Stroke-related Effects on Maximal Dynamic Hip Flexor Fatigability and Functional Implications

Introduction: Stroke-related changes in maximal dynamic hip flexor muscle fatigability may be more relevant functionally than isometric hip flexor fatigability. Methods: Ten chronic stroke survivors performed 5 sets of 30 hip flexion maximal dynamic voluntary contractions (MDVC). A maximal isometric voluntary contraction (MIVC) was performed before and after completion of the dynamic contractions. Both the paretic and nonparetic legs were tested. Results: Reduction in hip flexion MDVC torque in the paretic leg (44.7%) was larger than the nonparetic leg (31.7%). The paretic leg had a larger reduction in rectus femoris EMG (28.9%) between the first and last set of MDVCs than the nonparetic leg (7.4%). Reduction in paretic leg MDVC torque was correlated with self-selected walking speed (r2 = 0.43), while reduction in MIVC torque was not (r2 = 0.11). Conclusions: Reductions in maximal dynamic torque of paretic hip flexors may be a better predictor of walking function than reductions in maximal isometric contractions

Cholinergic Modulation of Locomotion and Striatal Dopamine Release Is Mediated by α6α4* Nicotinic Acetylcholine Receptors

Dopamine (DA) release in striatum is governed by firing rates of midbrain DA neurons, striatal cholinergic tone, and nicotinic ACh receptors (nAChRs) on DA presynaptic terminals. DA neurons selectively express α6* nAChRs, which show high ACh and nicotine sensitivity. To help identify nAChR subtypes that control DA transmission, we studied transgenic mice expressing hypersensitive α6^(L9’S*) receptors. α6^(L9’S) mice are hyperactive, travel greater distance, exhibit increased ambulatory behaviors such as walking, turning, and rearing, and show decreased pausing, hanging, drinking, and grooming. These effects were mediated by α6 α4* pentamers, as α6^(L9’S) mice lacking α4 subunits displayed essentially normal behavior. In α6^(L9’S) mice, receptor numbers are normal, but loss of α4 subunits leads to fewer and less sensitive α6* receptors. Gain-of-function nicotine-stimulated DA release from striatal synaptosomes requires α4 subunits, implicating α6α4β2* nAChRs in α6^(L9’S) mouse behaviors. In brain slices, we applied electrochemical measurements to study control of DA release by α6^(L9’S) nAChRs. Burst stimulation of DA fibers elicited increased DA release relative to single action potentials selectively in α6^(L9’S), but not WT or α4KO/ α6^(L9’S), mice. Thus, increased nAChR activity, like decreased activity, leads to enhanced extracellular DA release during phasic firing. Bursts may directly enhance DA release from α6^(L9’S) presynaptic terminals, as there was no difference in striatal DA receptor numbers or DA transporter levels or function in vitro. These results implicate α6α4β2* nAChRs in cholinergic control of DA transmission, and strongly suggest that these receptors are candidate drug targets for disorders involving the DA system

A DR4:tBID axis drives the p53 apoptotic response by promoting oligomerization of poised BAX

The cellular response to p53 activation varies greatly in a stimulus‐ and cell type‐specific manner. Dissecting the molecular mechanisms defining these cell fate choices will assist the development of effective p53‐based cancer therapies and also illuminate fundamental processes by which gene networks control cellular behaviour. Using an experimental system wherein stimulus‐specific p53 responses are elicited by non‐genotoxic versus genotoxic agents, we discovered a novel mechanism that determines whether cells undergo proliferation arrest or cell death. Strikingly, we observe that key mediators of cell‐cycle arrest (p21, 14‐3‐3σ) and apoptosis (PUMA, BAX) are equally activated regardless of outcome. In fact, arresting cells display strong translocation of PUMA and BAX to the mitochondria, yet fail to release cytochrome C or activate caspases. Surprisingly, the key differential events in apoptotic cells are p53‐dependent activation of the DR4 death receptor pathway, caspase 8‐mediated cleavage of BID, and BID‐dependent activation of poised BAX at the mitochondria. These results reveal a previously unappreciated role for DR4 and the extrinsic apoptotic pathway in cell fate choice following p53 activation.Fil: Henry, Ryan E. State University Of Colorado-boulder; Estados UnidosFil: Andrysik, Zdenek. State University Of Colorado-boulder; Estados UnidosFil: Paris, Ramiro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mar del Plata. Instituto de Investigaciones Biológicas; Argentina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Biológicas; Argentina. State University Of Colorado-boulder; Estados UnidosFil: Galbraith, Matthew D.. State University Of Colorado-boulder; Estados UnidosFil: Espinosa, Joaquín M.. State University Of Colorado-boulder; Estados Unido

