Plasminogen missense variants and their involvement in cardiovascular and inflammatory disease.

Human plasminogen (PLG), the zymogen of the fibrinolytic protease, plasmin, is a polymorphic protein with two widely distributed codominant alleles, PLG/Asp453 and PLG/Asn453. About 15 other missense or non-synonymous single nucleotide polymorphisms (nsSNPs) of PLG show major, yet different, relative abundances in world populations. Although the existence of these relatively abundant allelic variants is generally acknowledged, they are often overlooked or assumed to be non-pathogenic. In fact, at least half of those major variants are classified as having conflicting pathogenicity, and it is unclear if they contribute to different molecular phenotypes. From those, PLG/K19E and PLG/A601T are examples of two relatively abundant PLG variants that have been associated with PLG deficiencies (PD), but their pathogenic mechanisms are unclear. On the other hand, approximately 50 rare and ultra-rare PLG missense variants have been reported to cause PD as homozygous or compound heterozygous variants, often leading to a debilitating disease known as ligneous conjunctivitis. The true abundance of PD-associated nsSNPs is unknown since they can remain undetected in heterozygous carriers. However, PD variants may also contribute to other diseases. Recently, the ultra-rare autosomal dominant PLG/K311E has been found to be causative of hereditary angioedema (HAE) with normal C1 inhibitor. Two other rare pathogenic PLG missense variants, PLG/R153G and PLG/V709E, appear to affect platelet function and lead to HAE, respectively. Herein, PLG missense variants that are abundant and/or clinically relevant due to association with disease are examined along with their world distribution. Proposed molecular mechanisms are discussed when known or can be reasonably assumed.

HHV-8-associated diseases in transplantation: A case report and narrative review focused on diagnosis and prevention.

BACKGROUND: Human herpes virus 8 (HHV-8) or Kaposi sarcoma herpesvirus (KSHV) is an opportunistic oncovirus that causes multiple pathologic entities. METHODS: We present a case of fatal HHV-8-associated multisystem illness with disseminated Kaposi sarcoma and HHV8-associated lymphoproliferative disorder with systemic inflammation. We conducted a narrative review of the literature on HHV-8 in transplantation with a goal of illuminating the spectrum of HHV-8-associated diseases in this vulnerable population, modes of disease transmission, and the potential role for donor and recipient screening. RESULTS: HHV-8-associated KS, primary effusion lymphoma (PEL), multicentric Castleman disease (MCD), and KSHV inflammatory cytokine disorder (KICS) may affect transplant recipients; with the exception of KS, these conditions are rare but carry high morbidity and mortality. CONCLUSION: HHV-8-associated diseases have diverse and protean manifestations in transplant recipients, with potentially fatal outcomes. HHV-8 seroprevalence among organ donors and the magnitude of risk for donor-derived HHV-8 infection or clinically significant disease remain unknown and require further study.

Roles of Tubulin Concentration during Prometaphase and Ran-GTP during Anaphase of Caenorhabditis elegans Meiosis.

In many animal species, the oocyte meiotic spindle, which is required for chromosome segregation, forms without centrosomes. In some systems, Ran-GEF on chromatin initiates spindle assembly. We found that in Caenorhabditis elegans oocytes, endogenously-tagged Ran-GEF dissociates from chromatin during spindle assembly but re-associates during meiotic anaphase. Meiotic spindle assembly occurred after auxin-induced degradation of Ran-GEF, but anaphase I was faster than controls and extrusion of the first polar body frequently failed. In search of a possible alternative pathway for spindle assembly, we found that soluble tubulin concentrates in the nuclear volume during germinal vesicle breakdown. We found that the concentration of soluble tubulin in the metaphase spindle region is enclosed by ER sheets which exclude cytoplasmic organelles including mitochondria and yolk granules. Measurement of the volume occupied by yolk granules and mitochondria indicated that volume exclusion would be sufficient to explain the concentration of tubulin in the spindle volume. We suggest that this concentration of soluble tubulin may be a redundant mechanism promoting spindle assembly near chromosomes.

