Intratumoral NKT cell accumulation promotes antitumor immunity in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) is a potentially lethal disease lacking effective treatments. Its immunosuppressive tumor microenvironment (TME) allows it to evade host immunosurveillance and limits response to immunotherapy. Here, using the mouse KRT19-deficient (sgKRT19-edited) PDA model, we find that intratumoral accumulation of natural killer T (NKT) cells is required to establish an immunologically active TME. Mechanistically, intratumoral NKT cells facilitate type I interferon (IFN) production to initiate an antitumor adaptive immune response, and orchestrate the intratumoral infiltration of T cells, dendritic cells, natural killer cells, and myeloid-derived suppressor cells. At the molecular level, NKT cells promote the production of type I IFN through the interaction of their CD40L with CD40 on myeloid cells. To evaluate the therapeutic potential of these observations, we find that administration of folinic acid to mice bearing PDA increases NKT cells in the TME and improves their response to anti-PD-1 antibody treatment. In conclusion, NKT cells have an essential role in the immune response to mouse PDA and are potential targets for immunotherapy.

Interaction between MED12 and ΔNp63 activates basal identity in pancreatic ductal adenocarcinoma.

The presence of basal lineage characteristics signifies hyperaggressive human adenocarcinomas of the breast, bladder and pancreas. However, the biochemical mechanisms that maintain this aberrant cell state are poorly understood. Here we performed marker-based genetic screens in search of factors needed to maintain basal identity in pancreatic ductal adenocarcinoma (PDAC). This approach revealed MED12 as a powerful regulator of the basal cell state in this disease. Using biochemical reconstitution and epigenomics, we show that MED12 carries out this function by bridging the transcription factor ΔNp63, a known master regulator of the basal lineage, with the Mediator complex to activate lineage-specific enhancer elements. Consistent with this finding, the growth of basal-like PDAC is hypersensitive to MED12 loss when compared to PDAC cells lacking basal characteristics. Taken together, our genetic screens have revealed a biochemical interaction that sustains basal identity in human cancer, which could serve as a target for tumor lineage-directed therapeutics.

Disulfide Bonds as Functional Tethers in Metal-organic Frameworks.

The functionality of metal-organic frameworks (MOFs) is often encoded by particular chemical moieties found within these architectures. As such, new techniques to install increasingly more complex functionalities in MOFs are regularly being reported in the literature. One such functional group is the disulfide bond. The redox behavior of this covalent linkage renders MOFs responsive to stimuli, often under reducing conditions. Here, we review examples in which disulfide-containing MOFs are deployed in applications including drug delivery, therapeutic ferroptosis, exfoliation, energy storage, sensing, and others.

The Association of Female and Male Preconception Dyslipidemia with Live Birth in Couples Seeking Fertility Treatment.

CONTEXT: Dyslipidemia is common, and resultant endothelial dysfunction may impact reproductive outcomes. No prospective study has examined the effect of preconception lipid parameters in both female and male partners or their interaction on live birth. OBJECTIVE: To determine whether live birth is associated with preconception lipids in both partners by planned fertility treatment. DESIGN: Secondary analysis of the Folic Acid and Zinc Supplementation Trial, conducted between June 2013-December 2017. Couples were followed for nine months after randomization and until delivery. SETTING: Multicenter study. PARTICIPANTS: Couples seeking fertility treatment (n = 2370; females 18-45 years, males ≥18 years). EXPOSURES: Female, male, and couple abnormal versus normal preconception lipid concentrations (total cholesterol [TC], low-density lipoprotein [LDL], high-density lipoprotein [HDL], triglycerides [TG]). MAIN OUTCOME MEASURES: Live birth. RESULTS: Among 2370 couples, most males (84%) and females (76%) had at least one abnormal lipid parameter. Males planning in vitro fertilization (IVF, n = 373) with elevated LDL had lower probability of live birth than those with normal levels (47.4% vs. 59.7%, aRR 0.79, 95% CI 0.65-0.98). In couples planning IVF where both partners had elevated TC or LDL, live birth was lower than those with normal levels (TC: 32.4% vs. 58.0%, aRR 0.53, 95% CI 0.36-0.79; and LDL: 41.9% vs. 63.8%, aRR 0.69, 95% CI 0.55-0.85). Lipid parameters were not associated with live birth for couples planning non-IVF treatments. CONCLUSIONS: Couples planning IVF where both partners had elevated TC or LDL and males planning IVF with elevated LDL had decreased probability of live birth. These findings may support lipid screening in patients seeking fertility treatment for prognostic information for reproductive outcomes.

