the data suggests that the prevalence of DGBI is increased in less prosperous regions of the world.

The CCT chaperonin and actin modulate the ER and RNA-binding protein condensation during oogenesis to maintain translational repression of maternal mRNA and oocyte quality.

The regulation of maternal mRNAs is essential for proper oogenesis, the production of viable gametes, and to avoid birth defects and infertility. Many oogenic RNA-binding proteins have been identified with roles in mRNA metabolism, some of which localize to dynamic ribonucleoprotein granules and others that appear dispersed. Here, we use a combination of in vitro condensation assays and the in vivo C. elegans oogenesis model to determine the intrinsic properties of the conserved KH-domain MEX-3 protein and to identify novel regulators of MEX-3 and the Lsm protein, CAR-1. We demonstrate that MEX-3 undergoes liquid-liquid phase separation and appears to have intrinsic gel-like properties in vitro . We also identify novel roles for the CCT chaperonin and actin in preventing ectopic RNA-binding protein condensates in maturing oocytes that appear to be independent of MEX-3 folding. CCT and actin also oppose the expansion of ER sheets that may promote ectopic condensation of RNA-binding proteins that are associated with de-repression of maternal mRNA. This regulatory network is essential to preserve oocyte quality, prevent infertility, and may have implications for understanding the role of hMex3 phase transitions in cancer. Significance statement: The molecular mechanisms that regulate phase transitions of oogenic RNA-binding proteins are critical to elucidate but are not fully understood.We identify novel regulators of RNA-binding protein phase transitions in maturing oocytes that are required to maintain translational repression of maternal mRNAs and oocyte quality.This study is the first to elucidate a regulatory network involving the CCT chaperonin, actin, and the ER for phase transitions of RNA-binding proteins during oogenesis. Our findings for the conserved MEX-3 protein may also be applicable to better understanding the role of hMex3 phase transitions in cancer.

A Biparatopic Intrabody Renders Vero Cells Impervious to Ricin Intoxication.

Expression of camelid-derived, single-domain antibodies (V H Hs) within the cytoplasm of mammalian cells as "intrabodies" has opened-up novel avenues for medical countermeasures against fast-acting biothreat agents. In this report, we describe a heterodimeric intrabody that renders Vero cells virtually impervious to ricin toxin (RT), a potent Category B ribosome-inactivating protein (RIP). The intrabody consists of two structurally defined V H Hs that target distinct epitopes on RT's enzymatic subunit (RTA): V9E1 targets RTA's P-stalk recruitment site, and V2A11 targets RTA's active site. Resistance to RT conferred by the biparatopic V H H construct far exceeded that of either of the V H Hs alone and effectively inhibited all measurable RT-induced cytotoxicty in vitro . We propose that targeted delivery of bispecific intrabodies to lung tissues may represent a novel means to shield the airways from the effects of inhalational RT exposure.

Multi-omic profiling of intraductal papillary neoplasms of the pancreas reveals distinct expression patterns and potential markers of progression.

In order to advance our understanding of precancers in the pancreas, 69 pancreatic intraductal papillary neoplasms (IPNs), including 64 intraductal papillary mucinous neoplasms (IPMNs) and 5 intraductal oncocytic papillary neoplasms (IOPNs), 32 pancreatic cyst fluid samples, 104 invasive pancreatic ductal adenocarcinomas (PDACs), 43 normal adjacent tissues (NATs), and 76 macro-dissected normal pancreatic ducts (NDs) were analyzed by mass spectrometry. A total of 10,246 proteins and 22,284 glycopeptides were identified in all tissue samples, and 756 proteins with more than 1.5-fold increase in abundance in IPMNs relative to NDs were identified, 45% of which were also identified in cyst fluids. The over-expression of selected proteins was validated by immunolabeling. Proteins and glycoproteins overexpressed in IPMNs included those involved in glycan biosynthesis and the immune system. In addition, multiomics clustering identified two subtypes of IPMNs. This study provides a foundation for understanding tumor progression and targets for earlier detection and therapies. Significance: This multilevel characterization of intraductal papillary neoplasms of the pancreas provides a foundation for understanding the changes in protein and glycoprotein expression during the progression from normal duct to intraductal papillary neoplasm, and to invasive pancreatic carcinoma, providing a foundation for informed approaches to earlier detection and treatment.

Molecular analysis of persistent and recurrent Barrett's esophagus in the setting of endoscopic therapy.

