Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain.

Mutations in Leucine-rich repeat kinase 2 (LRRK2) and PTEN-induced kinase 1 (PINK1) are associated with familial Parkinson's disease (PD). LRRK2 phosphorylates Rab guanosine triphosphatase (GTPases) within the Switch II domain while PINK1 directly phosphorylates Parkin and ubiquitin (Ub) and indirectly induces phosphorylation of a subset of Rab GTPases. Herein we have crossed LRRK2 [R1441C] mutant knock-in mice with PINK1 knock-out (KO) mice and report that loss of PINK1 does not impact endogenous LRRK2-mediated Rab phosphorylation nor do we see significant effect of mutant LRRK2 on PINK1-mediated Rab and Ub phosphorylation.

Suppressing APOE4-induced neural pathologies by targeting the VHL-HIF axis.

The ε4 variant of human apolipoprotein E () is a key genetic risk factor for neurodegeneration in Alzheimer's disease and elevated all-cause mortality in humans. Understanding the factors and mechanisms that can mitigate the harmful effects of has significant implications. In this study, we find that inactivating the VHL-1 (Von Hippel-Lindau) protein can suppress mortality, neural and behavioral pathologies caused by transgenic human in .

Association between Delayed Broad-Spectrum Gram-negative Antibiotics and Clinical Outcomes: How Much Does Getting It Right with Empiric Antibiotics Matter?

Background: Clinicians often start unnecessarily broad-spectrum empiric Gram-negative antibiotics out of the concern that delaying effective therapy could lead to a worse clinical outcome. This study examined the consequences of delayed initiation of broad-spectrum Gram-negative antibiotics.

Methods: In a retrospective cohort of adult inpatients from 928 US hospitals, we compared clinical outcomes after (1) empiric narrow-spectrum antibiotics escalated to broad-spectrum antibiotics (delayed broad-spectrum therapy, DBT) and (2) empiric broad-spectrum antibiotics continued for at least 5 days (early broad-spectrum therapy, EBT) using Win Ratios.

Management of renin-angiotensin system inhibitors prior to major surgery: insights from the STOP-or-NOT trial.

Strong recommendations on how to manage renin-angiotensin system inhibitors, including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, before surgery are lacking because of a lack of evidence, which is mostly limited to data from observational studies. The STOP-or-NOT trial was a large multicentre randomised trial designed to determine whether chronic renin-angiotensin system inhibitors should be continued or discontinued before major noncardiac surgery. As principal investigators of the STOP-or-NOT trial, we discuss the trial's results and how they contribute to the existing literature on management of renin-angiotensin system inhibitors before surgery.

Polydipsia Induced Acute Angle-Closure Crisis.

We present a case of Acute Angle-Closure Crisis (AACC) precipitated by primary transient psychogenic polydipsia; we believe that our case is the first of its kind to be reported. A 74-year-old male presented to the emergency department with altered mental status due to acute-onset hyponatremia. Six days after admission, the patient noticed painful loss of vision in his right eye and an ipsilateral headache lasting 10-15 minutes.

Functional Characterization of an Aldol Condensation Synthase PheG for the Formation of Hispidin from Phellinus Igniarius.

Hispidin (1) is a polyphenolic compound with a wide range of pharmacological activities that is distributed in both plants and fungi. In addition to natural extraction, hispidin can be obtained by chemical or enzymatic synthesis. In this study, the identification and characterization of an undescribed enzyme, PheG, from Phellinus igniarius (P.

The 2021 Podiatric Residency Candidate and Program Virtual Interview Experience During COVID-19 with Multispecialty Reflections and Recommendations for a Successful Virtual Match: A 2024 Update.

This objective of this communication is to provide an update from the Council of Teaching Hospitals (COTH) and the American Association of Colleges of Podiatric Medicine (AACPM) with respect to the profession's residency interview process, otherwise known as the Centralized Residency Interview Process (CRIP). During the 2022-2023 academic year, CRIP returned to an in-person format following a period of virtual interviews during the COVID-19 pandemic. Survey data since this change indicate that a large majority of residency program directors and student applicants prefer an in-person format to the residency interview process.

Demographic, medical, and neighborhood barriers to clinical neuropsychological services in pediatric medulloblastoma patients treated in the United States.

Background: Medulloblastoma is the most commonly occurring malignant brain tumor of childhood. Treatment includes a combination of surgery, radiation therapy, and chemotherapy, all of which are associated with cognitive impairments. Despite appreciation of the value of neuropsychological evaluations to assess for cognitive impairments, there are barriers to these evaluations.

Buprenorphine Pharmacodynamics: A Bridge to Understanding Buprenorphine Clinical Benefits.

Buprenorphine is an agonist at the mu opioid receptor (MOR) and antagonist at the kappa (KOR) and delta (DOR) receptors and a nociceptin receptor (NOR) ligand. Buprenorphine has a relatively low intrinsic efficacy for G-proteins and a long brain and MOR dwell time. Buprenorphine ceiling on respiratory depression has theoretically been related multiple factors such as low intrinsic efficacy at MOR, binding to six-transmembrane MOR and interactions in MOR/NOR heterodimers.

Antiretroviral Use for HIV Prevention During Pregnancy: The Need to Strengthen Regulatory and Surveillance Systems in Africa.

HIV-prevention efforts focusing on women of child-bearing potential are needed to end the HIV epidemic in the African region. The use of antiretroviral drugs as pre-exposure prophylaxis (PrEP) is a critical HIV prevention tool. However, safety data on new antiretrovirals during pregnancy are often limited because pregnant people are excluded from drug development studies.