Double cervical cerclage for cervical insufficiency: Case report.

Recurrent pregnancy loss devastates parents and frustrates doctors, especially when the pregnancy progresses to the second trimester. Cervical insufficiency is the most common cause of second-trimester pregnancy loss. Abdominal cerclage is the treatment option for women with failed vaginally applied cervical cerclage. We report a 33-year-old para 0 with a history of nine second-trimester pregnancy losses. She had six failed transvaginal cerclages using McDonald's procedure. A vaginal double cervical cerclage was placed in her index pregnancy. Two mersilene tape purse-string sutures were placed in the submucosal layer of the cervix; the first 1cm below and the second at the level of the internal os. Both sutures were knotted at the 12 O'Clock position on the cervix. She carried her pregnancy to almost term and delivered a healthy baby girl weighing 2.5kg. We recommend a transvaginal double cervical cerclage with mersilene tape using a modified McDonald's technique as a viable alternative to abdominal cervical cerclage. (Afr J Reprod Health 2024; 28 [6]: 117-125).

Les fausses couches récurrentes sont dévastatrices pour les parents et frustrent les médecins, surtout lorsque la grossesse progresse jusqu'au deuxième trimestre. L'insuffisance cervicale est la cause la plus fréquente de fausse couche au deuxième trimestre. Le cerclage abdominal est l'option de traitement pour les femmes dont le cerclage cervical appliqué par voie vaginale a échoué. Nous rapportons une para 0 de 33 ans avec des antécédents de neuf fausses couches au deuxième trimestre. Elle a eu six cerclages transvaginaux selon la procédure McDonald's qui ont échoué. Un double cerclage vaginal vaginal a été placé lors de sa grossesse index. Deux fils de suture en bourse en ruban de mersilène ont été placés dans la couche sous-muqueuse du col de l'utérus ; le premier 1cm en dessous et le second au niveau de l'os interne. Les deux sutures ont été nouées à la position 12 heures sur le col. Elle a mené sa grossesse presque à terme et a donné naissance à une petite fille en bonne santé pesant 2,5 kg. Nous recommandons un double cerclage cervical transvaginal avec du ruban de mersilène en utilisant une technique McDonald's modifiée comme alternative viable au cerclage cervical abdominal. (Afr J Reprod Health 2024; 28 [6]: 117-125).

Independent inheritance of cognition and bipolar disorder in a family sample.

Cognitive deficits in people with bipolar disorder (BD) may be the result of the illness or its treatment, but they could also reflect genetic risk factors shared between BD and cognition. We investigated this question using empirical genetic relationships within a sample of patients with BD and their unaffected relatives. Participants with bipolar I, II, or schizoaffective disorder ("narrow" BD, n = 69), related mood disorders ("broad" BD, n = 135), and their clinically unaffected relatives (n = 227) completed five cognitive tests. General cognitive function (g) was quantified via principal components analysis (PCA). Heritability and genetic correlations were estimated with SOLAR-Eclipse. Participants with "narrow" or "broad" diagnoses showed deficits in g, although affect recognition was unimpaired. Cognitive performance was significantly heritable (h2 = 0.322 for g, p < 0.005). Coheritability between psychopathology and g was small (0.0184 for narrow and 0.0327 for broad) and healthy relatives of those with BD were cognitively unimpaired. In this family sample, cognitive deficits were present in participants with BD but were not explained by substantial overlaps in genetic determinants of mood and cognition. These findings support the view that cognitive deficits in BD are largely the result of the illness or its treatment.

No difference in midterm outcomes and complication rate between retroperitoneal and transperitoneal open aortic aneurysm repair in females.

