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Background: Better understanding of worldwide variation in simple tests of cognition and global function in older adults would aid the delivery and interpretation of multi-national studies of the prevention of dementia and functional decline. Method: In six RCTs that measured cognition with the mini-mental state examination (MMSE), Montreal cognitive assessment (MoCA), and activities of daily living (ADL) with the Standardised Assessment of Everyday Global Activities (SAGEA), we estimated average scores by global region with multilevel mixed-effects models. We estimated the proportion of participants with cognitive or functional impairment with previously defined thresholds (MMSE≤24 or MoCA≤25, SAGEA≥7), and with a country-standardised z-score threshold of cognitive or functional score of ≤-1. Results: In 91,396 participants (mean age 66.6 years [SD 7.8], 31% females) from seven world regions, all global regions differed significantly in estimated cognitive function (z-score differences 0.11–0.45, p

BackgroundBlood flow restriction combined with low load resistance training (LL-BFRT) is associated with increases in upper limb muscle strength and size. The effect of LL-BFRT on upper limb muscles located proximal to the BFR cuff application is unclear.ObjectiveThe aim of this systematic review was to evaluate the effect of LL-BFRT compared to low load, or high load resistance training (LL-RT, HL-RT) on musculature located proximal to cuff placement.MethodsSix electronic databases were searched for randomized controlled trials (RCTs). Two reviewers independently evaluated the risk of bias using the PEDro scale. We performed a meta-analysis using a random effects model, or calculated mean differences (fixed-effect) where appropriate. We judged the certainty of evidence using the GRADE approach.ResultsThe systematic literature searched yielded 346 articles, of which 9 studies were eligible. The evidence for all outcomes was of very low to low certainty. Across all comparisons, a significant increase in bench press and shoulder flexion strength was found in favor of LL-BFRT compared to LL-RT, and in shoulder lean mass and pectoralis major thickness in favor of the LL-BFRT compared to LL-RT and HL-RT, respectively. No significant differences were found between LL-BFRT and HL-RT in muscle strength.ConclusionWith low certainty LL-BFRT appears to be equally effective to HL-RT for improving muscle strength in upper body muscles located proximal to the BFR stimulus in healthy adults. Furthermore, LL-BFRT may induce muscle size increase, but these adaptations are not superior to LL-RT or HL-RT.

The article informs about the differences in quadriceps and hamstrings activation during repeated hops among athletes who underwent ACL reconstruction, emphasizing the need for nuanced assessment methods to detect these differences and ensure proper rehabilitation. Topics include the challenges athletes face after ACL reconstruction, the use of surface electromyography (SEMG) for neuromuscular analysis, and the importance of timing and magnitude of muscle activation in rehabilitation protocols.

Phalaris aquatica is pasture species introduced into Australia during early European settlement. Consumption of the plant can cause the neurological condition chronic phalaris toxicity (CPT) in sheep and cattle. In recent years, there has been an increase in reports of CPT in macropods, which has raised concerns regarding its impacts on their welfare. Currently, little is known about the distribution or seasonal patterns of this disease in wildlife, information pivotal in assessing its potential risks. Between 2021 and 2022, we conducted a survey targeting government bodies, veterinary businesses and wildlife organisations to investigate the locations and time of occurrence of CPT in macropods in the state of Victoria, Australia. We received 13 survey responses, 12 verbal reports, a full record of investigated cases from a university veterinary school and cases from a wildlife rescue organisation. Over the period of 11 years, Victoria had 918 cases of CPT recorded in macropods from 36 local government areas, with cases concentrated centrally just north of the state capital of Melbourne and July (midwinter) being the month with the highest case count (n = 220). There was a significant positive correlation between case count and both the abundance of kangaroos (Macropus giganteus and Macropus fuliginosus) (P < 0.01) and the abundance of P. aquatica (P = 0.009), and a significant negative correlation between annual case count and average rainfall of March (P = 0.016) and April (P = 0.02). Understanding these relationships will assist land and wildlife managers in predicting the risk and magnitude of disease outbreaks of CPT each in Victoria. [ABSTRACT FROM AUTHOR]

