Macrophage LRRK2 hyperactivity impairs autophagy and induces Paneth cell dysfunction.

polymorphisms (G2019S/N2081D) that increase susceptibility to Parkinson's disease and Crohn's disease (CD) lead to LRRK2 kinase hyperactivity and suppress autophagy. This connection suggests that LRRK2 kinase inhibition, a therapeutic strategy being explored for Parkinson's disease, may also benefit patients with CD. Paneth cell homeostasis is tightly regulated by autophagy, and their dysfunction is a precursor to gut inflammation in CD.

Association between Exposure to Metals during Pregnancy, Childhood Gut Microbiome, and Risk of Intestinal Inflammation in Late Childhood.

Alterations to the gut microbiome and exposure to metals during pregnancy have been suggested to impact inflammatory bowel disease. Nonetheless, how prenatal exposure to metals eventually results in long-term effects on the gut microbiome, leading to subclinical intestinal inflammation, particularly during late childhood, has not been studied. It is also unknown whether such an interactive effect drives a specific subgroup of children toward elevated susceptibility to intestinal inflammation.

Regulatory elements in (7q21.3) locus contribute to genetic control of coronal nonsyndromic craniosynostosis and bone density-related traits.

Purpose: The etiopathogenesis of coronal nonsyndromic craniosynostosis (cNCS), a congenital condition defined by premature fusion of 1 or both coronal sutures, remains largely unknown.

Methods: We conducted the largest genome-wide association study of cNCS followed by replication, fine mapping, and functional validation of the most significant region using zebrafish animal model.

Results: Genome-wide association study identified 6 independent genome-wide-significant risk alleles, 4 on chromosome 7q21.

Targeting Specific Kinase Substrates Rescues Increased Colitis Severity Induced by the Crohn's Disease-Linked LRRK2-N2081D Variant.

LRRK2 contains a kinase domain where both the N2081D Crohn's disease (CD) risk and the G2019S Parkinson's disease (PD)-pathogenic variants are located. The mechanisms by which the N2081D variant increase CD risk, and how these adjacent mutations result in distinct diseases, remain unclear. To investigate the pathophysiology of the CD-linked LRRK2 N2081D variant, we generated a knock-in (KI) mouse model and compared its effects to those of the LRRK2-G2019S mutation.

Micro- and nano-plastics, intestinal inflammation, and inflammatory bowel disease: A review of the literature.

Plastics, encompassing a wide range of polymeric materials, and their downstream products (micro- and nanoplastics, MNPs) are accumulating in the environment at an alarming rate, and they are linked to adverse human health outcomes. Considering that ingestion is a main source of MNPs exposure, the impact of plastics is particularly relevant towards intestinal inflammation and inflammatory bowel disease (IBD). However, the study of MNPs has been limited by obstacles relating to sample collection, preparation, and microplastics analysis based on optical microscopy and chemical analysis, which we detail in this review alongside potential solutions.

Age-related patterns of microbial dysbiosis in multiplex inflammatory bowel disease families.

Objective: IBD is characterised by dysbiosis, but it remains unclear to what extent dysbiosis develops in unaffected at-risk individuals. To address this, we investigated age-related patterns of faecal and serum markers of dysbiosis in high-risk multiplex IBD families (two or more affected first-degree relatives).

Design: Faecal and serum samples were collected from multiplex IBD and control families (95 IBD, 292 unaffected, 51 controls).

The landscape of rare genetic variation associated with inflammatory bowel disease and Parkinson's disease comorbidity.

Background: Inflammatory bowel disease (IBD) and Parkinson's disease (PD) are chronic disorders that have been suggested to share common pathophysiological processes. LRRK2 has been implicated as playing a role in both diseases. Exploring the genetic basis of the IBD-PD comorbidity through studying high-impact rare genetic variants can facilitate the identification of the novel shared genetic factors underlying this comorbidity.

Venous Thromboembolism Among People With HIV: Design, Implementation, and Findings of a Centralized Adjudication System in Clinical Care Sites Across the United States.

Background: People with HIV (PWH) are at increased risk for venous thromboembolism (VTE). We conducted this study to characterize VTE including provoking factors among PWH in the current treatment era.

Methods: We included PWH with VTE between 2010 and 2020 at 6 sites in the CFAR Network of Integrated Clinical Systems cohort.

Guide to assembling a successful K99/R00 application.

The National Institutes of Health's (NIH) K99/R00 Pathway to Independence Award offers promising postdoctoral researchers and clinician-scientists an opportunity to receive research support at both the mentored and the independent levels with the goal of facilitating a timely transition to a tenure-track faculty position. This transitional program has been generally successful, with most K99/R00 awardees successfully securing R01-equivalent funding by the end of the R00 period. However, often highly promising proposals fail because of poor grantsmanship.

African American/Black race, apolipoprotein L1 , and serum creatinine among persons with HIV.

Objective: Accurate estimation of kidney function is critical among persons with HIV (PWH) to avoid under-dosing of antiretroviral therapies and ensure timely referral for kidney transplantation. Existing estimation equations for kidney function include race, the appropriateness of which has been debated. Given advancements in understanding of race and the necessity of accuracy in kidney function estimation, this study aimed to examine whether race, or genetic factors, improved prediction of serum creatinine among PWH.