OBJECTIVES: Abdominal Aortic Aneurysms (AAA) in females are less prevalent, have higher expansion rates and experience rupture at smaller diameters than in males. Studies have compared outcomes of the retroperitoneal (RP) and transperitoneal (TP) approach in open aortic aneurysm repair (OAR) with conflicting results. No study to date has compared the two approaches solely in females. In this study we compare midterm outcomes of the RP and TP approach in females undergoing OAR. METHODS: Single-center, retrospective review of all females undergoing OAR from 2010 to 2021. Patients undergoing elective, symptomatic and ruptured OAR were included. The cohort was stratified by surgical approach RP versus TP and midterm outcomes were compared amongst the groups. Outcomes included mortality, graft related, and non-graft related complications. RESULTS: A total of 244 patients (RP n = 133; TP n = 111) were identified. Follow-up period was 28 ± 30.7 months. Baseline perioperative characteristics were similar except that more people in the RP group had ejection fraction ((EF) > 50% (82% vs 68%), p = .037). Patients who underwent RP repair had longer visceral/renal ischemia time (p = .01), larger graft diameter (18 vs 16 mm; p = <0.001), were more likely to have a suprarenal clamp placed(70.5 vs 48.2; p < .001), and had decreased autotransfusion volume (611 vs 861 mL; p < .01) compared to those who underwent TP repair. Number of deaths was higher in the TP group during study follow-up period (36.4 vs 23.8; p = .035), but the difference of the time to event analysis was not significant. There was no difference in all-cause survival at 36 months between RP and TP (77.8 vs 76.8; p = .045). Overall midterm complications were 9.5% in both groups. Any graft related complication was 1.8% in TP versus 3% RP (p = .69). In a multivariable model, after adjusting for age, urgency, smoking, prior aneurysm repair, and ASA level, the hazard ratio decreases with the RP approach, however this did not reach significance (p = .052). CONCLUSION: In a 12-year period of OAR in females, TP and RP results were comparable at midterm analysis. The RP approach appeared to be used more often for OAR requiring suprarenal clamping. Although the TP group had increased mortality, the difference of the time to event analysis was not significant. Midterm postoperative complications in both groups were low. This suggests that both approaches are safe in the female population and decision should be driven by anatomy and surgeon's preference.

Improving symptom management for survivors of young adult cancer: rationale and study protocol for a pilot randomized controlled trial.

BACKGROUND: Young adult (YA) cancer survivors are a growing, yet underserved population who often face significant and long-lasting cancer-related physical (e.g., pain, fatigue) and emotional (e.g., psychological distress) symptoms. Post-treatment symptoms can persist, disrupting YA's abilities to complete goals consistent with their developmental stage (e.g., completing their education, achieving autonomy and independence, building their careers, establishing peer and romantic relationships, building their families). While symptom management has been identified as a significant issue in YA's transitions to survivorship, the symptom management needs of this population largely go unmet. METHODS: We developed an eight-session, group-based behavioral intervention that is delivered using videoconferencing to address the unique symptom management needs of YA cancer survivors. The intervention was developed in conjunction with YA survivors, leading to the novel combination of traditional behavioral symptom coping strategies, home-based physical activity, strategies from contemporary cognitive-behavioral approaches (e.g., those derived from acceptance and commitment therapy, strategies to foster self-compassion), concepts from meaning centered psychotherapy, and behavioral strategies to improve communication and health care engagement. Participants receive printed intervention materials and access to a study-specific mobile application, both of which are used throughout the program. Herein, we report on a pilot study that is in progress. Recruitment has been completed. YA cancer survivors were recruited in cohorts of n = 10 or n = 11 (n = 61) and randomized to the intervention or waitlist control arms. All participants completed a baseline assessment and four additional assessments over 1 year, with each involving a battery of self-report measures. DISCUSSION: The primary objective is to evaluate intervention feasibility and acceptability. As a secondary objective, we will examine patterns of change in intervention targets (i.e., pain, fatigue, emotional distress, symptom interference). Changes from baseline among intervention targets will be estimated for each patient and compared between arms using unadjusted statistical testing. Unadjusted and adjusted multilevel modeling will be used to estimate the effect of the intervention on changes in intervention targets. Interaction models will be used to compare the trajectory of change over time between arms. We expect that this pilot trial will inform our future approach to identify, recruit, and retain participants and provide preliminary data to support a larger, fully powered randomized controlled trial evaluating the intervention. TRIAL REGISTRATION: NCT04035447 at clinicaltrials.gov; registered July 29, 2019.