INTRODUCTION: Early neoplastic progression of Barrett's esophagus (BE) is often treated with endoscopic therapy. While effective, some patients are refractory to therapy or recur after apparent eradication of the BE. The goal of this study was to determine whether genomic alterations within the treated BE may be associated with persistent or recurrent disease. METHODS: We performed DNA sequencing on pre-treatment esophageal samples from 45 patients who were successfully treated by endoscopic therapy and did not recur as well as pre- and post-treatment samples from 40 patients who had persistent neoplasia and 21 patients who had recurrent neoplasia. The genomic alterations were compared between groups. RESULTS: The genomic landscape was similar between all groups. Patients with persistent disease were more likely to have pre-treatment alterations involving the receptor tyrosine kinase pathway (p=0.01), amplifications of oncogenes (p=0.01), and deletions of tumor suppressor genes (p=0.02). These associations were no longer significant after adjusting for patient age and BE length. Over half of patients with persistent (52.5%) or recurrent (57.2%) disease showed pre- and post-treatment samples that shared at least 50% of their driver mutations. CONCLUSION: Pre-treatment samples were genomically similar between those who responded to endoscopic therapy and those who had persistent or recurrent disease, suggesting there is not a strong genomic component to treatment response. While it was expected to find shared driver mutations in pre- and post-treatment samples in patients with persistent disease, the finding that an equal number of patients with recurrent disease also showed this relation suggests that many recurrences represent undetected minimal residual disease.

The evolution of tumor enucleation partial nephrectomy: A comparison of perioperative outcomes for sutureless hemostatic bandage as an alternative to standard renorrhaphy.

BACKGROUND: The standard approach to hemostasis during partial nephrectomy (PN) is to perform suture renorrhaphy (SR). Application of a hemostatic bandage (HB) is an alternative to minimize blood loss and devitalized renal parenchyma. We aim to evaluate perioperative outcomes of PN with tumor enucleation (TE) comparing SR to HB. METHODS: We analyzed a retrospective cohort of 195 patients undergoing robot-assisted laparoscopic PN with TE performed at a tertiary referral center (2012-2022). Hemostasis was obtained with SR in 54 patients while 141 patients underwent application of HB consisting of Surgicel®, Gelfoam® soaked in thrombin, and Floseal®. RESULTS: SR patients had tumors of greater complexity by RENAL nephrometry score compared to HB patients (p < 0.001). Operative time (141 vs. 183 min, p < 0.001), warm ischemia time (11.6 vs. 24.2 min, p < 0.001), estimated blood loss (37 vs. 214 mL, p < 0.001), and length of stay (1.2 vs. 1.8 days, p < 0.001) favored HB. There was no significant difference in Clavien-Dindo grade ≥3 complications (p = 0.22). Renal function was comparable with mean estimated glomerular filtration rate decrease of 0.66 and 0.54 mL/min/1.73 m2 at 3 months postoperatively for HB and SR, respectively (p = 0.93). CONCLUSIONS: Application of an HB is a safe alternative to SR for hemostasis following PN with TE in appropriately selected patients.

Septin-dependent invasive growth by the rice blast fungus Magnaporthe oryzae.

Septin GTPases are morphogenetic proteins that are widely conserved in eukaryotic organisms fulfilling diverse roles in cell division, differentiation and development. In the filamentous fungal pathogen Magnaporthe oryzae, the causal agent of the devastating blast diseases of rice and wheat, septins have been shown to be essential for plant infection. The blast fungus elaborates a specialised infection structure called an appressorium with which it mechanically ruptures the plant cuticle. Septin aggregation and generation of a hetero-oligomeric ring structure at the base of the infection cell is indispensable for plant infection. Furthermore, once the fungus enters host tissue it develops another infection structure, the transpressorium, enabling it to move between living host plant cells, which also requires septins for its function. Specific inhibition of septin aggregation-either genetically or with chemical inhibitors-prevents plant infection. Significantly, by screening for inhibitors of septin aggregation, broad spectrum anti-fungal compounds have been identified that prevent rice blast and a number of other cereal diseases in field trials. We review the recent advances in our understanding of septin biology and their potential as targets for crop disease control.

Real world management of individuals with severe FXI deficiency and its impact on clinical outcomes: Experience from a haemophilia treatment centre.

