Suppression of MT5-MMP Reveals Early Modulation of Alzheimer's Pathogenic Events in Primary Neuronal Cultures of 5xFAD Mice.

We previously reported that membrane-type 5-matrix metalloproteinase (MT5-MMP) deficiency not only reduces pathological hallmarks of Alzheimer's disease (AD) in 5xFAD (Tg) mice in vivo but also impairs interleukin-1 beta (IL-1β)-mediated neuroinflammation and Aβ production in primary Tg immature neural cell cultures after 11 days in vitro. We now investigate the effect of MT5-MMP on incipient pathogenic pathways that are activated in cortical primary cultures at 21-24 days in vitro (DIV), during which time neurons are organized into a functional mature network. Using wild-type (WT), MT5-MMP (MT5), 5xFAD (Tg), and 5xFADxMT5-MMP (TgMT5) mice, we generated primary neuronal cultures that were exposed to IL-1β and/or different proteolytic system inhibitors.

Design and methods of the StepByStep randomized trial of a mobile health and social media physical activity intervention among adolescent and young adult survivors of childhood cancer: A report from the Children's Oncology Group.

Background: Interventions to increase physical activity are needed in adolescent and young adult survivors of childhood cancer who are largely inactive but at lifelong elevated risk of multiple chronic conditions improved by physical activity. The goals of the StepByStep study are to evaluate the effects of a 48-week distance-based, multi-component mobile health and social media behavioral intervention on physical activity, biomarkers of cardiometabolic health, and health-related quality of life.

Methods: This ongoing study is a two-arm, prospective, multi-site randomized controlled trial.

Typology and characterization of the agricultural productive units in the NE Amazonian region of Ecuador.

Objective: Many studies have observed different characteristics among productive systems in the rural territories of Latin America. Therefore, understanding and characterizing them while they function plays an essential role in determining their relationship between development and environment. A study has been conducted in the Orellana province of NE Ecuador to determine their typology and then classify them according to the variables that describe their main traits or attributes using cluster analysis (CA).

Olfactory-Related Adverse Events: An Analysis of the Food and Drug Administration Adverse Events Reporting System.

Objective: Olfactory dysfunction has gained considerable interest with its association to the coronavirus pandemic. Due to the limited literature on olfactory-related adverse events (ORAE) associated with medications, this study investigated ORAE reported in the Food and Drug Administration Adverse Event Reporting System (FAERS) to identify the most frequent medications associated with these reactions.

Study Design: Cross-sectional analysis SETTING: FAERS database.

Patients with COVID-19 Pneumonia Admitted to an Intensive Care Unit (ICU) at a Community Hospital in Flint, Michigan, in Early 2020: Characteristics and Mortality.

Introduction: Despite the many studies conducted on the factors affecting mortality in patients with COVID-19, there is ongoing debate about the role of race as a risk factor. Several studies have reported a geographic and racial disparity in COVID-19 cases in Michigan. This study aimed to examine the characteristics of the 2020 first cohort of Intensive Care Unit (ICU) COVID-19 patients admitted to a community teaching hospital in Flint, Michigan, and to determine the factors associated with ICU mortality, including race.

Liver-Selective Imidazolopyrazine Mitochondrial Uncoupler SHD865 Reverses Adiposity and Glucose Intolerance in Mice.

Excess body fat is a risk factor for metabolic diseases and is a leading preventable cause of morbidity and mortality worldwide. There is a strong need to find new treatments that decrease the burden of obesity and lower the risk of obesity-related comorbidities, including cardiovascular disease and type 2 diabetes. Pharmacologic mitochondrial uncouplers represent a potential treatment for obesity through their ability to increase nutrient oxidation.

A Review of Community Awareness for Colorectal Cancer Screening and Prevention in North and Central Asian Countries.

Objectives: Colorectal cancer (CRC) incidence and mortality rates are increasing in low- and middle-income countries (LMIC), including North and Central Asian countries (NCAC). Screening and risk factor reduction can aid in the prevention of colorectal cancer, but communities lack awareness of these screening programs. The review assessed community awareness about CRC screening and prevention in NCAC to facilitate cancer control policies.

Factors Associated With Hip Fracture Length of Stay Among Older Adults in a Community Hospital Setting.

Introduction: Hip fractures in geriatric populations constitute a heavy burden on the healthcare system. The study goal was to identify patient, hospital, and surgical factors associated with hospital length of stay (LOS) for geriatric patients with hip fractures requiring surgical intervention in a community hospital setting.

Methods: This was a cross-sectional retrospective chart review of geriatric hip fractures that underwent surgical fixation at a community hospital between 2017 and 2019.