Transcriptional regulation and therapeutic potential of cyclin-dependent kinase 9 (CDK9) in sarcoma.

Sarcomas include various subtypes comprising two significant groups - soft tissue and bone sarcomas. Although the survival rate for some sarcoma subtypes has improved over time, the current methods of treatment remain efficaciously limited, as recurrent, and metastatic diseases remain a major obstacle. There is a need for better options and therapeutic strategies in treating sarcoma. Cyclin dependent kinase 9 (CDK9) is a transcriptional kinase and has emerged as a promising target for treating various cancers. The aberrant expression and activation of CDK9 have been observed in several sarcoma subtypes, including rhabdomyosarcoma, synovial sarcoma, osteosarcoma, Ewing sarcoma, and chordoma. Enhanced CDK9 expression has also been correlated with poorer prognosis in sarcoma patients. As a master regulator of transcription, CDK9 promotes transcription elongation by phosphorylation and releasing RNA polymerase II (RNAPII) from its promoter proximal pause. Release of RNAPII from this pause induces transcription of critical genes in the tumor cell. Overexpression and activation of CDK9 have been observed to lead to the expression of oncogenes, including MYC and MCL-1, that aid sarcoma development and progression. Inhibition of CDK9 in sarcoma has been proven to reduce these oncogenes' expression and decrease proliferation and growth in different sarcoma cells. Currently, there are several CDK9 inhibitors in preclinical and clinical investigations. This review aims to highlight the recent discovery and results on the transcriptional role and therapeutic potential of CDK9 in sarcoma.

Slow proliferation of BAP1-deficient uveal melanoma cells is associated with reduced S6 signaling and resistance to nutrient stress.

Uveal melanoma (UM) is the deadliest form of eye cancer in adults. Inactivating mutations and/or loss of expression of the gene encoding BRCA1-associated protein 1 (BAP1) in UM tumors are associated with an increased risk of metastasis. To investigate the mechanisms underlying this risk, we explored the functional consequences of BAP1 deficiency. UM cell lines expressing mutant BAP1 grew more slowly than those expressing wild-type BAP1 in culture and in vivo. The ability of BAP1 reconstitution to restore cell proliferation in BAP1-deficient cells required its deubiquitylase activity. Proteomic analysis showed that BAP1-deficient cells had decreased phosphorylation of ribosomal S6 and its upstream regulator, p70S6K1, compared with both wild-type and BAP1 reconstituted cells. In turn, expression of p70S6K1 increased S6 phosphorylation and proliferation of BAP1-deficient UM cells. Consistent with these findings, BAP1 mutant primary UM tumors expressed lower amounts of p70S6K1 target genes, and S6 phosphorylation was decreased in BAP1 mutant patient-derived xenografts (PDXs), which grew more slowly than wild-type PDXs in the liver (the main metastatic site of UM) in mice. BAP1-deficient UM cells were also more resistant to amino acid starvation, which was associated with diminished phosphorylation of S6. These studies demonstrate that BAP1 deficiency slows the proliferation of UM cells through regulation of S6 phosphorylation. These characteristics may be associated with metastasis by ensuring survival during amino acid starvation.

Prevalence and Sociodemographic Correlates of Chronic Pain Among a Nationally Representative Sample of Older Adults in the United States.