INTRODUCTION: The management of Factor XI deficiency is challenged by a variable association between FXI level and bleeding phenotype. Additionally, there is scarce data describing management strategies and their outcomes, specifically bleeding, thrombosis, and other complications. AIMS: To evaluate bleeding, thrombosis, and other complications in individuals with severe FXI deficiency seen in our comprehensive haemophilia treatment centre (HTC). Peri-procedural management strategies and the resulting impact on bleeding and other clinically relevant outcomes were reported. METHODS: Retrospective review of the electronic medical record of adult patients with severe FXI deficiency (< 20% activity) seen at a New York City comprehensive HTC between 2017 and 2022. Procedures, haemostatic management, and outcomes were collected and analysed. RESULTS: We identified 38 individuals (64%) females with severe FXI deficiency. The mean age was 56 ± 21 years (SD). The median FXI activity level was 3% (IQR: 1-8%). The mean BAT score was 3.1 ± 2.4; (52%) individuals did not have a history of bleeding. A total of 256 surgeries and procedures were performed. There was reduced bleeding with preventative or reactive treatment during procedures. Arterial but not venous thrombotic complications were observed. Plasma was mostly used for procedures associated with higher risk of bleeding and antifibrinolytics for procedures at sites of high fibrinolysis. CONCLUSIONS: Current management strategies pose a burden of care for these patients and manifested as nonbleeding adverse events and changes in clinical management. These findings highlight the need for novel investigation in predicting and managing bleeding for individuals with severe FXI deficiency.

The Cannabis Gray Market: A Case for Cannabis Regulatory Science Research.

The cannabis gray market poses significant public health concerns and remains a major threat to consumer and/or potential consumer uptake of regulated cannabis markets in jurisdictions with legal state-sponsored cannabis programs. In this perspective, we provide an overview of the cannabis gray market, and describe an integrated epidemiological and regulatory science framework to study the gray market. Using tobacco regulatory science as a guide, we introduce example cannabis regulatory science research activities as a means to improve the field's understanding of the cannabis gray market. Cannabis regulatory science is a developing field that can improve our understanding of the cannabis regulatory ecosystem and provide regulatory officials and policymakers alike with much needed data to inform regulatory decision-making and improve the success and uptake of state-sponsored cannabis programs.

Covert actions of epidural stimulation on spinal locomotor circuits.

Spinal circuitry produces the rhythm and patterning of locomotion. However, both descending and sensory inputs are required to initiate and adapt locomotion to the environment. Spinal cord injury (SCI) disrupts descending controls of the spinal cord, producing paralysis. Epidural stimulation (ES) is a promising clinical therapy for motor control recovery and is capable of reactivating the lumbar spinal locomotor networks, yet little is known about the effects of ES on locomotor neurons. Previously, we found that both sensory afferent pathways and serotonin exert mixed excitatory and inhibitory actions on lumbar interneurons involved in the generation of the locomotor rhythm, identified by the transcription factor Shox2. However, after chronic complete SCI, sensory afferent inputs to Shox2 interneurons become almost exclusively excitatory and Shox2 interneurons are supersensitive to serotonin. Here, we investigated the effects of ES on these SCI-induced changes. Inhibitory input from sensory pathways to Shox2 interneurons was maintained and serotonin supersensitivity was not observed in SCI mice that received daily sub-motor threshold ES. Interestingly, the effects of ES were maintained for at least three weeks after the ES was discontinued. In contrast, the effects of ES were not observed in Shox2 interneurons from mice that received ES after the establishment of the SCI-induced changes. Our results demonstrate mechanistic actions of ES at the level of identified spinal locomotor circuit neurons and the effectiveness of early treatment with ES on preservation of spinal locomotor circuitry after SCI, suggesting possible therapeutic benefits prior to the onset of motor rehabilitation.

Gender-Affirming Hormone Treatment and Metabolic Syndrome Among Transgender Veterans.