Physiological role for S-nitrosylation of RyR1 in skeletal muscle function and development.

Excitation-contraction coupling in skeletal muscle myofibers depends upon Ca2+ release from the sarcoplasmic reticulum through the ryanodine receptor/Ca2+-release channel RyR1. The RyR1 contains ∼100 Cys thiols of which ∼30 comprise an allosteric network subject to posttranslational modification by S-nitrosylation, S-palmitoylation and S-oxidation. However, the role and function of these modifications is not understood. Although aberrant S-nitrosylation of multiple unidentified sites has been associated with dystrophic diseases, malignant hyperthermia and other myopathic syndromes, S-nitrosylation in physiological situations is reportedly specific to a single (1 of ∼100) Cys in RyR1, Cys3636 in a manner gated by pO2. Using mice expressing a form of RyR1 with a Cys3636→Ala point mutation to prevent S-nitrosylation at this site, we showed that Cys3636 was the principal target of endogenous S-nitrosylation during normal muscle function. The absence of Cys3636 S-nitrosylation suppressed stimulus-evoked Ca2+ release at physiological pO2 (at least in part by altering the regulation of RyR1 by Ca2+/calmodulin), eliminated pO2 coupling, and diminished skeletal myocyte contractility in vitro and measures of muscle strength in vivo. Furthermore, we found that abrogation of Cys3636 S-nitrosylation resulted in a developmental defect reflected in diminished myofiber diameter, altered fiber subtypes, and altered expression of genes implicated in muscle development and atrophy. Thus, our findings establish a physiological role for pO2-coupled S-nitrosylation of RyR1 in skeletal muscle contractility and development and provide foundation for future studies of RyR1 modifications in physiology and disease.

The human infertility single-cell testis atlas (HISTA): an interactive molecular scRNA-Seq reference of the human testis.

BACKGROUND: Single-cell RNA-seq (scRNA-Seq) has been widely adopted to study gene expression of the human testis. Several datasets of scRNA-Seq from human testis have been generated from different groups processed with different informatics pipelines. An integrated atlas of scRNA-Seq expression constructed from multiple donors, developmental ages, and fertility states would be widely useful for the testis research community. OBJECTIVE: To describe the generation and use of the human infertility single-cell testis atlas (HISTA), an interactive web tool for understanding human spermatogenesis through scRNA-Seq analysis. METHODS: We obtained scRNA-Seq datasets derived from 12 donors, including healthy adult controls, juveniles, and several infertility cases, and reprocessed these data using methods to remove batch effects. Using Shiny, an open-source environment for data visualization, we created numerous interactive tools for exploring the data, some of which support simple statistical hypothesis testing. We used the resulting HISTA browser and its underlying data to demonstrate HISTA's value for testis researchers. RESULTS: A primary application of HISTA is to search by a single gene or a set of genes; thus, we present various analyses that quantify and visualize gene expression across the testis cells and pathology. HISTA also contains machine-learning-derived gene modules ("components") that capture the entire transcriptional landscape of the testis tissue. We show how the use of these components can simplify the highly complex data in HISTA and assist with the interpretation of genes with unknown functions. Finally, we demonstrate the diverse ways HISTA can be used for new data analysis, including hypothesis testing. DISCUSSION AND CONCLUSIONS: HISTA is a research environment that can help scientists organize and understand the high-dimensional transcriptional landscape of the human testis. HISTA has already contributed to published testis research and can be updated as needed with input from the research community or downloaded and modified for individual needs.