Subgroup analyses conducted among U.S. national survey data have estimated that 27 to 34% of adults aged ≥65 years have chronic pain. However, none of these studies focused specifically on older adults or examined disparities in chronic pain in those aged ≥65 years. To obtain current information on the prevalence and sociodemographic correlates of chronic pain in U.S. older adults, a cross-sectional analysis was conducted of data collected from 3,505 older adults recruited from the AmeriSpeak Panel. Chronic pain was defined as pain on most or every day in the last 3 months. Nationally representative chronic pain prevalence estimates were computed by incorporating study-specific survey design weights. Logistic regression analyses evaluated differences in chronic pain status as a function of sociodemographic characteristics (eg, gender, race/ethnicity, and socioeconomic status). The results indicated that 37.8% of older adults reported chronic pain. Compared with White older adults, Black (odds ratio [OR] = .6, 95% CI: .4-.8) and Asian (OR = .2, 95% CI: .1-.8) older adults were less likely to report chronic pain. The prevalence of chronic pain was also lower among those who reported the highest (vs lowest) household income (OR = .6, 95% CI: .4-.8). Those who were not working due to disability (vs working as a paid employee) were more likely to report chronic pain (OR = 3.2, 95% CI: 2.1-5.0). This study was the first to recruit a large, representative sample of older adults to estimate the prevalence of chronic pain and extends prior work by identifying subgroups of older adults that are disproportionately affected. PERSPECTIVE: This study was the first to estimate the prevalence and sociodemographic correlates of chronic pain among a large, representative sample of U.S. older adults. The findings underscore the high prevalence of chronic pain and highlight disparities in chronic pain prevalence rates among this historically understudied population.

Protein disulfide isomerase-mediated transcriptional upregulation of Nox1 contributes to vascular dysfunction in hypertension.

Nox1 signaling is a causal key element in arterial hypertension. Recently, we identified protein disulfide isomerase A1 (PDI) as a novel regulatory protein that regulates Nox1 signaling in VSMCs. Spontaneously hypertensive rats (SHR) have increased levels of PDI in mesenteric resistance arteries compared with Wistar controls; however, its consequences remain unclear. Herein, we investigated the role of PDI in mediating Nox1 transcriptional upregulation and its effects on vascular dysfunction in hypertension. We demonstrate that PDI contributes to the development of hypertension via enhanced transcriptional upregulation of Nox1 in vascular smooth muscle cells (VSMCs). We show for the first time that PDI sulfenylation by hydrogen peroxide contributes to EGFR activation in hypertension via increased shedding of epidermal growth factor-like ligands. PDI also increases intracellular calcium levels, and contractile responses induced by ANG II. PDI silencing or pharmacological inhibition in VSMCs significantly decreases EGFR activation and Nox1 transcription. Overexpression of PDI in VSMCs enhances ANG II-induced EGFR activation and ATF1 translocation to the nucleus. Mechanistically, PDI increases ATF1-induced Nox1 transcription and enhances the contractile responses to ANG II. Herein we show that ATF1 binding to Nox1 transcription putative regulatory regions is augmented by PDI. Altogether, we provide evidence that HB-EGF in SHR resistance vessels promotes the nuclear translocation of ATF1, under the control of PDI, and thereby induces Nox1 gene expression and increases vascular reactivity. Thus, PDI acts as a thiol redox-dependent enhancer of vascular dysfunction in hypertension and could represent a novel therapeutic target for the treatment of this disease.

Variable effects of captivity on microbiomes in populations of IUCN-endangered Blanding's turtles (Emydoidea blandingii).