Importance: Gender-affirming hormone treatment (GAHT) is a common therapy for transgender individuals to reduce gender dysphoria and improve quality of life. Clarifying the long-term effects of GAHT remains a priority in transgender health research. Objective: To explore whether sex hormones (estradiol and testosterone) are associated with the development of metabolic syndrome in transgender veterans compared with cisgender veterans. Design, Setting, and Participants: This retrospective, longitudinal cohort study used International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis codes for gender dysphoria from the Veterans Health Administration national database to identify transfeminine and transmasculine veterans receiving documented feminizing (estradiol) or masculinizing (testosterone) treatment from January 1, 2006, to December 31, 2019, and for whom the GAHT initiation date and metabolic syndrome component-related data were available. Transgender veterans were matched to cisgender referents. Exposure: Gender-affirming hormone treatment. Main Outcomes and Measures: Metabolic syndrome z-scores were calculated based on body mass index, systolic blood pressure, and levels of high-density lipoprotein cholesterol, triglycerides, and blood glucose. Changes in mean z-scores were compared among the transgender and cisgender groups before and after the index date (corresponding to GAHT initiation) using a repeated-measures analysis of variance model. Results: The cohort included 1290 participants: 645 transgender (494 [38.3%] transfeminine, 151 [11.7%] transmasculine) and 645 cisgender (280 [21.7%] female, 365 [28.3%] male). Mean (SD) age at the index date was 41.3 (13.2) years. Metabolic syndrome z-scores changed significantly over time and differed significantly across groups. Overall, transmasculine veterans had the greatest percentage increase in mean (SEM) z-scores after vs before the index date (298.0% [57.0%]; P < .001), followed by cisgender females (108.3% [27.5%]; P < .001), cisgender males (49.3% [27.5%]; P = .02), and transfeminine persons (3.0% [10.7%]; P = .77). Conclusions and Relevance: In this cohort study, in both cisgender and transgender veterans, estradiol was associated with reduced metabolic syndrome risk, whereas testosterone was associated with increased risk. However, transmasculine individuals had the greatest risk and transfeminine individuals had the lowest risk of metabolic syndrome associated with these hormones. This is relevant for the management of metabolic syndrome risk factors in cisgender and transgender individuals and to potentially predict the risk of atherosclerotic cardiovascular disease, type 2 diabetes, systolic hypertension, insulin resistance, and nonalcoholic fatty liver disease.

Identification of ATP-Competitive Human CMG Helicase Inhibitors for Cancer Intervention that Disrupt CMG-Replisome Function.

The human CMG helicase (Cdc45-MCM-GINS) is a novel target for anti-cancer therapy. Tumor-specific weaknesses in the CMG are caused by oncogene-driven changes that adversely affect CMG function, and a requirement for CMG activity during recovery from replicative stresses such as chemotherapy. Here, we developed an orthogonal biochemical screening approach and identified CMG inhibitors (CMGi) that inhibit ATPase and helicase activities in an ATP-competitive manner at low micromolar concentrations. Structure-activity information, in silico docking, and testing with synthetic chemical compounds indicate that CMGi require specific chemical elements and occupy ATP binding sites and channels within MCM subunits leading to the ATP clefts, which are likely used for ATP/ADP ingress or egress. CMGi are therefore also MCM complex inhibitors (MCMi). Biological testing shows that CMGi/MCMi inhibit cell growth and DNA replication using multiple molecular mechanisms distinct from other chemotherapy agents. CMGi/MCMi block helicase assembly steps that require ATP binding/hydrolysis by the MCM complex, specifically MCM ring assembly on DNA and GINS recruitment to DNA-loaded MCM hexamers. During S-phase, inhibition of MCM ATP binding/hydrolysis by CMGi/MCMi causes a 'reverse allosteric' dissociation of Cdc45/GINS from the CMG that destabilizes replisome components Ctf4, Mcm10, and DNA polymerase-a, -d, -e, resulting in DNA damage. CMGi/MCMi display selective toxicity toward multiple solid tumor cell types with K-Ras mutations, targeting the CMG and inducing DNA damage, Parp cleavage, and loss of viability. This new class of CMGi/MCMi provides a basis for small chemical development of CMG helicase-targeted anti-cancer compounds with distinct mechanisms of action.

A review of the direct targets of the cannabinoids cannabidiol, Δ9-tetrahydrocannabinol, N-arachidonoylethanolamine and 2-arachidonoylglycerol.