Berotralstat for long-term prophylaxis of hereditary angioedema in Japan: Parts 2 and 3 of the randomized APeX-J Phase III trial.

Background: Berotralstat is a once-daily oral inhibitor of plasma kallikrein for the prophylaxis of hereditary angioedema (HAE) in patients ≥12 years. APeX-J aimed to evaluate the efficacy and safety of berotralstat in Japan. Methods: APeX-J was a Phase III trial comprising 3 parts (NCT03873116). Part 1 was a randomized, placebo-controlled evaluation of berotralstat 150 or 110 mg over 24 weeks. Part 2 was a 28-week dose-blinded phase in which berotralstat-treated patients continued the same dose and placebo patients were re-randomized to berotralstat 150 or 110 mg. In Part 3, all patients remaining on study received berotralstat 150 mg in an open-label manner for up to an additional 52 weeks. The primary endpoint of Parts 2 and 3 was long-term safety and tolerability, and secondary endpoints examined effectiveness. Results: Seventeen patients entered Part 2, and 11 continued into Part 3. Treatment-emergent adverse events (TEAEs) were reported by 14/17 patients (82.4%) in Parts 2 or 3; the most common were nasopharyngitis, abdominal pain, cystitis, influenza, and vertigo. One patient (5.9%) experienced a drug-related TEAE (Grade 4 increased hepatic enzyme). No drug-related serious TEAEs were reported. For patients who completed 26 months of treatment with berotralstat 150 mg (n = 5), mean (standard error of the mean) monthly HAE attack rates and on-demand medication use decreased from baseline by 1.15 (0.09) attacks/month and 2.8 (0.64) doses/month, respectively. Sustained improvements were also observed in patient quality of life and treatment satisfaction. Conclusions: Long-term prophylaxis with berotralstat raised no new safety signals and was effective at reducing attacks and improving patient-reported outcomes. Trial registration: ClinicalTrials.gov NCT03873116. Registered March 13, 2019. Retrospectively registered.

Long-term open-label vebicorvir for chronic HBV infection: Safety and off-treatment responses.

Background & Aims: The investigational first-generation core inhibitor vebicorvir (VBR) demonstrated safety and antiviral activity over 24 weeks in two phase IIa studies in patients with chronic HBV infection. In this long-term extension study, patients received open-label VBR with nucleos(t)ide reverse transcriptase inhibitors (NrtIs). Methods: Patients in this study (NCT03780543) previously received VBR + NrtI or placebo + NrtI in parent studies 201 (NCT03576066) or 202 (NCT03577171). After receiving VBR + NrtI for ≥52 weeks, stopping criteria (based on the treatment history and hepatitis B e antigen status in the parent studies) were applied, and patients either discontinued both VBR + NrtI, discontinued VBR only, or continued both VBR + NrtI. The primary efficacy endpoint was the proportion of patients with HBV DNA <20 IU/ml at 24 weeks off treatment. Results: Ninety-two patients entered the extension study and received VBR + NrtI. Long-term VBR + NrtI treatment led to continued suppression of HBV nucleic acids and, to a lesser extent, HBV antigens. Forty-three patients met criteria to discontinue VBR + NrtI, with no patients achieving the primary endpoint; the majority of virologic rebound occurred ≥4 weeks off treatment. Treatment was generally well tolerated, with few discontinuations due to adverse events (AEs). There were no deaths. Most AEs and laboratory abnormalities were related to elevations in alanine aminotransferase and occurred during the off-treatment or NrtI-restart phases. No drug-drug interactions between VBR + NrtI and no cases of treatment-emergent resistance among patients who adhered to treatment were observed. Conclusions: Long-term VBR + NrtI was safe and resulted in continued reductions in HBV nucleic acids following completion of the 24-week parent studies. Following treatment discontinuation, virologic relapse was observed in all patients. This first-generation core inhibitor administered with NrtI for at least 52 weeks was not sufficient for HBV cure. Clinical trial number: NCT03780543. Impact and implications: Approved treatments for chronic hepatitis B virus infection (cHBV) suppress viral replication, but viral rebound is almost always observed after treatment discontinuation, highlighting an unmet need for improved therapies with finite treatment duration producing greater therapeutic responses that can be sustained off treatment. First-generation core inhibitors, such as vebicorvir, have mechanisms of action orthogonal to standard-of-care therapies that deeply suppress HBV viral replication during treatment; however, to date, durable virologic responses have not been observed after treatment discontinuation. The results reported here will help researchers with the design and interpretation of future studies investigating core inhibitors as possible components of finite treatment regimens for patients with cHBV. It is possible that next-generation core inhibitors with enhanced potency may produce deeper and more durable antiviral activity than first-generation agents, including vebicorvir.

