The rockefeller university

The human metabolic and excretion profile of zalunfiban, a novel glycoprotein IIb/IIIa inhibitor, was studied in a phase 1 clinical trial.C-14-zalunfiban was administered subcutaneously as a single fixed dose (9.5 mg with 5 mu Ci total radioactivity). Zalunfiban whole blood concentrations were measured using liquid chromatography-mass spectrometry. C-14-zalunfiban and metabolites were measured using liquid scintillation counting and accelerator mass spectrometry in whole blood, urine, and faeces. Eight participants were enrolled. Zalunfiban was well-tolerated. Following injection zalunfiban was detectable within 5 minutes and the last measurable concentration was observed within 4 hours. The median T-max was 0.25 hours and mean half-life was 0.96 hours. Zalunfiban accounted for 35.6% of total whole blood radioactivity AUC at 4 hours. The single major identified metabolite was des-gly-zalunfiban (M1), which has <1% of zalunfiban's antiplatelet activity. M1 was the primary urinary metabolite (52.98% of dose) with minor amounts of zalunfiban (1.31%) detected. M1 was also the major metabolite in faeces (2.87%). Total dose recovery reached >90% by 240 hours. Zalunfiban is rapidly metabolised to the nearly inactive M1 metabolite, which is excreted primarily in urine. Renal impairment, therefore, is unlikely to significantly prolong zalunfiban effects and dose adjustment in patients with reduced renal function may not be required.

Although the etiological relevance of the detection of microsporidia in human stool samples remains uncertain, the immunological status of patients has been posited as an important determinant of potential clinical impact of these parasites. To further assess the interplay between the epidemiology of microsporidia and immunological markers, we conducted a study utilizing real-time PCR targeting Enterocytozoon bieneusi, Encephalitozoon cuniculi, Encephalitozoon hellem, and Encephalitozoon intestinalis, combined in a single fluorescence channel. The study involved a cohort of 595 clinically and immunologically well-characterized Ghanaian HIV patients, alongside 82 HIV-negative control individuals from Ghana. While microsporidial DNA was absent in HIV-negative controls, among people living with HIV, its prevalence was inversely correlated with CD4+ lymphocyte counts: 6.0% in those with >500 cells/mu L, 9.5% in those with 200-499 cells/mu L, 13.8% in those with 50-199 cells/mu L, and 27.5% in those with <50 cells/L, respectively. Correspondingly, microsporidia were more frequently detected in HIV patients who were not receiving antiretroviral therapy. There were no associations with clinical symptoms including gastroenteritis with the exception of a non-significant trend towards weight loss. HLA-DR+CD38+ on CD4+ T lymphocytes, a marker of immune activation, as well as Ki67, a marker of cell proliferation, were increased on CD4+ T lymphocytes in HIV patients with microsporidia, suggesting an immune response may be triggered. In conclusion, our assessment indicates a higher prevalence of microsporidia in the stool of Ghanaian HIV patients, which varies with their immunological status. However, given the lack of clear associations with clinical symptoms, the detection of microsporidia in the stool of HIV patients needs to be cautiously interpreted in clinical settings.

Glioblastoma is incurable and in urgent need of improved therapeutics(1). Here we identify a small compound, gliocidin, that kills glioblastoma cells while sparing non-tumour replicative cells. Gliocidin activity targets a de novo purine synthesis vulnerability in glioblastoma through indirect inhibition of inosine monophosphate dehydrogenase 2 (IMPDH2). IMPDH2 blockade reduces intracellular guanine nucleotide levels, causing nucleotide imbalance, replication stress and tumour cell death(2). Gliocidin is a prodrug that is anabolized into its tumoricidal metabolite, gliocidin-adenine dinucleotide (GAD), by the enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) of the NAD(+) salvage pathway. The cryo-electron microscopy structure of GAD together with IMPDH2 demonstrates its entry, deformation and blockade of the NAD(+) pocket(3). In vivo, gliocidin penetrates the blood-brain barrier and extends the survival of mice with orthotopic glioblastoma. The DNA alkylating agent temozolomide induces Nmnat1 expression, causing synergistic tumour cell killing and additional survival benefit in orthotopic patient-derived xenograft models. This study brings gliocidin to light as a prodrug with the potential to improve the survival of patients with glioblastoma.

In view of changing climatic conditions and disappearing natural resources such as fertile soil and water, exploring alternatives to today's industrial monocrop farming becomes essential. One promising farming practice is intercropping (IC), in which two or more crop species are grown together. Many experiments have shown that, under certain circumstances, IC can decrease soil erosion and fertilizer use, improve soil health and land management, while preserving crop production levels. However, there have been no quantitative approaches to predict, design, and control appropriate IC implementation for given particular environmental and farming conditions, and to assess its robustness. Here, we develop such an approach, based on methods and concepts developed in data science and systems biology. Our dataset groups the results of 2258 IC experiments, involving 274 pairs of 69 different plants. The data include 4 soil characteristics and 5 environmental and farming conditions, together with 8 traits for each of the two intercropped plants. We performed a dimensional reduction of the resulting 25-dimensional variable space and showed that, from a few quantities, one can predict IC yield relative to sole cultivation with good accuracy. For given environmental conditions, our computational approach can help to choose a companion plant and appropriate farming practices. It also indicates how to estimate the robustness of IC to external perturbations. This approach, together with its results, can be viewed as an initial step toward "systems agriculture," which would ultimately develop systems of multiple plant grown together in appropriately designed and controlled settings.

