Interspecies co-feeding transmission of Powassan virus between a native tick, Ixodes scapularis, and the invasive East Asian tick, Haemaphysalis longicornis.

BACKGROUND: Powassan virus, a North American tick-borne flavivirus, can cause severe neuroinvasive disease in humans. While Ixodes scapularis are the primary vectors of Powassan virus lineage II (POWV II), also known as deer tick virus, recent laboratory vector competence studies showed that other genera of ticks can horizontally and vertically transmit POWV II. One such tick is the Haemaphysalis longicornis, an invasive species from East Asia that recently established populations in the eastern USA and already shares overlapping geographic range with native vector species such as I. scapularis. Reports of invasive H. longicornis feeding concurrently with native I. scapularis on multiple sampled hosts highlight the potential for interspecies co-feeding transmission of POWV II. Given the absence of a clearly defined vertebrate reservoir host for POWV II, it is possible that this virus is sustained in transmission foci via nonviremic transmission between ticks co-feeding on the same vertebrate host. The objective of this study was to evaluate whether uninfected H. longicornis co-feeding in close proximity to POWV II-infected I. scapularis can acquire POWV independent of host viremia. METHODS: Using an in vivo tick transmission model, I. scapularis females infected with POWV II ("donors") were co-fed on mice with uninfected H. longicornis larvae and nymphs ("recipients"). The donor and recipient ticks were infested on mice in various sequences, and mouse infection status was monitored by temporal screening of blood for POWV II RNA via quantitative reverse transcription polymerase chain reaction (q-RT-PCR). RESULTS: The prevalence of POWV II RNA was highest in recipient H. longicornis that fed on viremic mice. However, nonviremic mice were also able to support co-feeding transmission of POWV, as demonstrated by the detection of viral RNA in multiple H. longicornis dispersed across different mice. Detection of viral RNA at the skin site of tick feeding but not at distal skin sites indicates that a localized skin infection facilitates transmission of POWV between donor and recipient ticks co-feeding in close proximity. CONCLUSIONS: This is the first report examining transmission of POWV between co-feeding ticks. Against the backdrop of multiple unknowns related to POWV ecology, findings from this study provide insight on possible mechanisms by which POWV could be maintained in nature.

Population Density and Health Outcomes in Women with HIV in the Southern United States: A Retrospective Longitudinal Analysis.

Purpose: Published studies have revealed challenges for people with human immunodeficiency virus (HIV) living in rural areas compared to those in urban areas, such as poor access to HIV care, insufficient transportation, and isolation. The purpose of this study was to examine associations between population density and multiple psychosocial and clinical outcomes in the largest cohort of women with HIV (WWH) in the United States. Methods: Women's Interagency HIV Study (WIHS) participants from Southern sites (n = 561) in 2013-2018 were categorized and compared by population density quartiles. The most urban quartile was compared with the most rural quartile in several psychosocial and clinical variables, including HIV viral load suppression, HIV medication adherence, HIV care attendance, depression, internalized HIV stigma, and perceived discrimination in healthcare settings. Results: Although women in the lowest density quartile were unexpectedly more highly resourced, women in that quartile had greater odds of not attending an HIV care visit in the last six months (odds ratio [OR] = 0.64, 95% confidence interval [CI] [0.43-0.95]), yet higher odds for having fully suppressed HIV when compared to women in the highest density quartile (OR = 1.64, 95% CI [1.13-2.38]). Highly urban WWH had greater likelihood of unsuppressed HIV, even after controlling for income, employment, and health insurance, despite reporting greater HIV care adherence and similar medication adherence. Discussion: Further investigation into the reasons for these disparities by population density is needed, and particular clinical attention should be focused on individuals from high population density areas to help maximize their health outcomes.

Conformational Dynamics of the Hepatitis C Virus 3'X RNA.

The 3' end of the hepatitis C virus genome is terminated by a highly conserved, 98-nucleotide sequence called 3'X. This untranslated structural element is thought to regulate several essential RNA-dependent processes associated with infection. 3'X has two proposed conformations comprised of either three- or two stem-loop structures that result from different base pairing interactions within the first 55 nucleotides. Here, we used single-molecule FRET spectroscopy to monitor the conformational status of fluorescently labeled constructs that isolate this region of the RNA (3'X55). We observed that 3'X55 can adopt both proposed conformations and the relative abundance of them can be modulated by either solution conditions or nucleotide deletions. Furthermore, interconversion between the two conformations is slow and takes place over the course of several hours. The simultaneous existence of two slowly interconverting conformations may help prime individual copies of the viral genome for either viral protein or RNA synthesis, thereby minimizing conflicts between these two competing processes.

Mesenchymal stem cells in autoimmune disease: A systematic review and meta-analysis of pre-clinical studies.

Mesenchymal Stem Cells (MSCs) are of interest in the clinic because of their immunomodulation capabilities, capacity to act upstream of inflammation, and ability to sense metabolic environments. In standard physiologic conditions, they play a role in maintaining the homeostasis of tissues and organs; however, there is evidence that they can contribute to some autoimmune diseases. Gaining a deeper understanding of the factors that transition MSCs from their physiological function to a pathological role in their native environment, and elucidating mechanisms that reduce their therapeutic relevance in regenerative medicine, is essential. We conducted a Systematic Review and Meta-Analysis of human MSCs in preclinical studies of autoimmune disease, evaluating 60 studies that included 845 patient samples and 571 control samples. MSCs from any tissue source were included, and the study was limited to four autoimmune diseases: multiple sclerosis, rheumatoid arthritis, systemic sclerosis, and lupus. We developed a novel Risk of Bias tool to determine study quality for in vitro studies. Using the International Society for Cell & Gene Therapy's criteria to define an MSC, most studies reported no difference in morphology, adhesion, cell surface markers, or differentiation into bone, fat, or cartilage when comparing control and autoimmune MSCs. However, there were reported differences in proliferation. Additionally, 308 biomolecules were differentially expressed, and the abilities to migrate, invade, and form capillaries were decreased. The findings from this study could help to explain the pathogenic mechanisms of autoimmune disease and potentially lead to improved MSC-based therapeutic applications.