According to contemporary accounts, linguistic behavior reflects the interaction of distinct representations supporting word meaning and phonology. However, there is controversy about the extent to which this interaction occurs within task-specific systems, specialized for reading and short-term memory (STM), as opposed to between components that support the full range of linguistic tasks. We examined whether individual differences in the efficiency of phonological processing would relate to the application of lexical-semantic knowledge to support verbal STM, single word reading and repetition. In a sample of 83 participants, we related nonword performance in each task (as a marker of phonological capacity in the absence of meaning) to the effects of word imageability (a lexical-semantic variable). We found stronger reliance on lexical-semantic knowledge in participants with weaker phonological processing. This relationship held across tasks, suggesting that lexical-semantic processing can compensate for phonological weakness which would otherwise give rise to poor performance. Our results are consistent with separable yet interacting primary systems for phonology and semantics, with lexical-semantic knowledge supporting pattern completion within the phonological system in a similar way across STM and reading tasks.

The metabolic state of a cell is influenced by cell-extrinsic factors, including nutrient availability and growth factor signaling. Here, we present extracellular matrix (ECM) remodeling as another fundamental node of cell-extrinsic metabolic regulation. Unbiased analysis of glycolytic drivers identified the hyaluronan-mediated motility receptor as being among the most highly correlated with glycolysis in cancer. Confirming a mechanistic link between the ECM component hyaluronan and metabolism, treatment of cells and xenografts with hyaluronidase triggers a robust increase in glycolysis. This is largely achieved through rapid receptor tyrosine kinase-mediated induction of the mRNA decay factor ZFP36, which targets TXNIP transcripts for degradation. Because TXNIP promotes internalization of the glucose transporter GLUT1, its acute decline enriches GLUT1 at the plasma membrane. Functionally, induction of glycolysis by hyaluronidase is required for concomitant acceleration of cell migration. This interconnection between ECM remodeling and metabolism is exhibited in dynamic tissue states, including tumorigenesis and embryogenesis.

The most widely used cancer animal model is the human-murine tumor xenograft. Unbiased molecular dissection of tumor parenchyma versus stroma in human-murine xenografts is critical for elucidating dysregulated protein networks/pathways and developing therapeutics that may target these two functionally codependent compartments. Although antibody-reliant technologies (e.g., immunohistochemistry, imaging mass cytometry) are capable of distinguishing tumor-proper versus stromal proteins, the breadth or extent of targets is limited. Here, we report an antibody-free targeted cross-species glycoproteomic (TCSG) approach that enables direct dissection of human tumor parenchyma from murine tumor stroma at the molecular/protein level in tumor xenografts at a selectivity rate presently unattainable by other means. This approach was used to segment/dissect and obtain the protein complement phenotype of the tumor stroma and parenchyma of the metastatic human lung adenocarcinoma A549 xenograft, with no need for tissue microdissection prior to mass-spectrometry analysis. An extensive molecular map of the tumor proper and the associated microenvironment was generated along with the top functional N-glycosylated protein networks enriched in each compartment. Importantly, immunohistochemistry-based cross-validation of selected parenchymal and stromal targets applied on human tissue samples of lung adenocarcinoma and normal adjacent tissue is indicative of a noteworthy translational capacity for this unique approach that may facilitate identifications of novel targets for next generation antibody therapies and development of real time preclinical tumor models.

Disrupted in schizophrenia 1 (DISC1) is a multi-functional scaffolding protein that has been associated with neuropsychiatric disease. The role of DISC1 is to assemble protein complexes that promote neural development and signaling, hence tight control of the concentration of cellular DISC1 in neurons is vital to brain function. Using structural and biochemical techniques, we show for we believe the first time that not only is DISC1 turnover elicited by the ubiquitin proteasome system (UPS) but that it is orchestrated by the F-Box protein, FBXW7. We present the structure of FBXW7 bound to the DISC1 phosphodegron motif and exploit this information to prove that disruption of the FBXW7-DISC1 complex results in a stabilization of DISC1. This action can counteract DISC1 deficiencies observed in neural progenitor cells derived from induced pluripotent stem cells from schizophrenia patients with a DISC1 frameshift mutation. Thus manipulation of DISC1 levels via the UPS may provide a novel method to explore DISC1 function.