Marijuana has been used by humans for thousands of years for both medicinal and recreational purposes. This included the treatment of pain, inflammation, seizures, and nausea. In the 1960s, the structure of the principal psychoactive ingredient Δ9-tetrahydrocannabinol was determined, and over the next few decades, two cannabinoid receptors were characterized along with the human endocannabinoid system and what it affects. This includes metabolism, the cardiovascular and reproductive systems, and it is involved in such conditions as inflammation, cancer, glaucoma, and liver and musculoskeletal disorders. In the central nervous system, the endocannabinoid system has been linked to appetite, learning, memory, and conditions such as depression, anxiety, schizophrenia, stroke, multiple sclerosis, neurodegeneration, addiction, and epilepsy. It was the profound effectiveness of cannabidiol, a non-psychoactive ingredient of marijuana, to relieve the symptoms of Dravet syndrome, a severe form of childhood epilepsy, that recently helped spur marijuana research. This has helped substantially to change society's attitude towards this potential source of useful drugs. However, research has also revealed that the actions of endocannabinoids, such as anandamide and 2-arachidonoylglycerol, and the phytocannabinoids, tetrahydrocannabinol and cannabidiol, were not just due to interactions with the two cannabinoid receptors but by acting directly on many other targets including various G-protein receptors and cation channels, such as the transient receptor potential channels for example. This mini-review attempts to survey the effects of these 4 important cannabinoids on these currently identified targets.

Utility of Targeted Sequencing Compared to FISH for Detection of Chronic Lymphocytic Leukemia Copy Number Alterations.

Chronic lymphocytic leukemia (CLL) is characterized by multiple copy number alterations (CNAs) and somatic mutations that are central to disease prognosis, risk stratification, and mechanisms of therapy resistance. Fluorescence in situ hybridization (FISH) panels are widely used in clinical applications as the gold standard for screening prognostic chromosomal abnormalities in CLL. DNA sequencing is an alternative approach to identifying CNAs but is not an established method for clinical CNA screening. We sequenced DNA from 509 individuals with CLL or monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, using a targeted sequencing panel of 59 recurrently mutated genes in CLL and additional amplicons across regions affected by clinically relevant CNAs [i.e., del(17p), del(11q), del(13q), and trisomy 12]. We used the PatternCNV algorithm to call CNA and compared the concordance of calling clinically relevant CNAs by targeted sequencing to that of FISH. We found a high accuracy of calling CNAs via sequencing compared to FISH. With FISH as the gold standard, the specificity of targeted sequencing was >95%, sensitivity was >86%, positive predictive value was >90%, and negative predictive value was >84% across the clinically relevant CNAs. Using targeted sequencing, we were also able to identify other common CLL-associated CNAs, including del(6q), del(14q), and gain 8q, as well as complex karyotype, defined as the presence of 3 or more chromosomal abnormalities, in 26 patients. In a single and cost-effective assay that can be performed on stored DNA samples, targeted sequencing can simultaneously detect CNAs, somatic mutations, and complex karyotypes, which are all important prognostic features in CLL.

DHODH inhibition enhances the efficacy of immune checkpoint blockade by increasing cancer cell antigen presentation.

Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway that can be targeted by clinically approved inhibitors. However, despite robust preclinical anticancer efficacy, DHODH inhibitors have shown limited single-agent activity in phase 1 and 2 clinical trials. Therefore, novel combination therapy strategies are necessary to realize the potential of these drugs. To search for therapeutic vulnerabilities induced by DHODH inhibition, we examined gene expression changes in cancer cells treated with the potent and selective DHODH inhibitor brequinar (BQ). This revealed that BQ treatment causes upregulation of antigen presentation pathway genes and cell surface MHC class I expression. Mechanistic studies showed that this effect is (1) strictly dependent on pyrimidine nucleotide depletion, (2) independent of canonical antigen presentation pathway transcriptional regulators, and (3) mediated by RNA polymerase II elongation control by positive transcription elongation factor B (P-TEFb). Furthermore, BQ showed impressive single-agent efficacy in the immunocompetent B16F10 melanoma model, and combination treatment with BQ and dual immune checkpoint blockade (anti-CTLA-4 plus anti-PD-1) significantly prolonged mouse survival compared to either therapy alone. Our results have important implications for the clinical development of DHODH inhibitors and provide a rationale for combination therapy with BQ and immune checkpoint blockade.

TLR10 (CD290) Is a Regulator of Immune Responses in Human Plasmacytoid Dendritic Cells.