Hidradenitis suppurativa (HS) is a chronic, debilitating inflammatory skin disease characterized by keratinized epithelial tunnels that grow deeply into the dermis. Here, we examined the immune microenvironment within human HS lesions. Multi-omics profiling and multiplexed imaging identified tertiary lymphoid structures (TLSs) near HS tunnels. These TLSs were enriched with proliferative T cells, including follicular helper (Tfh), regulatory (Treg), and pathogenic T cells ( IL17A + and IFNG +), alongside extensive clonal expansion of plasma cells producing antibodies reactive to keratinocytes. HS fibroblasts express CXCL13 or CCL19 in response to immune cytokines. Using a microfluidic system to mimic TLS on a chip, we found that HS fibroblasts critically orchestrated lymphocyte aggregation via tumor necrosis factor alpha (TNF-a)-CXCL13 and TNF-a-CCL19 feedback loops with B and T cells, respectively; early TNF-a blockade suppressed aggregate initiation. Our findings provide insights into TLS formation in the skin, suggest therapeutic avenues for HS, and reveal mechanisms that may apply to other autoimmune settings, including Crohn's disease.

Early time-restricted eating (eTRE) is a dietary strategy that restricts caloric intake to the first 6-8 h of the day and can effect metabolic benefits independent of weight loss. However, the extent of these benefits is unknown. We conducted a randomized crossover feeding study to investigate the weight-independent effects of eTRE on glycemic variation, multiple time-in-range metrics, and levels of inflammatory markers. Ten adults with prediabetes were randomized to eTRE (8-h feeding window, 80% of calories consumed before 14:00 h) or usual feeding (50% of calories consumed after 16:00 h) for 1 week followed by crossover to the other schedule. Using continuous glucose monitoring, we showed that eTRE decreased glycemic variation (mean amplitude of glycemic excursion) and time in hyperglycemia greater than 140 mg/dL without affecting inflammatory markers (erythrocyte sedimentation rate and C-reactive protein). These data implicate eTRE as a candidate dietary intervention for the weight-independent management of dysglycemia in high-risk individuals.

Common variable immunodeficiency (CVID) is one of the most common groups of human inborn errors of immunity. In addition to infections resulting from insufficient levels of immunoglobulins and antibodies, a signifi cant proportion of patients develop autoimmune cytopenias, especially immune thrombocytopenia, hemolytic anemia, or neutropenia. They may be the initial manifestation of CVID in a patient who has not had significant infections, and similar episodes may recur at intervals over time. Treatment of these hematologic complications includes the use of corticosteroids or other medications, often including rituximab; splenectomy is discouraged. Here we outline the overall occurrence of these blood cytopenias in a cohort of 408 patients, as well as the clinical and genetic associations noted in these individuals.

The molecular mechanism by which inborn errors of the human RNA lariat-debranching enzyme 1 (DBR1) underlie brainstem viral encephalitis is unknown. We show here that the accumulation of RNA lariats in human DBR1-deficient cells interferes with stress granule (SG) assembly, promoting the proteasome degradation of at least G3BP1 and G3BP2, two key components of SGs. In turn, impaired assembly of SGs, which normally recruit PKR, impairs PKR activation and activity against viruses, including HSV-1. Remarkably, the genetic ablation of PKR abolishes the corresponding antiviral effect of DBR1 in vitro. We also show that Dbr1Y17H/Y17H mice are susceptible to similar viral infections in vivo. Moreover, cells and brain samples from Dbr1Y17H/Y17H mice exhibit decreased G3BP1/2 expression and PKR phosphorylation. Thus, the debranching of RNA lariats by DBR1 permits G3BP1/2- and SG assembly-mediated PKR activation and cell-intrinsic antiviral immunity in mice and humans. DBR1-deficient patients are prone to viral disease because of intracellular lariat accumulation, which impairs G3BP1/2- and SG assembly-dependent PKR activation.

ZAP is an antiviral protein that binds to and depletes viral RNA, which is often distinguished from vertebrate host RNA by its elevated CpG content. Two ZAP cofactors, TRIM25 and KHNYN, have activities that are poorly understood. Here, we show that functional interactions between ZAP, TRIM25 and KHNYN involve multiple domains of each protein, and that the ability of TRIM25 to multimerize via its RING domain augments ZAP activity and specificity. We show that KHNYN is an active nuclease that acts in a partly redundant manner with its homolog N4BP1. The ZAP N-terminal RNA binding domain constitutes a minimal core that is essential for antiviral complex activity, and we present a crystal structure of this domain that reveals contacts with the functionally required KHNYN C-terminal domain. These contacts are remote from the ZAP CpG binding site and would not interfere with RNA binding. Based on our dissection of ZAP, TRIM25 and KHNYN functional anatomy, we could design artificial chimeric antiviral proteins that reconstitute the antiviral function of the intact authentic proteins, but in the absence of protein domains that are otherwise required for activity. Together, these results suggest a model for the RNA recognition and action of ZAP-containing antiviral protein complexes.

Identifying the scaling rules describing ecological patterns across time and space is a central challenge in ecology. Taylor's law of fluctuation scaling, which states that the variance of a population's size or density is proportional to a positive power of the mean size or density, has been widely observed in population dynamics and characterizes variability in multiple scientific domains. However, it is unclear if this phenomenon accurately describes ecological patterns across many orders of magnitude in time, and therefore links otherwise disparate observations. Here, we use water clarity observations from 10,531 days of high-frequency measurements in 35 globally distributed lakes, and lower-frequency measurements over multiple decades from 6342 lakes to test this unknown. We focus on water clarity as an integrative ecological characteristic that responds to both biotic and abiotic drivers. We provide the first documentation that variations in ecological measurements across diverse sites and temporal scales exhibit variance patterns consistent with Taylor's law, and that model coefficients increase in a predictable yet non-linear manner with decreasing observation frequency. This discovery effectively links high-frequency sensor network observations with long-term historical monitoring records, thereby affording new opportunities to understand and predict ecological dynamics on time scales from days to decades.