AIMS: Microbiome composition is increasingly considered in species reintroduction efforts and may influence survival and reproductive success. Many turtle species are threatened by anthropogenic pressures and are frequently raised in captivity for reintroduction efforts, yet little is known about turtle microbiome composition in either wild or captive settings. Here, we investigated trends in microbiome composition of captive and wild IUCN-endangered Blanding's turtles (Emydoidea blandingii). METHODS AND RESULTS: We amplified and sequenced the V4 region of the 16S rDNA locus from plastron, cloaca, and water samples of wild E. blandingii adults and two populations of captive E. blandingii juveniles being raised for headstarting. Plastron, cloaca, and water-associated microbiomes differed strongly from each other and were highly variable among captive sites and between captive and wild sites. Across plastron, cloaca, and water-associated microbial communities, microbial diversity changed over time, but not in a predictable direction between captive sites. Plastron beta diversity correlated with growth rate in captive samples, indicating that external microbiomes may correlate with individual fitness. CONCLUSIONS: Our results indicate that external and internal microbiomes vary between captive and wild turtles and may reflect differences in fitness of captive-raised individuals.

Pedicled omental flaps for complex wound reconstruction following surgery for primary spine tumors of the mobile spine and sacrum.

OBJECTIVE: Surgery for primary tumors of the mobile spine and sacrum often requires complex reconstruction techniques to cover soft-tissue defects and to treat wound and CSF-related complications. The anatomical, vascular, and immunoregulatory characteristics of the omentum make it an excellent local substrate for the management of radiation soft-tissue injury, infection, and extensive wound defects. This study describes the authors' experience in complex wound reconstruction using pedicled omental flaps to cover defects in surgery for mobile spine and sacral primary tumors. METHODS: A retrospective cohort analysis was conducted on 34 patients who underwent pedicled omental flap reconstruction after en bloc resection of primary sacral and mobile spine tumors between 2010 and 2020. The study focused on assessing the indications for omental flap usage, including soft-tissue coverage, protection against postoperative radiation therapy, infection management, vascular supply for bone grafts, and dural defect and CSF leak repair. Patient demographic characteristics, tumor characteristics, surgical outcomes, and follow-up data were analyzed to determine the procedure's efficacy and complication rates. RESULTS: From 2010 to 2020, 34 patients underwent pedicled omental flap reconstruction after en bloc resection of sacral (24 of 34 [71%]) and mobile spine (10 of 34 [29%]) primary tumors, mostly chordomas. The patient cohort included 21 men and 13 women with a median (range) age of 60 (32-89) years. The most common indication for omental flap was soft-tissue coverage (20 of 34 [59%]). Other indications included protecting abdominopelvic organs for postoperative radiation therapy (6 of 34 [18%]), treating infections (5 of 34 [15%]), providing vascular supply for free fibular bone graft (1 of 34 [3%]), and repairing large dural defects and CSF leak (2 of 34 [6%]). The median (range) follow-up was 24 (0-132) months, during which 71% (24 of 34) of patients did not require additional surgery for wound-related complications. At last follow-up, 59% (20 of 34) had stable disease and 32% (11 of 34) had recurrence, had progression of disease, or had been discharged to hospice after treatment. CONCLUSIONS: The pedicled omentum is an effective local tissue graft that can be used for complex wound reconstruction and management of high-risk closures in primary spine tumors. This technique may have a lower rate of complications than other approaches and may influence surgical planning and flap selection in challenging cases.

Pathway-based analyses of gene expression profiles at low doses of ionizing radiation.

Radiation exposure poses a significant threat to human health. Emerging research indicates that even low-dose radiation once believed to be safe, may have harmful effects. This perception has spurred a growing interest in investigating the potential risks associated with low-dose radiation exposure across various scenarios. To comprehensively explore the health consequences of low-dose radiation, our study employs a robust statistical framework that examines whether specific groups of genes, belonging to known pathways, exhibit coordinated expression patterns that align with the radiation levels. Notably, our findings reveal the existence of intricate yet consistent signatures that reflect the molecular response to radiation exposure, distinguishing between low-dose and high-dose radiation. Moreover, we leverage a pathway-constrained variational autoencoder to capture the nonlinear interactions within gene expression data. By comparing these two analytical approaches, our study aims to gain valuable insights into the impact of low-dose radiation on gene expression patterns, identify pathways that are differentially affected, and harness the potential of machine learning to uncover hidden activity within biological networks. This comparative analysis contributes to a deeper understanding of the molecular consequences of low-dose radiation exposure.