Read’s formal analysis of kinship terminologies is well known and widely respected, as is his leadership in promoting the formal analysis of kinship through the formation of panels and conferences, and his role in this journal. As in all his work the paper is strongly reasoned and draws upon a knowledge of the literature that is long and deep.  All of these are reasons we welcome the piece before us.  On the other hand, the spirit of this work is somewhat different from that of our book, engendering in us some reservations.  Taking the strengths for granted, we will confine our comment to a couple of things in Read’s article with which we take issue.

While there have been tremendous efforts to target oncogenic RAS signaling from inside the cell, little effort has focused on the cell-surface. Here, we used quantitative surface proteomics to reveal a signature of proteins that are upregulated on cells transformed with KRASG12V, and driven by MAPK pathway signaling. We next generated a toolkit of recombinant antibodies to seven of these RAS-induced proteins. We found that five of these proteins are broadly distributed on cancer cell lines harboring RAS mutations. In parallel, a cell-surface CRISPRi screen identified integrin and Wnt signaling proteins as critical to RAS-transformed cells. We show that antibodies targeting CDCP1, a protein common to our proteomics and CRISPRi datasets, can be leveraged to deliver cytotoxic and immunotherapeutic payloads to RAS-transformed cancer cells and report for RAS signaling status in vivo. Taken together, this work presents a technological platform for attacking RAS from outside the cell.

Xenophagy is a selective macroautophagic process that protects the host cytosol by entrapping and delivering microbes to a degradative compartment. Both noncanonical autophagic pathways and xenophagy are activated by microbes during infection, but the relative importance and function of these distinct processes are not clear. In this study, we used bacterial and host mutants to dissect the contribution of autophagic processes responsible for bacterial growth restriction of Listeria monocytogenesL. monocytogenes is a facultative intracellular pathogen that escapes from phagosomes, grows in the host cytosol, and avoids autophagy by expressing three determinants of pathogenesis: two secreted phospholipases C (PLCs; PlcA and PlcB) and a surface protein (ActA). We found that shortly after phagocytosis, wild-type (WT) L. monocytogenes escaped from a noncanonical autophagic process that targets damaged vacuoles. During this process, the autophagy marker LC3 localized to single-membrane phagosomes independently of the ULK complex, which is required for initiation of macroautophagy. However, growth restriction of bacteria lacking PlcA, PlcB, and ActA required FIP200 and TBK1, both involved in the engulfment of microbes by xenophagy. Time-lapse video microscopy revealed that deposition of LC3 on L. monocytogenes-containing vacuoles via noncanonical autophagy had no apparent role in restricting bacterial growth and that, upon access to the host cytosol, WT L. monocytogenes utilized PLCs and ActA to avoid subsequent xenophagy. In conclusion, although noncanonical autophagy targets phagosomes, xenophagy was required to restrict the growth of L. monocytogenes, an intracellular pathogen that damages the entry vacuole.