Perspective on the current state of the LRRK2 field.

Almost 2 decades after linking LRRK2 to Parkinson's disease, a vibrant research field has developed around the study of this gene and its protein product. Recent studies have begun to elucidate molecular structures of LRRK2 and its complexes, and our understanding of LRRK2 has continued to grow, affirming decisions made years ago to therapeutically target this enzyme for PD. Markers of LRRK2 activity, with potential to monitor disease progression or treatment efficacy, are also under development.

Dietary Intake of Pregnant Women with and without Inflammatory Bowel Disease in the United States.

Background: Pregnancy is a vulnerable time where the lives of mother and baby are affected by diet, especially high-risk pregnancies in women with inflammatory bowel disease (IBD). Limited research has examined diet during pregnancy with IBD.

Aims: Describe and compare the diet quality of pregnant women with and without IBD, and examine associations between dietary intake and guidelines during pregnancy.

Influence of Early Life Factors, including breast milk Composition, on the Microbiome of Infants Born to Mothers with and without Inflammatory Bowel Disease.

Background And Aims: Herein we analysed the influence of early life factors, including breast milk composition, on the development of the intestinal microbiota of infants born to mothers with and without IBD.

Methods: The MECONIUM [Exploring MEChanisms Of disease traNsmission In Utero through the Microbiome] study is a prospective cohort study consisting of pregnant women with or without IBD and their infants. Longitudinal stool samples were collected from babies and analysed using 16s rRNA sequencing and faecal calprotectin.

Polygenic risk scores point toward potential genetic mechanisms of type 2 myocardial infarction in people with HIV.

Background: People with human immunodeficiency virus (HIV) infection (PWH) are at higher risk of myocardial infarction (MI) than those without HIV. About half of MIs in PWH are type 2 (T2MI), resulting from mismatch between myocardial oxygen supply and demand, in contrast to type 1 MI (T1MI), which is due to primary plaque rupture or coronary thrombosis. Despite worse survival and rising incidence in the general population, evidence-based treatment recommendations for T2MI are lacking.

Immunological Features of LRRK2 Function and Its Role in the Gut-Brain Axis Governing Parkinson's Disease.

Emerging evidence implicates intestinal involvement in the onset and/or progression on the selective degeneration of dopaminergic neurons characterizing Parkinson's disease (PD). On the one hand, there are studies supporting the Braak hypothesis that holds that pathologic α-synuclein, a hallmark of PD, is secreted by enteric nerves into intestinal tissue and finds its way to the central nervous system (CNS) via retrograde movement in the vagus nerve. On the other hand, there is data showing that cells bearing leucine-rich repeat kinase 2 (LRRK2), a signaling molecule with genetic variants associated with both PD and with inflammatory bowel disease, can be activated in intestinal tissue and contribute locally to intestinal inflammation, or peripherally to PD pathogenesis via cell trafficking to the CNS.

Associations between female birth sex and risk of chronic kidney disease development among people with HIV in the USA: A longitudinal, multicentre, cohort study.

Background: Women represent a meaningful proportion of new HIV diagnoses, with Black women comprising 58% of new diagnoses among women. As HIV infection also increases risk of chronic kidney disease (CKD), understanding CKD risk among women with HIV (WWH), particularly Black women, is critical.

Methods: In this longitudinal cohort study of people with HIV (PWH) enrolled in CFAR Network of Integrated Clinical Systems (CNICS), a multicentre study comprised of eight academic medical centres across the United States from Jan 01, 1996 and Nov 01, 2019, adult PWH were excluded if they had ≤2 serum creatinine measurements, developed CKD prior to enrollment, or identified as intersex or transgendered, leaving a final cohort of 33,998 PWH.

Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility.

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls.

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson's disease are associated with LRRC37A/2 expression in astrocytes.

Background: Parkinson's disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified.

Tobacco smoking and binge alcohol use are associated with incident venous thromboembolism in an HIV cohort.

Background: People with HIV (PWH) are at increased risk of cardiovascular comorbidities and substance use is a potential predisposing factor. We evaluated associations of tobacco smoking and alcohol use with venous thromboembolism (VTE) in PWH.

Methods: We assessed incident, centrally adjudicated VTE among 12 957 PWH within the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort between January 2009 and December 2018.

Pre- and Perinatal Factors Predicting Inflammatory Bowel Disease: A Population-Based Study with Fifty Years of Follow-Up.

Background: Pre- and perinatal events may be associated with an increased risk of inflammatory bowel disease [IBD]. We aimed to investigate the role of pre- and perinatal factors as potential risk factors for the development of IBD in a population with a follow-up of 50 years.

Methods: We conducted a nested case-control study, reporting IBD incidence among individuals born in 1964-76, for whom pre- and perinatal exposures were reported as part of the Jerusalem Perinatal Study [JPS], by linking them to the database of the epidemiology group of the Israeli IBD Research Nucleus [epi-IIRN], including all IBD patients in Israel since 2005 and their matched controls.

Breastfeeding Is Associated with Lower Likelihood of Helicobacter Pylori Colonization in Babies, Based on a Prospective USA Maternal-Infant Cohort.

Background: Mother-to-child transmission of Helicobacter pylori (H. pylori) is the primary source of intrafamilial spread in early childhood in regions of high H. pylori prevalence.