Concordance of Blood Glucose and CGM During a Pilot Trial of Automated Insulin Delivery in Type 1 Diabetes Pregnancies.

Background: Customized and standard automated insulin delivery (AID) systems for use in pregnancies of women with preexisting type 1 diabetes (T1D) are being developed and tested to achieve pregnancy appropriate continuous glucose monitoring (CGM) targets. Guidance on the use of CGM for treatment decisions during pregnancy in the United States is limited. Methods: Ten pregnant women with preexisting T1D participated in a trial evaluating at-home use of a pregnancy-specific AID system. Seven-point self-monitoring of blood glucose (SMBG) was compared to the closest sensor glucose (Dexcom G6 CGM) value biweekly to assess safety and reliability based on the 20%/20 mg/dL criteria. Results: All participants completed the study with 7 participants satisfying the safety and reliability criteria with a mean absolute relative difference of 10.3%. Three participants did not fulfill the criteria, mainly because the frequency of SMBG did not meet the requirements. Conclusion: Dexcom G6 CGM is safe and accurate in the real-world setting for use in pregnant women with preexisting T1D with reduced SMBG testing as part of a pregnancy-specific AID system.

Quantitative evaluation of soil health based on a minimum dataset under various short-term crop rotations on the Canadian prairies.

Maintaining and improving soil health (SH) is essential for the long-term sustainability and productivity of agriculture, notably in the face of climate change. This study addressed the challenge of selecting appropriate soil indicators, scoring methods, and indexing approaches for SH evaluation under no-till crop rotations. This study aimed to develop minimum datasets (MDS) and assess SH in six crop rotations (denoted as conventional, diversified, high-risk and high-reward, market-driven, pulse-oilseed intensified, and soil health-enhanced rotations) at three sites on the Canadian prairies. Fourteen soil indicators in the total dataset (TDS) were examined, encompassing both chemical (0-7.5 cm depth) and physical (5-10 cm depth) properties. Principal component analysis (PCA) identified MDSs from the TDS. Two scoring [linear (L) and non-linear (NL)] and two SH indexing approaches [additive (A) and weighted additive (WA)] were used to calculate the SH index (SHI). One-way ANOVA evaluated the SHI among crop rotations. The PCA revealed variations in the number of indicators in the MDS across sites, with soil organic carbon, bulk density, macroporosity, and plant-available water capacity as the common indicators for MDS across sites. Other indicators such as particulate organic matter carbon, aggregate stability, field capacity, and microporosity were found to be important, depending on the site. The non-linear weighted additive SH indexing (SHI.NLWA) proved to be the most sensitive and effective for differentiating among crop rotations in the short-term across study sites (R2 = 0.89-0.94, P < 0.05). Crop rotations significantly influenced SHI, with the diversified and high-risk and high-reward rotations having the highest SHI at Lethbridge and Scott, respectively. Overall, the diversified rotation at Lethbridge and Swift Current, along with the high-risk and high-reward rotation at Scott, exhibited better soil function than other rotations. Monitoring SHI over time and selecting crop rotations that improve SH can collectively enhance soil functions and agroecosystem productivity.

Selecting Invalid Instruments to Improve Mendelian Randomization with Two-Sample Summary Data.