Child Protective Service Referrals Involving Exposure to Domestic Violence: Prevalence, Associated Maltreatment Types, and Likelihood of Formal Case Openings

Childhood exposure to domestic violence (CEDV) is widely understood as potentially harmful to children. Accordingly, many child welfare systems in the United States construe CEDV as maltreatment when the exposure results in harm or threatened harm to the child. The purpose of the current study was to investigate substantiated child welfare referrals directly related to CEDV to better understand the prevalence and patterns of CEDV-related maltreatment and how child welfare workers respond under the “harm or threatened harm” standard. Data were drawn from 23,704 substantiated referrals between 2009 and 2013 in a large Midwestern child welfare system. Approximately 20% of substantiated referrals were CEDV related. A plurality of CEDV-related referrals included both a male caregiver and female caregiver who were co-substantiated for maltreatment. The most common maltreatment types substantiated for these referrals were neglect based rather than abuse based, and just under a quarter (23%) of CEDV-related referrals were formally opened for services. Referrals involving co-occurring substance abuse were most likely to be opened for services based on predicted probabilities derived from multilevel modeling. Implications for policy and practice are considered

An Alternative Pathway for Okazaki Fragment Processing - Resolution of Fold-Back Flaps by Pif1 Helicase

Two pathways have been proposed for eukaryotic Okazaki fragment RNA primer removal. Results presented here provide evidence for an alternative pathway. Primer extension by DNA polymerase δ (pol δ) displaces the downstream fragment into an RNA-initiated flap. Most flaps are cleaved by flap endonuclease 1 (FEN1) while short, and the remaining nicks joined in the first pathway. A small fraction escapes immediate FEN1 cleavage and is further lengthened by Pif1 helicase. Long flaps are bound by replication protein A (RPA), which inhibits FEN1. In the second pathway, Dna2 nuclease cleaves an RPA-bound flap and displaces RPA, leaving a short flap for FEN1. Pif1 flap lengthening creates a requirement for Dna2. This relationship should not have evolved unless Pif1 had an important role in fragment processing. In this study, biochemical reconstitution experiments were used to gain insight into this role. Pif1 did not promote synthesis through GC-rich sequences, which impede strand displacement. Pif1 was also unable to open fold-back flaps that are immune to cleavage by either FEN1 or Dna2 and cannot be bound by RPA. However, Pif1 working with pol δ readily unwound a full-length Okazaki fragment initiated by a fold-back flap. Additionally, a fold-back in the template slowed pol δ synthesis, so that the fragment could be removed before ligation to the lagging strand. These results suggest an alternative pathway in which Pif1 removes Okazaki fragments initiated by fold-back flaps in vivo

National Estimates of Emergency Department Visits for Pediatric Severe Sepsis in the United States