Vascular risk burden is a key player in the early progression of Alzheimer's disease.

Understanding whether vascular risk factors (VRFs) synergistically potentiate Alzheimer's disease (AD) progression is important in the context of emerging treatments for preclinical AD. In a group of 503 cognitively unimpaired individuals, we tested whether VRF burden interacts with AD pathophysiology to accelerate neurodegeneration and cognitive decline. Baseline VRF burden was calculated considering medical data and AD pathophysiology was assessed based on cerebrospinal fluid (CSF) amyloid-ß1-42 (Aß1-42) and tau phosphorylated at threonine 181 (p-tau181). Neurodegeneration was assessed with plasma neurofilament light (NfL) and global cognition with the modified version of the Preclinical Alzheimer's Cognitive Composite. The mean (SD) age of participants was 72.9 (6.1) years, and 220 (43.7%) were men. Linear mixed-effects models revealed that an elevated VRF burden synergistically interacted with AD pathophysiology to drive longitudinal plasma NfL increase and cognitive decline. Additionally, VRF burden was not associated with CSF Aß1-42 or p-tau181 changes over time. Our results suggest that VRF burden and AD pathophysiology are independent processes; however, they synergistically lead to neurodegeneration and cognitive deterioration. In preclinical stages, the combination of therapies targeting VRFs and AD pathophysiology might potentiate treatment outcomes.

The IRAK1/IRF5 axis initiates IL-12 response by dendritic cells and control of Toxoplasma gondii infection.

Activation of endosomal Toll-like receptor (TLR) 7, TLR9, and TLR11/12 is a key event in the resistance against the parasite Toxoplasma gondii. Endosomal TLR engagement leads to expression of interleukin (IL)-12 via the myddosome, a protein complex containing MyD88 and IL-1 receptor-associated kinase (IRAK) 4 in addition to IRAK1 or IRAK2. In murine macrophages, IRAK2 is essential for IL-12 production via endosomal TLRs but, surprisingly, Irak2-/- mice are only slightly susceptible to T. gondii infection, similar to Irak1-/- mice. Here, we report that upon T. gondii infection IL-12 production by different cell populations requires either IRAK1 or IRAK2, with conventional dendritic cells (DCs) requiring IRAK1 and monocyte-derived DCs (MO-DCs) requiring IRAK2. In both populations, we identify interferon regulatory factor 5 as the main transcription factor driving the myddosome-dependent IL-12 production during T. gondii infection. Consistent with a redundant role of DCs and MO-DCs, mutations that affect IL-12 production in both cell populations show high susceptibility to infection in vivo.

Itaconate impairs immune control of Plasmodium by enhancing mtDNA-mediated PD-L1 expression in monocyte-derived dendritic cells.