Objectives Hospital-acquired pressure injuries (PIs) are a source of morbidity and mortality, and many are potentially preventable.Design This study prospectively evaluated the prevalence and the associated factors of PIs in adult critical care patients admitted to intensive care units (ICU) in the UK.Setting This service evaluation was part of a larger, international, single-day point prevalence study of PIs in adult ICU patients. Training was provided to healthcare givers using an electronic platform to ensure standardised recognition and staging of PIs across all sites.Participants The characteristics of the ICUs were recorded before the survey; deidentified patient data were collected using a case report form and uploaded onto a secure online platform.Primary and secondary outcome measures Factors associated with ICU-acquired PIs in the UK were analysed descriptively and using mixed multiple logistic regression analysis.Results Data from 1312 adult patients admitted to 94 UK ICUs were collected. The proportion of individuals with at least one PI was 16% (211 out of 1312 patients), of whom 8.8% (n=115/1312) acquired one or more PIs in the ICU and 7.3% (n=96/1312) prior to ICU admission. The total number of PIs was 311, of which 148 (47.6%) were acquired in the ICU. The location of majority of these PIs was the sacral area, followed by the heels. Braden score and prior length of ICU stay were associated with PI development.Conclusions The prevalence and the stage of severity of PIs were generally low in adult critically ill patients admitted to participating UK ICUs during the study period. However, PIs are a problem in an important minority of patients. Lower Braden score and longer length of ICU stay were associated with the development of injuries; most ICUs assess risk using tools which do not account for this.Trial registration number NCT03270345.

Upon entry into the host cell cytosol, the facultative intracellular pathogen Listeria monocytogenes coordinates the expression of numerous essential virulence factors by allosteric binding of glutathione (GSH) to the Crp-Fnr family transcriptional regulator PrfA. Here, we report that robust virulence gene expression can be recapitulated by growing bacteria in a synthetic medium containing GSH or other chemical reducing agents. Bacteria grown under these conditions were 45-fold more virulent in an acute murine infection model and conferred greater immunity to a subsequent lethal challenge than bacteria grown in conventional media. During cultivation in vitro, PrfA activation was completely dependent on the intracellular levels of GSH, as a glutathione synthase mutant (ΔgshF) was activated by exogenous GSH but not reducing agents. PrfA activation was repressed in a synthetic medium supplemented with oligopeptides, but the repression was relieved by stimulation of the stringent response. These data suggest that cytosolic L. monocytogenes interprets a combination of metabolic and redox cues as a signal to initiate robust virulence gene expression in vivoIMPORTANCE Intracellular pathogens are responsible for much of the worldwide morbidity and mortality from infectious diseases. These pathogens have evolved various strategies to proliferate within individual cells of the host and avoid the host immune response. Through cellular invasion or the use of specialized secretion machinery, all intracellular pathogens must access the host cell cytosol to establish their replicative niches. Determining how these pathogens sense and respond to the intracellular compartment to establish a successful infection is critical to our basic understanding of the pathogenesis of each organism and for the rational design of therapeutic interventions. Listeria monocytogenes is a model intracellular pathogen with robust in vitro and in vivo infection models. Studies of the host-sensing and downstream signaling mechanisms evolved by L. monocytogenes often describe themes of pathogenesis that are broadly applicable to less tractable pathogens. Here, we describe how bacteria use external redox states as a cue to activate virulence.

This article reports on research regarding interprofessional education (IPE) in child welfare conducted in 2009 and 2010. Pre service nursing, social worker and teacher education candidates participated in a workshop that "exposed" (Charles, Bainbridge & Gilbert, 2010) students to IPE in child welfare. This paper addresses a gap in literature in IPE in child welfare. Literature in IPE precedes a description of the workshop followed by an explanation of the integrated expert presentation, case study, modeling, reflection and small and large group processes. Results of the survey administered to workshop attendees are presented. Likert scaled questions indicate a high degree of satisfaction with the workshop organization, pedagogy and objectives. Responses to the open-ended questions align closely with the Thistlethwaite and Moran (2010) learning outcomes framework. It is clear that pre-service students learned with, from and about each other's discipline. 2 tables and an extensive reference list are included.

A 43-year-old woman presented with localised areas of prominent, tender superficial veins in her right arm and both legs, and chest pain, following the second dose of AstraZeneca vaccine and possible contemporaneous Covid-19 infection. Electrocardiogram, troponin and d -dimer had all been normal. However, a venous duplex ultrasound scan showed a perivenous inflammation without thrombosis in the areas of her limbs with prominent tender veins, but not elsewhere. We suggest that patients may present with prominent and tender superficial veins secondary to non-thrombotic phlebitis following Covid-19 infection or the AstraZeneca vaccine, which appears to be self-limiting. In addition, this case raises the possibility that Covid-19 infection or the AstraZeneca vaccine may directly affect cells in the vein wall, resulting in phlebitis without any evidence of thrombosis or microthrombosis. This phenomenon appears to be transient and self-limiting.

