Reconstitution of human DNA licensing and the structural and functional analysis of key intermediates.

Human DNA licensing initiates replication fork assembly and DNA replication. This reaction promotes the loading of the hMCM2-7 complex on DNA, which represents the core of the replicative helicase that unwinds DNA during S-phase. Here, we report the reconstitution of human DNA licensing using purified proteins.

Opinions about climate change, health, and pharmacy education among pharmacy faculty and administrators in the United States: A cross-sectional survey.

Background: The pharmacy profession must address climate change and its impact on health. Student pharmacists should be made aware of roles in sustainability, education, patient care, and advocacy; yet, pharmacy educators' perceptions of climate change and health may impact the extent and quality of education provided.

Objective: The primary objective was to assess pharmacy educators' beliefs regarding climate change and whether its effects on health should be included in Doctor of Pharmacy curricula.

MCM2-7 ring closure involves the Mcm5 C-terminus and triggers Mcm4 ATP hydrolysis.

The eukaryotic helicase MCM2-7, is loaded by ORC, Cdc6 and Cdt1 as a double-hexamer onto replication origins. The insertion of DNA into the helicase leads to partial MCM2-7 ring closure, while ATP hydrolysis is essential for consecutive steps in pre-replicative complex (pre-RC) assembly. Currently it is unknown how MCM2-7 ring closure and ATP-hydrolysis are controlled.

MCM2-7 loading-dependent ORC release ensures genome-wide origin licensing.

Origin recognition complex (ORC)-dependent loading of the replicative helicase MCM2-7 onto replication origins in G1-phase forms the basis of replication fork establishment in S-phase. However, how ORC and MCM2-7 facilitate genome-wide DNA licensing is not fully understood. Mapping the molecular footprints of budding yeast ORC and MCM2-7 genome-wide, we discovered that MCM2-7 loading is associated with ORC release from origins and redistribution to non-origin sites.

Pharmacy Interns' Perception of Climate Change and Its Impact on Health.

: The effects of climate change are major threats to health and well-being. While the profession of pharmacy can make a difference through patient care activities, sustainability, and advocacy, literature detailing U.S.

Endoscopic Ultrasound-Guided Transrectal Pelvic Abscess Drainage (EUS-PAD) - Bridging to Surgery: Report of Two Cases.

 Currently, the methods for drainage of pelvic abscess primarily use computed tomography- or ultrasound-guided percutaneous drainage or surgical drainage. Endoscopic ultrasound-guided pelvic abscess drainage (EUS-PAD) is an alternative, minimally invasive tool to drain an abscess, localized close to the rectum or left colon, and therefore not accessible by other means.  We report on the success of endoscopic ultrasound-guided drainage of peridiverticulitic abscess based on the two cases presented here.

Tau PET burden in Brodmann areas 35 and 36 is associated with individual differences in cognition in non-demented older adults.

Introduction: The accumulation of neurofibrillary tau tangles, a neuropathological hallmark of Alzheimer's disease (AD), occurs in medial temporal lobe (MTL) regions early in the disease process, with some of the earliest deposits localized to subregions of the entorhinal cortex. Although functional specialization of entorhinal cortex subregions has been reported, few studies have considered functional associations with localized tau accumulation.

Methods: In this study, stepwise linear regressions were used to examine the contributions of regional tau burden in specific MTL subregions, as measured by F-MK6240 PET, to individual variability in cognition.

Pre-RNA splicing in metabolic homeostasis and liver disease.

The liver plays a key role in sensing nutritional and hormonal inputs to maintain metabolic homeostasis. Recent studies into pre-mRNA splicing and alternative splicing (AS) and their effects on gene expression have revealed considerable transcriptional complexity in the liver, both in health and disease. While the contribution of these mechanisms to cell and tissue identity is widely accepted, their role in physiological and pathological contexts within tissues is just beginning to be appreciated.

Pharmacists' perception of climate change and its impact on health.

Objectives: This study's primary objective was to assess pharmacists' knowledge and beliefs regarding climate change and health. Secondary objectives included assessing perceptions of its relevance to pharmacists and pharmacy practice as well as potential roles in mitigating climate change.

Methods: An 18-question, anonymous survey was developed using questions adapted from previously published surveys that evaluated the general public's views of international issues and health professionals' perceptions of climate change and health, with additions specific to the Midwestern United States and Ohio.

The relationship between weight loss and cognitive function in bariatric surgery.

Background: Previously, we reported short-term improvements in auditory attention, oromotor processing speed, and executive function during the active weight loss phase following bariatric surgery that persisted out to 3 months. In this study, our aims were to investigate the relationship between weight loss and cognitive performance in these patients 1 year following vertical sleeve gastrectomy (VSG) and Roux-en Y gastric bypass (RYGB) surgery and to determine whether preoperative cognitive performance predicted weight loss.

Methods: Adult women ages 18-55 approved for bariatric surgery completed a cognitive battery prior to and at 2, 12, 24, and 52 weeks following VSG (N = 17) or RYGB (N = 18).

The structural basis of Cdc7-Dbf4 kinase dependent targeting and phosphorylation of the MCM2-7 double hexamer.

The controlled assembly of replication forks is critical for genome stability. The Dbf4-dependent Cdc7 kinase (DDK) initiates replisome assembly by phosphorylating the MCM2-7 replicative helicase at the N-terminal tails of Mcm2, Mcm4 and Mcm6. At present, it remains poorly understood how DDK docks onto the helicase and how the kinase targets distal Mcm subunits for phosphorylation.

Lateral entorhinal cortex dysfunction in amnestic mild cognitive impairment.