Severe forms of malaria are associated with systemic inflammation and host metabolism disorders; however, the interplay between these outcomes is poorly understood. Using a Plasmodium chabaudi model of malaria, we demonstrate that interferon (IFN) γ boosts glycolysis in splenic monocyte-derived dendritic cells (MODCs), leading to itaconate accumulation and disruption in the TCA cycle. Increased itaconate levels reduce mitochondrial functionality, which associates with organellar nucleic acid release and MODC restraint. We hypothesize that dysfunctional mitochondria release degraded DNA into the cytosol. Once mitochondrial DNA is sensitized, the activation of IRF3 and IRF7 promotes the expression of IFN-stimulated genes and checkpoint markers. Indeed, depletion of the STING-IRF3/IRF7 axis reduces PD-L1 expression, enabling activation of CD8+ T cells that control parasite proliferation. In summary, mitochondrial disruption caused by itaconate in MODCs leads to a suppressive effect in CD8+ T cells, which enhances parasitemia. We provide evidence that ACOD1 and itaconate are potential targets for adjunct antimalarial therapy.

Biohybrid Robotic Hand to Investigate Tactile Encoding and Sensorimotor Integration.

For people who have experienced a spinal cord injury or an amputation, the recovery of sensation and motor control could be incomplete despite noteworthy advances with invasive neural interfaces. Our objective is to explore the feasibility of a novel biohybrid robotic hand model to investigate aspects of tactile sensation and sensorimotor integration with a pre-clinical research platform. Our new biohybrid model couples an artificial hand with biological neural networks (BNN) cultured in a multichannel microelectrode array (MEA). We decoded neural activity to control a finger of the artificial hand that was outfitted with a tactile sensor. The fingertip sensations were encoded into rapidly adapting (RA) or slowly adapting (SA) mechanoreceptor firing patterns that were used to electrically stimulate the BNN. We classified the coherence between afferent and efferent electrodes in the MEA with a convolutional neural network (CNN) using a transfer learning approach. The BNN exhibited the capacity for functional specialization with the RA and SA patterns, represented by significantly different robotic behavior of the biohybrid hand with respect to the tactile encoding method. Furthermore, the CNN was able to distinguish between RA and SA encoding methods with 97.84% ± 0.65% accuracy when the BNN was provided tactile feedback, averaged across three days in vitro (DIV). This novel biohybrid research platform demonstrates that BNNs are sensitive to tactile encoding methods and can integrate robotic tactile sensations with the motor control of an artificial hand. This opens the possibility of using biohybrid research platforms in the future to study aspects of neural interfaces with minimal human risk.

Once-Daily Oral Berotralstat for Long-Term Prophylaxis of Hereditary Angioedema: The Open-Label Extension of the APeX-2 Randomized Trial.

BACKGROUND: Berotralstat is a first-line, once-daily oral plasma kallikrein inhibitor approved for prophylaxis of hereditary angioedema (HAE) attacks in patients 12 years or older. OBJECTIVE: This analysis examined the safety and effectiveness of long-term prophylaxis with berotralstat. METHODS: APeX-2 was a phase 3, parallel-group, multicenter trial in patients with HAE caused by C1-inhibitor deficiency (NCT03485911). Part 1 was a randomized, double-blind, placebo-controlled evaluation of 150 and 110 mg of berotralstat over 24 weeks. In part 2, berotralstat-treated patients continued the same treatment, and placebo-treated patients were re-randomized to 150 or 110 mg of berotralstat for 24 weeks. In part 3, all patients were treated with open-label berotralstat at 150 mg, which could be continued for up to an additional 4 years. In part 3, the primary endpoint was long-term safety and tolerability. Secondary endpoints included HAE attack rates and quality of life (QoL). RESULTS: Eighty-one patients entered part 3. Treatment-emergent adverse events (TEAEs) occurred in 82.7% of patients, with most being mild or moderate in severity. The most common TEAEs were nasopharyngitis, urinary tract infection, abdominal pain, arthralgia, coronavirus infection, and diarrhea. Drug-related TEAEs occurred in 14.8% of patients, but none were serious. For patients who completed 96 weeks of berotralstat treatment (n = 70), the mean (standard error) change in attack rate from baseline was -2.21 (0.20) attacks/mo. Clinically meaningful improvements in QoL were also observed, with the largest improvements in the functioning domain. CONCLUSION: Berotralstat was generally well tolerated, provided rapid and sustained reductions in HAE attacks and improved QoL over 96 weeks.