Improving Compliance with the CMS SEP-1 Sepsis Bundle at a Community-Based Teaching Hospital Emergency Department.

Introduction: The Centers for Medicare & Medicaid Services (CMS) designed Hospital Quality Initiatives (HQI) to assure delivery of quality health care for institutions receiving Medicare payments. Like many teaching institutions, the SEP-1 compliance rates at McLaren Oakland in Pontiac fluctuated monthly and were not achieving institutional target expectations.

Methods: The project team designed a Sepsis Macro and a Sepsis Order Set in the electronic medical record system.

The Helico Maze Detects Early Impairment of Reference Memory at Three Months of Age in the 5XFAD Mouse Model of Alzheimer's Disease.

Background: The 5XFAD model of Alzheimer's disease (AD) bearing five familial mutations of Alzheimer's disease on human APP and PSEN1 transgenes shows deposits of amyloid-β peptide (Aβ) as early as 2 months, while deficits in long-term memory can be detected at 4 months using the highly sensitive olfactory-dependent tests that we previously reported.

Objective: Given that detecting early dysfunctions in AD prior to overt pathology is of major interest in the field, we sought to detect memory deficits at earlier stages of the disease in 3-month-old male 5XFAD mice.

Methods: To this end, we used the Helico Maze, a behavioral task that was recently developed and patented.

APOE4 drives inflammation in human astrocytes via TAGLN3 repression and NF-κB activation.

Apolipoprotein E4 (APOEε4) is the major allelic risk factor for late-onset sporadic Alzheimer's disease (sAD). Inflammation is increasingly considered as critical in sAD initiation and progression. Identifying brain molecular mechanisms that could bridge these two risk factors remain unelucidated.

Conversion of oxadiazolo[3,4-b]pyrazines to imidazo[4,5-b]pyrazines via a tandem reduction-cyclization sequence generates new mitochondrial uncouplers.

We report new mitochondrial uncouplers derived from the conversion of [1,2,5]oxadiazolo[3,4-b]pyrazines to 1H-imidazo[4,5-b]pyrazines. The in situ Fe-mediated reduction of the oxadiazole fragment followed by cyclization gave access to imidazopyrazines in moderate to good yields. A selection of orthoesters also allowed functionalization on the 2-position of the imidazole ring.

MT5-MMP promotes neuroinflammation, neuronal excitability and Aβ production in primary neuron/astrocyte cultures from the 5xFAD mouse model of Alzheimer's disease.

Background: Membrane-type matrix metalloproteinase 5 (MT5-MMP) deficiency in the 5xFAD mouse model of Alzheimer's disease (AD) reduces brain neuroinflammation and amyloidosis, and prevents deficits in synaptic activity and cognition in prodromal stages of the disease. In addition, MT5-MMP deficiency prevents interleukin-1 beta (IL-1β)-mediated inflammation in the peripheral nervous system. In this context, we hypothesized that the MT5-MMP/IL-1β tandem could regulate nascent AD pathogenic events in developing neural cells shortly after the onset of transgene activation.

Deficiency in MT5-MMP Supports Branching of Human iPSCs-Derived Neurons and Reduces Expression of GLAST/S100 in iPSCs-Derived Astrocytes.

For some time, it has been accepted that the β-site APP cleaving enzyme 1 (BACE1) and the γ-secretase are two main players in the amyloidogenic processing of the β-amyloid precursor protein (APP). Recently, the membrane-type 5 matrix metalloproteinase (MT5-MMP/MMP-24), mainly expressed in the nervous system, has been highlighted as a new key player in APP-processing, able to stimulate amyloidogenesis and also to generate a neurotoxic APP derivative. In addition, the loss of MT5-MMP has been demonstrated to abrogate pathological hallmarks in a mouse model of Alzheimer's disease (AD), thus shedding light on MT5-MMP as an attractive new therapeutic target.

MT5-MMP controls APP and β-CTF/C99 metabolism through proteolytic-dependent and -independent mechanisms relevant for Alzheimer's disease.

We previously discovered the implication of membrane-type 5-matrix metalloproteinase (MT5-MMP) in Alzheimer's disease (AD) pathogenesis. Here, we shed new light on pathogenic mechanisms by which MT5-MMP controls the processing of amyloid precursor protein (APP) and the fate of amyloid beta peptide (Aβ) as well as its precursor C99, and C83. We found in human embryonic kidney cells (HEK) carrying the APP Swedish familial mutation (HEKswe) that deleting the C-terminal non-catalytic domains of MT5-MMP hampered its ability to process APP and release the soluble 95 kDa form (sAPP95).