TLRs are the most thoroughly studied group of pattern-recognition receptors that play a central role in innate immunity. Among them, TLR10 (CD290) remains the only TLR family member without a known ligand and clearly defined functions. One major impediment to studying TLR10 is its absence in mice. A recent study on TLR10 knock-in mice demonstrated its intrinsic inhibitory role in B cells, indicating that TLR10 is a potential drug target in autoimmune diseases. In this study, we interrogated the expression and function of TLR10 in human plasmacytoid dendritic cells (pDCs). We have seen that primary human pDCs, B cells, and monocytes constitutively express TLR10. Upon preincubation with an anti-TLR10 Ab, production of cytokines in pDCs was downregulated in response to stimulation with DNA and RNA viruses. Upon further investigation into the possible mechanism, we documented phosphorylation of STAT3 upon Ab-mediated engagement of TLR10. This leads to the induction of inhibitory molecule suppressor of cytokine signaling 3 (SOCS3) expression. We have also documented the inhibition of nuclear translocation of transcription factor IFN regulatory factor 7 (IRF7) in pDCs following TLR10 engagement. Our data provide the (to our knowledge) first evidence that TLR10 is constitutively expressed on the surface of human pDCs and works as a regulator of their innate response. Our findings indicate the potential of harnessing the function of pDCs by Ab-mediated targeting of TLR10 that may open a new therapeutic avenue for autoimmune disorders.

Cerebrospinal Creatine Kinase BB Isoenzyme: A Biomarker for Predicting Outcome After Cardiac Arrest.

BACKGROUND: Cerebrospinal fluid creatine kinase BB isoenzyme (CSF CK-BB) after cardiac arrest (CA) has been shown to have a high positive predictive value for poor neurological outcome, but it has not been evaluated in the setting of targeted temperature management (TTM) and modern CA care. We aimed to evaluate CSF CK-BB as a prognostic biomarker after CA. METHODS: We performed a retrospective cohort study of patients with CA admitted between 2010 and 2020 to a three-hospital health system who remained comatose and had CSF CK-BB assayed between 36 and 84 h after CA. We examined the proportion of patients at hospital discharge who achieved favorable or intermediate neurological outcome, defined as Cerebral Performance Category score of 1-3, compared with those with poor outcome (Cerebral Performance Category score 4-5) for various CSF CK-BB thresholds. We also evaluated additive value of bilateral absence of somatosensory evoked potentials (SSEPs). RESULTS: Among 214 eligible patients, the mean age was 54.7 ± 4.8 years, 72% of patients were male, 33% were nonwhite, 17% had shockable rhythm, 90% were out-of-hospital CA, and 83% received TTM. A total of 19 (9%) awakened. CSF CK-BB ≥ 230 U/L predicted a poor outcome at hospital discharge, with a specificity of 100% (95% confidence interval [CI] 82-100%) and sensitivity of 69% (95% CI 62-76%). When combined with bilaterally absent N20 response on SSEP, specificity remained 100% while sensitivity increased to 80% (95% CI 73-85%). Discordant CK-BB and SSEP findings were seen in 13 (9%) patients. CONCLUSIONS: Cerebrospinal fluid creatine kinase BB isoenzyme levels accurately predicted poor neurological outcome among CA survivors treated with TTM. The CSF CK-BB cutoff of 230 U/L optimizes sensitivity to 69% while maintaining a specificity of 100%. CSF CK-BB could be a useful addition to multimodal neurological prognostication after CA.

Proteome-wide analysis identifies plasma immune regulators of amyloid-beta progression.

While immune function is known to play a mechanistic role in Alzheimer's disease (AD), whether immune proteins in peripheral circulation influence the rate of amyloid-ß (Aß) progression - a central feature of AD - remains unknown. In the Baltimore Longitudinal Study of Aging, we quantified 942 immunological proteins in plasma and identified 32 (including CAT [catalase], CD36 [CD36 antigen], and KRT19 [keratin 19]) associated with rates of cortical Aß accumulation measured with positron emission tomography (PET). Longitudinal changes in a subset of candidate proteins also predicted Aß progression, and the mid- to late-life (20-year) trajectory of one protein, CAT, was associated with late-life Aß-positive status in the Atherosclerosis Risk in Communities (ARIC) study. Genetic variation that influenced plasma levels of CAT, CD36 and KRT19 predicted rates of Aß accumulation, including causal relationships with Aß PET levels identified with two-sample Mendelian randomization. In addition to associations with tau PET and plasma AD biomarker changes, as well as expression patterns in human microglia subtypes and neurovascular cells in AD brain tissue, we showed that 31 % of candidate proteins were related to mid-life (20-year) or late-life (8-year) dementia risk in ARIC. Our findings reveal plasma proteins associated with longitudinal Aß accumulation, and identify specific peripheral immune mediators that may contribute to the progression of AD pathophysiology.