The Green Transfer-Long-Term Results.

PURPOSE: The purpose of this study was to determine the long-term results of the Green transfer (flexor carpi ulnaris to extensor carpi radialis brevis) for patient-reported outcomes, wrist position, and range of motion. METHODS: We re-examined 13 patients from a previous prospective study involving surgery for hemiplegia that included a Green transfer. The average follow-up was 8 years with the range from 5 to 11 years. The wrist range of motion and the postoperative position of the wrists were measured. The surgical outcomes were measured via the Pediatric Orthopedic Data Collection Instrument, the Shriner's Hospital Upper Extremity Evaluation, Pediatric Quality of Life, and visual analog score for appearance from the patient and the parent. RESULTS: At this follow-up, only 7 of the 13 patients had a wrist position near neutral with the ability to flex and extend the wrist. Wrist range of motion was improved in four, decreased in four, and stayed the same in five patients. In contrast to these positional wrist results, statistically significant improvements were noted in several aspects of the Pediatric Orthopedic Data Collection Instrument, visual analog scores, and Shriner's Hospital Upper Extremity Evaluation scores. CONCLUSIONS: Long-term follow-up of the flexor carpi ulnaris to extensor carpi radialis brevis tendon transfer in hemiplegic patients reveals the results to be variable but favorable from a patient-reported outcome standpoint. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Neuropsychiatric Symptoms and Microglial Activation in Patients with Alzheimer Disease.

Importance: Neuropsychiatric symptoms are commonly encountered and are highly debilitating in patients with Alzheimer disease. Understanding their underpinnings has implications for identifying biomarkers and treatment for these symptoms. Objective: To evaluate whether glial markers are associated with neuropsychiatric symptoms in individuals across the Alzheimer disease continuum. Design, Setting, and Participants: This cross-sectional study was conducted from January to June 2023, leveraging data from the Translational Biomarkers in Aging and Dementia cohort at McGill University, Canada. Recruitment was based on referrals of individuals from the community or from outpatient clinics. Exclusion criteria included active substance abuse, major surgery, recent head trauma, safety contraindications for positron emission tomography (PET) or magnetic resonance imaging, being currently enrolled in other studies, and having inadequately treated systemic conditions. Main Outcomes and Measures: All individuals underwent assessment for neuropsychiatric symptoms (Neuropsychiatry Inventory Questionnaire [NPI-Q]), and imaging for microglial activation ([11C]PBR28 PET), amyloid-ß ([18F]AZD4694 PET), and tau tangles ([18F]MK6240 PET). Results: Of the 109 participants, 72 (66%) were women and 37 (34%) were men; the median age was 71.8 years (range, 38.0-86.5 years). Overall, 70 had no cognitive impairment and 39 had cognitive impairment (25 mild; 14 Alzheimer disease dementia). Amyloid-ß PET positivity was present in 21 cognitively unimpaired individuals (30%) and in 31 cognitively impaired individuals (79%). The NPI-Q severity score was associated with microglial activation in the frontal, temporal, and parietal cortices (ß = 7.37; 95% CI, 1.34-13.41; P = .01). A leave-one-out approach revealed that irritability was the NPI-Q domain most closely associated with the presence of brain microglial activation (ß = 6.86; 95% CI, 1.77-11.95; P = .008). Furthermore, we found that microglia-associated irritability was associated with study partner burden measured by NPI-Q distress score (ß = 5.72; 95% CI, 0.33-11.10; P = .03). Conclusions and Relevance: In this cross-sectional study of 109 individuals across the AD continuum, microglial activation was associated with and a potential biomarker of neuropsychiatric symptoms in Alzheimer disease. Moreover, our findings suggest that the combination of amyloid-ß- and microglia-targeted therapies could have an impact on relieving these symptoms.