Utility and value of pre-operative CT and MRI for cochlear implantation in the elderly.

Purpose: To determine the utility and value of pre-operative imaging among the elderly population ≥70 y.o. with bilateral progressive sensorineural hearing loss undergoing cochlear implantation.

Comparison of associated comorbid conditions in patients with benign paroxysmal positional vertigo with or without migraine history: A large single institution study.

Purpose: In the largest reported United States (U.S.) cohort of benign paroxysmal positional vertigo (BPPV), does the presence or absence of migraine correlate with increased associations of other factors?

Materials & Methods: A retrospective chart review from a single U.

Matrix Metalloproteinases as New Targets in Alzheimer's Disease: Opportunities and Challenges.

Although matrix metalloproteinases (MMPs) are implicated in the regulation of numerous physiological processes, evidence of their pathological roles have also been obtained in the last decades, making MMPs attractive therapeutic targets for several diseases. Recent discoveries of their involvement in central nervous system (CNS) disorders, and in particular in Alzheimer's disease (AD), have paved the way to consider MMP modulators as promising therapeutic strategies. Over the past few decades, diverse approaches have been undertaken in the design of therapeutic agents targeting MMPs for various purposes, leading, more recently, to encouraging developments.

[1,2,5]Oxadiazolo[3,4-]pyrazine-5,6-diamine Derivatives as Mitochondrial Uncouplers for the Potential Treatment of Nonalcoholic Steatohepatitis.

Small molecule mitochondrial uncouplers are emerging as a new class of molecules for the treatment of nonalcoholic steatohepatitis. We utilized BAM15, a potent protonophore that uncouples the mitochondria without depolarizing the plasma membrane, as a lead compound for structure-activity profiling. Using oxygen consumption rate as an assay for determining uncoupling activity, changes on the 5- and 6-position of the oxadiazolopyrazine core were introduced.

Gendered powerlessness in at-risk adolescent and young women: an empirical model.

In the United States, youth aged 13-24 comprised approximately 21% of new HIV infections in 2017; 13% of these infections occurred among women, the majority of whom (86%) acquired HIV through heterosexual contact (Centers for Disease Control and Prevention. 2019a. .

Donecopride, a Swiss army knife with potential against Alzheimer's disease.

Background And Purpose: We recently identified donecopride as a pleiotropic compound able to inhibit AChE and to activate 5-HT receptors. Here, we have assessed the potential therapeutic effects of donecopride in treating Alzheimer's disease (AD).

Experimental Approach: We used two in vivo animal models of AD, transgenic 5XFAD mice and mice exposed to soluble amyloid-β peptides and, in vitro, primary cultures of rat hippocampal neurons.

Emerging Alternative Proteinases in APP Metabolism and Alzheimer's Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP.

Processing of amyloid beta precursor protein (APP) into amyloid-beta peptide (Aβ) by β-secretase and γ-secretase complex is at the heart of the pathogenesis of Alzheimer's disease (AD). Targeting this proteolytic pathway effectively reduces/prevents pathology and cognitive decline in preclinical experimental models of the disease, but therapeutic strategies based on secretase activity modifying drugs have so far failed in clinical trials. Although this may raise some doubts on the relevance of β- and γ-secretases as targets, new APP-cleaving enzymes, including meprin-β, legumain (δ-secretase), rhomboid-like protein-4 (RHBDL4), caspases and membrane-type matrix metalloproteinases (MT-MMPs/η-secretases) have confirmed that APP processing remains a solid mechanism in AD pathophysiology.

Distinguishing patients with laboratory-confirmed chikungunya from dengue and other acute febrile illnesses, Puerto Rico, 2012-2015.

Chikungunya, a mosquito-borne viral, acute febrile illness (AFI) is associated with polyarthralgia and polyarthritis. Differentiation from other AFI is difficult due to the non-specific presentation and limited availability of diagnostics. This 3-year study identified independent clinical predictors by day post-illness onset (DPO) at presentation and age-group that distinguish chikungunya cases from two groups: other AFI and dengue.

Long-Term Pantethine Treatment Counteracts Pathologic Gene Dysregulation and Decreases Alzheimer's Disease Pathogenesis in a Transgenic Mouse Model.

The low-molecular weight thiol pantethine, known as a hypolipidemic and hypocholesterolemic agent, is the major precursor of co-enzyme A. We have previously shown that pantethine treatment reduces amyloid-β (Aβ)-induced IL-1β release and alleviates pathological metabolic changes in primary astrocyte cultures. These properties of pantethine prompted us to investigate its potential benefits in vivo in the 5XFAD (Tg) mouse model of Alzheimer's disease (AD).