Levetiracetam prevents Aβ production through SV2a-dependent modulation of App processing in Alzheimer's disease models.

In Alzheimer's disease (AD), amyloid-beta (Aβ) peptides are produced by proteolytic cleavage of the amyloid precursor protein (APP), which can occur during synaptic vesicle (SV) cycling at presynapses. Precisely how amyloidogenic APP processing may impair presynaptic proteostasis and how to therapeutically target this process remains poorly understood. Using knock-in mouse models of early Aβ pathology, we found proteins with hampered degradation accumulate at presynaptic sites.

Derailed protein turnover in the aging mammalian brain.

Efficient protein turnover is essential for cellular homeostasis and organ function. Loss of proteostasis is a hallmark of aging culminating in severe dysfunction of protein turnover. To investigate protein turnover dynamics as a function of age, we performed continuous in vivo metabolic stable isotope labeling in mice along the aging continuum.

Amyloid fibril proteomics of AD brains reveals modifiers of aggregation and toxicity.

Background: The accumulation of amyloid beta (Aβ) peptides in fibrils is prerequisite for Alzheimer's disease (AD). Our understanding of the proteins that promote Aβ fibril formation and mediate neurotoxicity has been limited due to technical challenges in isolating pure amyloid fibrils from brain extracts.

Methods: To investigate how amyloid fibrils form and cause neurotoxicity in AD brain, we developed a robust biochemical strategy.

Hydrological models for climate-based assessments at the watershed scale: A critical review of existing hydrologic and water quality models.

Global changes, including climate and land use changes, can result in significant impact to water resources. Planning for these changes requires making projections, even in the face of considerable uncertainties, to make informed management and policy decisions. A number of climate change scenarios and projections at global and regional levels are available that can be used to predict the likely range of outcomes.

Electron Tomographic Methods for Studying Organelles of the Murine Chemical Synapse.

Electron tomography of the chemical synapse provides important architectural information regarding the organization of synaptic organelles including synaptic vesicles, Nissl bodies, and early endosomes. Here, we describe methods for the preparation of select murine brain regions for high-pressure freezing, freeze substitution, and EM tomographic analysis of synaptic structures. The method uses fresh brain slices prepared using a vibratome and biopsy punches to collect specific brain regions of interest suitable for subsequent preservation and EM tomographic imaging.

Levetiracetam Treatment Normalizes Levels of Presynaptic Endocytosis Machinery and Restores Nonamyloidogenic APP Processing in Knock-in Mice.

Toxic amyloid-beta (Aβ) peptides, produced by sequential proteolytic cleavage of the amyloid precursor protein (APP), play a key role in the initial stage of Alzheimer's disease (AD). Increasing evidence indicates that Aβ induces neuronal circuit hyperexcitability in the early stages of AD pathology. As a result, researchers have investigated treatments that modulate the excitatory/inhibitory imbalance as potential AD therapies.

Pulse-Chase Proteomics of the App Knockin Mouse Models of Alzheimer's Disease Reveals that Synaptic Dysfunction Originates in Presynaptic Terminals.

Compromised protein homeostasis underlies accumulation of plaques and tangles in Alzheimer's disease (AD). To observe protein turnover at early stages of amyloid beta (Aβ) proteotoxicity, we performed pulse-chase proteomics on mouse brains in three genetic models of AD that knock in alleles of amyloid precursor protein (APP) prior to the accumulation of plaques and during disease progression. At initial stages of Aβ accumulation, the turnover of proteins associated with presynaptic terminals is selectively impaired.

Landscape of clinically actionable mutations in breast cancer 'A cohort study'.

Breast cancer (BC) is a heterogeneous disease. Numerous chemotherapeutic agents are available for early stage or advanced/metastatic breast cancer to provide maximum benefit with minimum side effects. However, the clinical outcome of patients with the same clinical and pathological characteristics and treated with similar treatments may show major differences and a vast majority of patients still develop treatment resistance and eventually succumb to disease.

A Rare De Novo Gene Mutation Affecting BDNF-Enhancer-Driven Transcription Activity Associated with Autism and Atypical Smith-Magenis Syndrome Presentation.

Deletions and mutations involving the Retinoic Acid Induced 1 () gene at 17p11.2 cause Smith-Magenis syndrome (SMS). Here we report a patient with autism as the main clinical presentation, with some SMS-like features and a rare de novo gene mutation, c.

Effects of a Yoga Program on Mood States, Quality of Life, and Toxicity in Breast Cancer Patients Receiving Conventional Treatment: A Randomized Controlled Trial.