Comorbidity clusters and in-hospital outcomes in patients admitted with acute myocardial infarction in the USA: A national population-based study.

BACKGROUND: The prevalence of multimorbidity in patients with acute myocardial infarction (AMI) is increasing. It is unclear whether comorbidities cluster into distinct phenogroups and whether are associated with clinical trajectories. METHODS: Survey-weighted analysis of the United States Nationwide Inpatient Sample (NIS) for patients admitted with a primary diagnosis of AMI in 2018. In-hospital outcomes included mortality, stroke, bleeding, and coronary revascularisation. Latent class analysis of 21 chronic conditions was used to identify comorbidity classes. Multivariable logistic and linear regressions were fitted for associations between comorbidity classes and outcomes. RESULTS: Among 416,655 AMI admissions included in the analysis, mean (±SD) age was 67 (±13) years, 38% were females, and 76% White ethnicity. Overall, hypertension, coronary heart disease (CHD), dyslipidaemia, and diabetes were common comorbidities, but each of the identified five classes (C) included ≥1 predominant comorbidities defining distinct phenogroups: cancer/coagulopathy/liver disease class (C1); least burdened (C2); CHD/dyslipidaemia (largest/referent group, (C3)); pulmonary/valvular/peripheral vascular disease (C4); diabetes/kidney disease/heart failure class (C5). Odds ratio (95% confidence interval [CI]) for mortality ranged between 2.11 (1.89-2.37) in C2 to 5.57 (4.99-6.21) in C1. For major bleeding, OR for C1 was 4.48 (3.78; 5.31); for acute stroke, ORs ranged between 0.75 (0.60; 0.94) in C2 to 2.76 (2.27; 3.35) in C1; for coronary revascularization, ORs ranged between 0.34 (0.32; 0.36) in C1 to 1.41 (1.30; 1.53) in C4. CONCLUSIONS: We identified distinct comorbidity phenogroups that predicted in-hospital outcomes in patients admitted with AMI. Some conditions overlapped across classes, driven by the high comorbidity burden. Our findings demonstrate the predictive value and potential clinical utility of identifying patients with AMI with specific comorbidity clustering.

Deinterpenetration of IRMOF-9.

One of the iconic characteristics of metal-organic frameworks (MOFs) is the possesssion of guest-accessible pores. Increasing pore size has a direct and often beneficial impact on a MOF's adsorption and separation properties. However, as pore size increases, the resulting void spaces are often filled by interpenetrated frameworks, where one or more networks crystallize within the pore system of another identical network, reducing the MOF's free volume and pore size. Furthermore, due to the thermodynamic favorability of interpenetration during solvothermal synthesis, techniques to synthetically differentiate interpenetrated from non-interpenetrated MOFs are paramount. This study reports the synthesis of deinterpenetrated IRMOF-9 via halide mediated deinterpenetrative conversion of Zn4 O-derived IRMOF-9. IRMOF-9, when treated with ethylammonium bromide, is quasi-selectively etched, revealing the non-interpenetrated analogue, IRMOF-10 (deinterpenetrated IRMOF-9), which can be isolated prior to complete dissolution by the bromide solution. Dye adsorption, surface area and pore size distribution analysis, and powder X-ray diffraction are consistent with successful deinterpenetration.

Plasma cells in human pancreatic ductal adenocarcinoma secrete antibodies against self-antigens.