Objective. We sought to determine the characteristics of children presenting to United States (US) Emergency Departments (ED) with severe sepsis. Study design. Cross-sectional analysis using data from the National Hospital Ambulatory Medical Care Survey (NHAMCS). Using triage vital signs and ED diagnoses (defined by the International Classification of Diseases, Ninth Revision codes), we identified children(triage fever or ICD-9 infection) and organ dysfunction (triage hypotension or ICD-9 organ dysfunction). Results. Of 28.2 million pediatric patients presenting to US EDs each year, severe sepsis was present in 95,055 (0.34%; 95% CI: 0.29-0.39%). Fever and respiratory infection were the most common indicators of an infection. Hypotension and respiratory failure were the most common indicators of organ dysfunction. Most severe sepsis occurred in children ages 31 days-1 year old (32.1%). Most visits for pediatric severe sepsis occurred during winter months (37.4%), and only 11.1% of patients arrived at the ED by ambulance. Over half of severe sepsis cases were self-pay or insured by Medicaid. A large portion (44.1%) of pediatric severe sepsis ED visits occurred in the South census region. ED length of stay was over 3 h, and 16.5% were admitted to the hospital. Conclusion. Nearly 100,000 children annually present to US EDs with severe sepsis. The findings of this study highlight the unique characteristics of children treated in the ED for severe sepsis

Evidence for Reduced Specific Star Formation Rates in the Centers of Massive Galaxies at z = 4

We perform the first spatially-resolved stellar population study of galaxies in the early universe (z = 3.5 - 6.5), utilizing the Hubble Space Telescope Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey (CANDELS) imaging dataset over the GOODS-S field. We select a sample of 418 bright and extended galaxies at z = 3.5 - 6.5 from a parent sample of ~ 8000 photometric-redshift selected galaxies from Finkelstein et al. (2015). We first examine galaxies at 3.5< z < 4.0 using additional deep K-band survey data from the HAWK-I UDS and GOODS Survey (HUGS) which covers the 4000A break at these redshifts. We measure the stellar mass, star formation rate, and dust extinction for galaxy inner and outer regions via spatially-resolved spectral energy distribution fitting based on a Markov Chain Monte Carlo algorithm. By comparing specific star formation rates (sSFRs) between inner and outer parts of the galaxies we find that the majority of galaxies with the high central mass densities show evidence for a preferentially lower sSFR in their centers than in their outer regions, indicative of reduced sSFRs in their central regions. We also study galaxies at z ~ 5 and 6 (here limited to high spatial resolution in the rest-frame ultraviolet only), finding that they show sSFRs which are generally independent of radial distance from the center of the galaxies. This indicates that stars are formed uniformly at all radii in massive galaxies at z ~ 5 - 6, contrary to massive galaxies at z < 4.Comment: Accepted to ApJ, 20 pages, 15 figure

Selective nitrogen adsorption via backbonding in a metal-organic framework with exposed vanadium sites.

Industrial processes prominently feature π-acidic gases, and an adsorbent capable of selectively interacting with these molecules could enable important chemical separations1-4. Biological systems use accessible, reducing metal centres to bind and activate weakly π-acidic species, such as N2, through backbonding interactions5-7, and incorporating analogous moieties into a porous material should give rise to a similar adsorption mechanism for these gaseous substrates8. Here, we report a metal-organic framework featuring exposed vanadium(II) centres capable of back-donating electron density to weak π acids to successfully target π acidity for separation applications. This adsorption mechanism, together with a high concentration of available adsorption sites, results in record N2 capacities and selectivities for the removal of N2 from mixtures with CH4, while further enabling olefin/paraffin separations at elevated temperatures. Ultimately, incorporating such π-basic metal centres into porous materials offers a handle for capturing and activating key molecular species within next-generation adsorbents

Cardioplastic Approach to Omental Flap Coverage for Severe Aortic Root Infections in the Opioid Era

Aortic root abscesses are severe sequelae of endocarditis that clinically manifest as life-threatening infection. As the opioid epidemic continues to yield a national crisis, the incidence and severity of this disease process have increased. Reconstruction of the aortic root is a challenging undertaking and carries the risk of recurrent infection. The omentum has an established reputation as a reliable flap in thoracic reconstruction, given its amorphous form and immunogenic properties, but it has not been utilized for aortic root infections. We present a novel indication for the omental flap using a cardioplastic approach in coverage of aortic root reconstruction. Four patients were treated with pedicled omental flap coverage after aortic root reconstruction. All patients had successful flap healing with no evidence of recurrent infection. This series demonstrates the technical feasibility and clinical utility for providing soft tissue coverage and antimicrobial protection when used in aortic root reconstruction