There is intense interest in developing therapeutic strategies for RAS proteins, the most frequently mutated oncoprotein family in cancer. Development of effective anti-RAS therapies will be aided by the greater appreciation of RAS isoform-specific differences in signaling events that support neoplastic cell growth. However, critical issues that require resolution to facilitate the success of these efforts remain. In particular, the use of well-validated anti-RAS antibodies is essential for accurate interpretation of experimental data. We evaluated 22 commercially available anti-RAS antibodies with a set of distinct reagents and cell lines for their specificity and selectivity in recognizing the intended RAS isoforms and mutants. Reliability varied substantially. For example, we found that some pan- or isoform-selective anti-RAS antibodies did not adequately recognize their intended target or showed greater selectivity for another; some were valid for detecting G12D and G12V mutant RAS proteins in Western blotting, but none were valid for immunofluorescence or immunohistochemical analyses; and some antibodies recognized nonspecific bands in lysates from "Rasless" cells expressing the oncoprotein BRAFV600E Using our validated antibodies, we identified RAS isoform-specific siRNAs and shRNAs. Our results may help to ensure the accurate interpretation of future RAS studies.

Cyclic diadenosine monophosphate (c-di-AMP) is a conserved nucleotide second messenger critical for bacterial growth and resistance to cell wall-active antibiotics. In Listeria monocytogenes, the sole diadenylate cyclase, DacA, is essential in rich, but not synthetic media and ΔdacA mutants are highly sensitive to the β-lactam antibiotic cefuroxime. In this study, loss of function mutations in the oligopeptide importer (oppABCDF) and glycine betaine importer (gbuABC) allowed ΔdacA mutants to grow in rich medium. Since oligopeptides were sufficient to inhibit growth of the ΔdacA mutant we hypothesized that oligopeptides act as osmolytes, similar to glycine betaine, to disrupt intracellular osmotic pressure. Supplementation with salt stabilized the ΔdacA mutant in rich medium and restored cefuroxime resistance. Additional suppressor mutations in the acetyl-CoA binding site of pyruvate carboxylase (PycA) rescued cefuroxime resistance and resulted in a 100-fold increase in virulence of the ΔdacA mutant. PycA is inhibited by c-di-AMP and these mutations prompted us to examine the role of TCA cycle enzymes. Inactivation of citrate synthase, but not down-stream enzymes suppressed ΔdacA phenotypes. These data suggested that c-di-AMP modulates central metabolism at the pyruvate node to moderate citrate production and indeed, the ΔdacA mutant accumulated six times the concentration of citrate present in wild-type bacteria.

Our understanding of neural population coding has been limited by a lack of analysis methods to characterize spiking data from large populations. The biggest challenge comes from the fact that the number of possible network activity patterns scales exponentially with the number of neurons recorded ([Formula: see text]). Here we introduce a new statistical method for characterizing neural population activity that requires semi-independent fitting of only as many parameters as the square of the number of neurons, requiring drastically smaller data sets and minimal computation time. The model works by matching the population rate (the number of neurons synchronously active) and the probability that each individual neuron fires given the population rate. We found that this model can accurately fit synthetic data from up to 1000 neurons. We also found that the model could rapidly decode visual stimuli from neural population data from macaque primary visual cortex about 65 ms after stimulus onset. Finally, we used the model to estimate the entropy of neural population activity in developing mouse somatosensory cortex and, surprisingly, found that it first increases, and then decreases during development. This statistical model opens new options for interrogating neural population data and can bolster the use of modern large-scale in vivo Ca[Formula: see text] and voltage imaging tools.