Intratumoral B cell responses are associated with more favorable clinical outcomes in human pancreatic ductal adenocarcinoma (PDAC). However, the antigens driving these B cell responses are largely unknown. We sought to discover these antigens by using single-cell RNA sequencing (scRNA-Seq) and immunoglobulin (Ig) sequencing of tumor-infiltrating immune cells from 7 primary PDAC samples. We identified activated T and B cell responses and evidence of germinal center reactions. Ig sequencing identified plasma cell (PC) clones expressing isotype-switched and hypermutated Igs, suggesting the occurrence of T cell-dependent B cell responses. We assessed the reactivity of 41 recombinant antibodies that represented the products of 235 PCs and 12 B cells toward multiple cell lines and PDAC tissues and observed frequent staining of intracellular self-antigens. Three of these antigens were identified: the filamentous actin (F-actin), the nucleic protein RuvB like AAA ATPase 2 (RUVBL2), and the mitochondrial protein heat shock protein family D (Hsp60) member 1 (HSPD1). Antibody titers against F-actin and HSPD1 were substantially elevated in the plasma of patients with PDAC compared with healthy donors. Thus, PCs in PDAC produce autoantibodies reacting with intracellular self-antigens, which may result from promotion of preexisting, autoreactive B cell responses. These observations indicate the chronic inflammatory microenvironment of PDAC can support the adaptive immune response.

APOEε4 potentiates amyloid ß effects on longitudinal tau pathology.

The mechanisms by which the apolipoprotein E ε4 (APOEε4) allele influences the pathophysiological progression of Alzheimer's disease (AD) are poorly understood. Here we tested the association of APOEε4 carriership and amyloid-ß (Aß) burden with longitudinal tau pathology. We longitudinally assessed 94 individuals across the aging and AD spectrum who underwent clinical assessments, APOE genotyping, magnetic resonance imaging, positron emission tomography (PET) for Aß ([18F]AZD4694) and tau ([18F]MK-6240) at baseline, as well as a 2-year follow-up tau-PET scan. We found that APOEε4 carriership potentiates Aß effects on longitudinal tau accumulation over 2 years. The APOEε4-potentiated Aß effects on tau-PET burden were mediated by longitudinal plasma phosphorylated tau at threonine 217 (p-tau217+) increase. This longitudinal tau accumulation as measured by PET was accompanied by brain atrophy and clinical decline. Our results suggest that the APOEε4 allele plays a key role in Aß downstream effects on the aggregation of phosphorylated tau in the living human brain.

Plasma p-tau231 and p-tau217 inform on tau tangles aggregation in cognitively impaired individuals.

INTRODUCTION: Phosphorylated tau (p-tau) biomarkers have been recently proposed to represent brain amyloid-ß (Aß) pathology. Here, we evaluated the plasma biomarkers' contribution beyond the information provided by demographics (age and sex) to identify Aß and tau pathologies in individuals segregated as cognitively unimpaired (CU) and impaired (CI). METHODS: We assessed 138 CU and 87 CI with available plasma p-tau231, 217+ , and 181, Aß42/40, GFAP and Aß- and tau-PET. RESULTS: In CU, only plasma p-tau231 and p-tau217+ significantly improved the performance of the demographics in detecting Aß-PET positivity, while no plasma biomarker provided additional information to identify tau-PET positivity. In CI, p-tau217+ and GFAP significantly contributed to demographics to identify both Aß-PET and tau-PET positivity, while p-tau231 only provided additional information to identify tau-PET positivity. DISCUSSION: Our results support plasma p-tau231 and p-tau217+ as state markers of early Aß deposition, but in later disease stages they inform on tau tangle accumulation. HIGHLIGHTS: It is still unclear how much plasma biomarkers contribute to identification of AD pathology across the AD spectrum beyond the information already provided by demographics (age + sex). Plasma p-tau231 and p-tau217+ contribute to demographic information to identify brain Aß pathology in preclinical AD. In CI individuals, plasma p-tau231 contributes to age and sex to inform on the accumulation of tau tangles, while p-tau217+ and GFAP inform on both Aß deposition and tau pathology.