Pharmacoinformatics-based screening and construction of a neutralizing anti-SARS-CoV-2 camelidae nanobody drug conjugate.

Nanobodies or variable antigen-binding domains (VH) derived from heavy chain-only antibodies (HcAb) occurring in the Camelidae family offer certain superior physicochemical characteristics like enhanced stability, solubility, and low immunogenicity compared to conventional antibodies. Their efficient antigen-binding capabilities make them a preferred choice for next-generation small biologics. In the present work, we design an anti-SARS-CoV-2 bi-paratopic nanobody drug conjugate by screening a nanobody database.

Bioinformatics and immunoinformatics approaches in the design of a multi-epitope vaccine targeting CTLA-4 for melanoma treatment.

Melanoma, a highly aggressive skin cancer, remains a significant cause of mortality despite advancements in therapeutic strategies. There is an urgent demand for developing vaccines that can elicit strong and comprehensive immune responses against this malignancy. Achieving this goal is crucial to enhance the efficacy of immunological defense mechanisms in combating this disease.

Inhibition of amyloid-beta aggregation by phenyl butyric acid analogs and bile acids: a comprehensive in silico study.

Alzheimer's disease (AD) is a degenerative neurological disorder defined by the formation of β-amyloid (Aβ) plaques and neurofibrillary tangles within the brain. Current pharmacological treatments for AD only provide symptomatic relief, and there is a lack of definitive disease-modifying therapies. Chemical chaperones, such as 4-Phenylbutyric acid (4PBA) and Tauroursodeoxycholic acid, have shown neuroprotective effects in animal and cell culture models.

Methodologies and characteristics of studies investigating the cost of the palliative phase of cancer: a systematic review.

Purpose: Improvements in the treatment of advanced cancer have increased life expectancy but have also increased the costs to healthcare systems, patients and their families. A systematic review is needed to summarize research work on the cost of cancer. The primary objective was to describe the characteristics and methodology of studies investigating the cost of cancer during the palliative phase.

Head and Neck Classic Hodgkin, T and NK Lymphomas with Eosinophilia.

Eosinophilia is a notable feature in various hematological malignancies, including specific types of leukemias and lymphomas that may occur in the head and neck. In hematologic malignancies, eosinophilia can be primary, driven by genetic abnormalities, or secondary, resulting from cytokine and chemokine production by the neoplastic cells or the tumor microenvironment. This review examines the association between eosinophilia and head and neck hematolymphoid malignancies including Classic Hodgkin lymphoma, T-cell lymphoblastic leukemia, mature T and NK-cell lymphomas, and Langerhans cell histiocytosis.

Cardiovascular preventive service access challenges among African immigrants: a discussion paper.

This paper highlights cardiovascular disease (CVD) preventive access challenges and potential intervention strategies that address cardiovascular preventive service access gaps among African immigrants living in developed countries. Migration, coupled with changes in dietary habits, socio-economic factors, and cultural adjustments, contributes to a heightened risk of CVD among African immigrants. This risk is compounded by a lack of targeted preventive interventions and culturally tailored programmes, as well as challenges related to language barriers, health literacy, and digital literacy.

Progesterone induces meiosis through two obligate co-receptors with PLA2 activity.

The steroid hormone progesterone (P4) regulates multiple aspects of reproductive and metabolic physiology. Classical P4 signaling operates through nuclear receptors that regulate transcription. In addition, P4 signals through membrane P4 receptors (mPRs) in a rapid nongenomic modality.

Carboxy-Amidated AamAP1-Lys has Superior Conformational Flexibility and Accelerated Killing of Gram-Negative Bacteria.

C-terminal amidation of antimicrobial peptides (AMPs) is a frequent minor modification used to improve antibacterial potency, commonly ascribed to increased positive charge, protection from proteases, and a stabilized secondary structure. Although the activity of AMPs is primarily associated with the ability to penetrate bacterial membranes, hitherto the effect of amidation on this interaction has not been understood in detail. Here, we show that amidation of the scorpion-derived membranolytic peptide AamAP1-Lys produces a potent analog with faster bactericidal activity, increased membrane permeabilization, and greater Gram-negative membrane penetration associated with greater conformational flexibility.

Time dependency for human papillomavirus circulating tumor DNA detection after chemoradiation as a prognostic biomarker for localized anal cancer.

Background: While detection of circulating tumor DNA (ctDNA) weeks after surgery is linked to recurrence for other solid tumors, the optimal time point for ctDNA assessment as a prognostic biomarker following chemoradiation for anal cancer is undefined.

Methods: Patients with stages I-III anal cancer treated with chemoradiation between 12/2020-5/2024 were evaluated for HPV ctDNA status at baseline, at the end of chemoradiation, and during surveillance using a droplet digital HPV ctDNA PCR assay targeting HPV E6 and E7 oncogenes for 13 oncogenic HPV types. Median recurrence-free survival (RFS) according to HPV ctDNA status was estimated via Kaplan-Meier and compared using a log-rank test.

Association of Obesity and Skeletal Muscle with Postoperative Survival in Non-Small Cell Lung Cancer.

Background A comprehensive assessment of skeletal muscle health is crucial to understanding the association between improved clinical outcomes and obesity as defined by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) in lung cancer, but limited studies have been conducted on this topic. Purpose To investigate the association between BMI-defined obesity and survival in patients with non-small cell lung cancer who underwent curative resection, with a specific focus on the status of skeletal muscle assessed at CT. Materials and Methods This retrospective study investigated Korean patients with non-small cell lung cancer who underwent curative resection between January 2008 and December 2019.