Mendelian randomization (MR) is a widely-used method to estimate the causal relationship between a risk factor and disease. A fundamental part of any MR analysis is to choose appropriate genetic variants as instrumental variables. Genome-wide association studies often reveal that hundreds of genetic variants may be robustly associated with a risk factor, but in some situations investigators may have greater confidence in the instrument validity of only a smaller subset of variants. Nevertheless, the use of additional instruments may be optimal from the perspective of mean squared error even if they are slightly invalid; a small bias in estimation may be a price worth paying for a larger reduction in variance. For this purpose, we consider a method for "focused" instrument selection whereby genetic variants are selected to minimise the estimated asymptotic mean squared error of causal effect estimates. In a setting of many weak and locally invalid instruments, we propose a novel strategy to construct confidence intervals for post-selection focused estimators that guards against the worst case loss in asymptotic coverage. In empirical applications to: (i) validate lipid drug targets; and (ii) investigate vitamin D effects on a wide range of outcomes, our findings suggest that the optimal selection of instruments does not involve only a small number of biologically-justified instruments, but also many potentially invalid instruments.

High sugar diet alters immune function and the gut microbiome in juvenile green iguanas (Iguana iguana).

The present work aimed to study whether a high sugar diet can alter immune responses and the gut microbiome in green iguanas. Thirty-six iguanas were split into four treatment groups using a 2×2 design. Iguanas received either a sugar-supplemented diet or a control diet, and either a lipopolysaccharide (LPS) injection or a phosphate-buffered saline (PBS) injection. Iguanas were given their respective diet treatment through the entire study (∼3 months) and received a primary immune challenge 1 and 2 months into the experiment. Blood samples and cloacal swabs were taken at various points in the experiment and used to measure changes in the immune system (bacterial killing ability, lysis and agglutination scores, LPS-specific IgY concentrations), and alterations in the gut microbiome. We found that a sugar diet reduces bacterial killing ability following an LPS challenge, and sugar and the immune challenge temporarily alters gut microbiome composition while reducing alpha diversity. Although sugar did not directly reduce lysis and agglutination following the immune challenge, the change in these scores over a 24-h period following an immune challenge was more drastic (it decreased) relative to the control diet group. Moreover, sugar increased constitutive agglutination outside of the immune challenges (i.e. pre-challenge levels). In this study, we provide evidence that a high sugar diet affects the immune system of green iguanas (in a disruptive manner) and alters the gut microbiome.

Extracellular histones: a unifying mechanism driving platelet-dependent extracellular vesicle release and thrombus formation in COVID-19.

BACKGROUND: COVID-19 can cause profound inflammation and coagulopathy, and while many mechanisms have been proposed, there is no known common pathway leading to a prothrombotic state. OBJECTIVES: From the beginning of the COVID-19 pandemic, elevated levels of extracellular histones have been found in plasma of patients infected with SARS-CoV-2. We hypothesized that platelet activation triggered by extracellular histones might represent a unifying mechanism leading to increased thrombin generation and thrombosis. METHODS: We utilized blood samples collected from an early clinical trial of hospitalized COVID-19 patients (NCT04360824) and recruited healthy subjects as controls. Using plasma samples, we measured the procoagulant and prothrombotic potential of circulating extracellular histones and extracellular vesicles (EVs). Platelet prothrombotic activity was assessed via thrombin generation potential and platelet thrombus growth. Circulating EVs were assessed for thrombin generation potential in vitro in plasma and enhancement of thrombotic susceptibility in vivo in mice. RESULTS: Compared with controls, COVID-19 patients had elevated plasma levels of citrullinated histone H3, cell-free DNA, nucleosomes, and EVs. Plasma from COVID-19 patients promoted platelet activation, platelet-dependent thrombin generation, thrombus growth under venous shear stress, and release of platelet-derived EVs. These prothrombotic effects of COVID-19 plasma were inhibited by an RNA aptamer that neutralizes both free and DNA-bound histones. EVs isolated from COVID-19 plasma enhanced thrombin generation in vitro and potentiated venous thrombosis in mice in vivo. CONCLUSION: We conclude that extracellular histones and procoagulant EVs drive the prothrombotic state in COVID-19 and that histone-targeted therapy may prove beneficial.