Aims: The aim of this study is to compare the effects of yoga program with supportive therapy counseling on mood states, treatment-related symptoms, toxicity, and quality of life in Stage II and III breast cancer patients on conventional treatment.

Methods: Ninety-eight Stage II and III breast cancer patients underwent surgery followed by adjuvant radiotherapy (RT) or chemotherapy (CT) or both at a cancer center were randomly assigned to receive yoga ( = 45) and supportive therapy counseling ( = 53) over a 24-week period. Intervention consisted of 60-min yoga sessions, daily while the control group was imparted supportive therapy during their hospital visits.

Rai1 Haploinsufficiency Is Associated with Social Abnormalities in Mice.

Autism is characterized by difficulties in social interaction, communication, and repetitive behaviors; with different degrees of severity in each of the core areas. Haploinsufficiency and point mutations of are associated with Smith-Magenis syndrome (SMS), a genetic condition that scores within the autism spectrum range for social responsiveness and communication, and is characterized by neurobehavioral abnormalities, intellectual disability, developmental delay, sleep disturbance, and self-injurious behaviors. To investigate the relationship between and social impairment, we evaluated the mice with a battery of tests to address social behavior in mice.

Effects of an integrated Yoga Program on Self-reported Depression Scores in Breast Cancer Patients Undergoing Conventional Treatment: A Randomized Controlled Trial.

Aim: To compare the effects of yoga program with supportive therapy on self-reported symptoms of depression in breast cancer patients undergoing conventional treatment.

Patients And Methods: Ninety-eight breast cancer patients with stage II and III disease from a cancer center were randomly assigned to receive yoga (n = 45) and supportive therapy (n = 53) over a 24-week period during which they underwent surgery followed by adjuvant radiotherapy (RT) or chemotherapy (CT) or both. The study stoppage criteria was progressive disease rendering the patient bedridden or any physical musculoskeletal injury resulting from intervention or less than 60% attendance to yoga intervention.

Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial.

Background: Cilengitide is a selective αvβ3 and αvβ5 integrin inhibitor. Data from phase 2 trials suggest that it has antitumour activity as a single agent in recurrent glioblastoma and in combination with standard temozolomide chemoradiotherapy in newly diagnosed glioblastoma (particularly in tumours with methylated MGMT promoter). We aimed to assess cilengitide combined with temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter.

The influence of culture on couples coping with breast cancer: a comparative analysis of couples from China, India, and the United States.

This study examines the process of dyadic coping among couples who are managing stress related to a partner's breast cancer diagnosis and identifies cultural factors that affect how couples cope together. Utilizing a qualitative method based on relational psychologies, the "Listening Guide," the authors analyzed the narratives of 28 couples who where coping with early-stage breast cancer and lived in Hong Kong-China, India, and the United States. Analysis revealed four cultural factors influencing the process of coping with breast cancer.

Extreme vulnerability of smallholder farmers to agricultural risks and climate change in Madagascar.

Across the tropics, smallholder farmers already face numerous risks to agricultural production. Climate change is expected to disproportionately affect smallholder farmers and make their livelihoods even more precarious; however, there is limited information on their overall vulnerability and adaptation needs. We conducted surveys of 600 households in Madagascar to characterize the vulnerability of smallholder farmers, identify how farmers cope with risks and explore what strategies are needed to help them adapt to climate change.

Preoperative decolonization effective at reducing staphylococcal colonization in total joint arthroplasty patients.

Staphylococcus decolonization prior to surgery is used to prevent surgical site infections (SSIs) after total joint arthroplasty (TJA). To determine if current treatment protocols result in successful decolonization of methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S.

Staphylococcus aureus screening and decolonization in orthopaedic surgery and reduction of surgical site infections.

Background: Staphylococcus aureus is the most common organism responsible for orthopaedic surgical site infections (SSIs). Patients who are carriers for methicillin-sensitive S. aureus or methicillin-resistant S.

Executive summary: diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America.

These guidelines are intended for use by infectious disease specialists, orthopedists, and other healthcare professionals who care for patients with prosthetic joint infection (PJI). They include evidence-based and opinion-based recommendations for the diagnosis and management of patients with PJI treated with debridement and retention of the prosthesis, resection arthroplasty with or without subsequent staged reimplantation, 1-stage reimplantation, and amputation.

Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America.

These guidelines are intended for use by infectious disease specialists, orthopedists, and other healthcare professionals who care for patients with prosthetic joint infection (PJI). They include evidence-based and opinion-based recommendations for the diagnosis and management of patients with PJI treated with debridement and retention of the prosthesis, resection arthroplasty with or without subsequent staged reimplantation, 1-stage reimplantation, and amputation.