The entorhinal cortex is the site of some of the earliest pathological changes in Alzheimer's disease, including neuronal, synaptic and volumetric loss. Specifically, the lateral entorhinal cortex shows significant accumulation of tau neurofibrillary tangles in the amnestic mild cognitive impairment (aMCI) phase of Alzheimer's disease. Although decreased entorhinal cortex activation has been observed in patients with aMCI in the context of impaired memory function, it remains unclear if functional changes in the entorhinal cortex can be localized to the lateral or medial entorhinal cortex.

The structure of ORC-Cdc6 on an origin DNA reveals the mechanism of ORC activation by the replication initiator Cdc6.

The Origin Recognition Complex (ORC) binds to sites in chromosomes to specify the location of origins of DNA replication. The S. cerevisiae ORC binds to specific DNA sequences throughout the cell cycle but becomes active only when it binds to the replication initiator Cdc6.

Evolution of DNA replication origin specification and gene silencing mechanisms.

DNA replication in eukaryotic cells initiates from replication origins that bind the Origin Recognition Complex (ORC). Origin establishment requires well-defined DNA sequence motifs in Saccharomyces cerevisiae and some other budding yeasts, but most eukaryotes lack sequence-specific origins. A 3.

Comparison of male and female patients with amnestic mild cognitive impairment: Hippocampal hyperactivity and pattern separation memory performance.

Introduction: Recent studies have suggested that sex confers a differential risk in the incidence and prevalence of Alzheimer's disease (AD) thought to be the result of the increased lifespan of women compared to men. However, other factors may contribute to risk beyond the effect of increased lifespan.

Methods: This study examined the role of sex in hippocampal hyperactivity localized to the dentate gyrus (DG)/CA3 subregion of the hippocampus and associated episodic memory impairment, considered a characteristic feature of AD in patients with amnestic mild cognitive impairment (aMCI).

Structural mechanism of helicase loading onto replication origin DNA by ORC-Cdc6.

DNA replication origins serve as sites of replicative helicase loading. In all eukaryotes, the six-subunit origin recognition complex (Orc1-6; ORC) recognizes the replication origin. During late M-phase of the cell-cycle, Cdc6 binds to ORC and the ORC-Cdc6 complex loads in a multistep reaction and, with the help of Cdt1, the core Mcm2-7 helicase onto DNA.

Evolution of an Amniote-Specific Mechanism for Modulating Ubiquitin Signaling via Phosphoregulation of the E2 Enzyme UBE2D3.

Genetic variation in the enzymes that catalyze posttranslational modification of proteins is a potentially important source of phenotypic variation during evolution. Ubiquitination is one such modification that affects turnover of virtually all of the proteins in the cell in addition to roles in signaling and epigenetic regulation. UBE2D3 is a promiscuous E2 enzyme, which acts as an ubiquitin donor for E3 ligases that catalyze ubiquitination of developmentally important proteins.

Individual variation of the masticatory system dominates 3D skull shape in the herbivory-adapted marsupial wombats.

Background: Within-species skull shape variation of marsupial mammals is widely considered low and strongly size-dependent (allometric), possibly due to developmental constraints arising from the altricial birth of marsupials. However, species whose skulls are impacted by strong muscular stresses - particularly those produced through mastication of tough food items - may not display such intrinsic patterns very clearly because of the known plastic response of bone to muscle activity of the individual. In such cases, allometry may not dominate within-species shape variation, even if it is a driver of evolutionary shape divergence; ordination of shape in a geometric morphometric context through principal component analysis (PCA) should reveal main variation in areas under masticatory stress (incisor region/zygomatic arches/mandibular ramus); but this main variation should emerge from high individual variability and thus have low eigenvalues.

An integrated workflow for crosslinking mass spectrometry.

We present a concise workflow to enhance the mass spectrometric detection of crosslinked peptides by introducing sequential digestion and the crosslink identification software xiSEARCH. Sequential digestion enhances peptide detection by selective shortening of long tryptic peptides. We demonstrate our simple 12-fraction protocol for crosslinked multi-protein complexes and cell lysates, quantitative analysis, and high-density crosslinking, without requiring specific crosslinker features.

High Availability of the α7-Nicotinic Acetylcholine Receptor in Brains of Individuals with Mild Cognitive Impairment: A Pilot Study Using F-ASEM PET.

Emerging evidence supports a hypothesized role for the α7-nicotinic acetylcholine receptor (α7-nAChR) in the pathophysiology of Alzheimer's disease. F-ASEM (3-(1,4-diazabicyclo[3.2.

Short-term improvements in cognitive function following vertical sleeve gastrectomy and Roux-en Y gastric bypass: a direct comparison study.

Background: Cognitive deficits are observed in individuals with obesity. While bariatric surgery can reverse these deficits, it remains unclear whether surgery type differentially influences cognitive outcome. We compared the extent to which vertical sleeve gastrectomy (VSG) and Roux-en Y gastric bypass (RYGB) ameliorated cognitive impairments associated with obesity.

Intertidal clams exhibit population synchrony across spatial and temporal scales.

Long-term datasets can be particularly useful for parsing out factors influencing populations, yet few studies have utilized continuous datasets to quantify population dynamics in bivalve molluscs. We used dynamic factor analysis on a clam biomass dataset spanning 28 yr and five distinct regions in the southern Salish Sea to determine (1) if native intertidal clam populations exhibit synchrony and (2) what environmental covariates may be correlated with these population trends. Once covariates were accounted for, the model with the most data support included three predominant trends to describe multidecadal change in clam biomass.