A 3-Year Study Investigating the Utility of Patient-Reported Outcomes Measurement Information System-29 for Long-Term Follow-Up in Adult Spinal Deformity.

BACKGROUND: Adult spinal deformity (ASD) significantly impacts the quality of life due to three-dimensional spinal abnormalities. Patient-reported outcome measures, such as the Patient-Reported Outcomes Measurement Information System (PROMIS-29), play a crucial role in assessing postoperative outcomes. This study aims to investigate trends in PROMIS-29 scores over 36 months in patients undergoing long-segment thoracolumbar fusion for ASD and provide insights into its long-term utility. METHODS: A retrospective study including 163 ASD patients undergoing long-segment thoracolumbar fusion was conducted. PROMIS-29 scores were collected at baseline and at postoperative (0-), 3-, 6-, 12-, 18-, 24-, 30-, and 36-month follow-ups. Statistical analyses was performed to assess significant score changes from baseline and in consecutive recordings. RESULTS: Significant improvements in all PROMIS-29 categories were observed at 36 months, with the greatest changes in pain intensity (-35.19%, P < 0.001), physical function (+29.13%, P < 0.001), and pain interference (-28.8%, P < 0.001). Between the 0 and 3 month mark, the greatest significant changes were recorded in pain intensity (-26.5%, P < 0.001), physical function (+24.3%, P < 0.001), and anxiety (-16.9%, P < 0.018). However, scores plateaued after the 3-month mark, with zero categories showing significant changes with subsequent consecutive recordings. CONCLUSIONS: PROMIS-29 scores demonstrated notable improvements in ASD patients particularly in pain intensity, pain interference, and physical function. However, scores plateaued beyond the 3-month mark, suggesting PROMIS-29's limited sensitivity to nuanced changes in long-term patient recovery. Future investigations exploring optimal combinations of patient reported outcome measures for comprehensive short- and long-term outcome assessments in ASD surgery would be beneficial.

Frailty-Related Factors among Women Living with and without HIV Aged 40 Years and Older. The Women's Interagency HIV Study.

BACKGROUND: Frailty is a clinical, geriatric syndrome linked to disability and mortality; and may be associated with a variety of factors among underrepresented and underserved women living with HIV (WLWH) and without HIV (WLWOH) transitioning through the adult life course. OBJECTIVES: Determine whether a published set of factors associated cross-sectionally with frailty in WLWH and similar WLWOH at average age 39 years in 2005/2006 were associated with frailty in 2018/2019 among women who initiated frailty assessments at age ≥40 years, or whether a new set of factors were associated with frailty. DESIGN: Cross-sectional analyses within a longitudinal cohort study. SETTING: The multi-center Women's Interagency HIV Study (WIHS). PARTICIPANTS: 1285 participants (951 WLWH, 334 WLWOH), median age 53 years (interquartile range 47-58 years). MEASUREMENTS: The Fried Frailty Phenotype (FFP) in association with 23 factors representing HIV serostatus, other infections, sociodemographic factors, health behaviors, and chronic diseases. RESULTS: Frailty prevalence was 11.1% in 2018/2019 (12.6% among WLWOH, 9.6% among WLWH, p=0.121). The published 2005/2006 final multivariable stepwise regression model contained 9 predictors of frailty. When refit to women in 2018/2019, only age ≥50 years and annual income ≤$12,000 were independently positively associated with frailty; other significant 2005/2006 factors, HIV serostatus, CD4+ count <500 cells/mL among WLWH, smoking, drinking, FIB-4 and eGFR, were not. A newly-derived stepwise model considering all 23 predictors measured in 2018/2019, showed independent positive associations between frailty and age ≥50 years, annual income ≤$12,000, obesity (body mass index (BMI) ≥30kg/m2), and history of tuberculosis and cancer. CONCLUSION: Different chronic and infectious disease factors were associated with frailty among WLWH and WLWOH over the adult life course. Understanding factors associated with frailty by adult life stage, allows identification and implementation of novel, temporal interventions to alleviate frailty-associated outcomes and enhance quality of life among WLWH and WLWOH.

Changes in alcohol consumption during the COVID-19 pandemic: a longitudinal cohort study using smart-breathalyzer data.

Previous studies relying on alcohol sales, alcohol-related injuries, and surveys have suggested that alcohol consumption increased during the COVID-19 pandemic. We sought to leverage over 1 million Breath Alcohol Concentration (BrAC) measurements from Bluetooth-enabled breathalyzers to conduct an objective and longitudinal assessment of alcohol use during the pandemic. Serial BrAC measurements revealed a decrease in drinking between January 1, 2020 and March 30, 2020, an increase between March 30, 2020 and May 25, 2020, a statistically insignificant decrease between May 25, 2020 and January 1, 2021, and an increase again between January 1, 2021 and June 4, 2021. No statistically significant relationships between shelter-in-place orders and alcohol consumption were detected. These findings demonstrate the complex relationship between the pandemic and alcohol consumption patterns, providing insights that may be relevant to the use of this commonly consumed substance with implications relevant to long-term effects from the patterns observed.

Mechanically-primed voltage-gated proton channels from angiosperm plants.

Voltage-gated and mechanically-gated ion channels are distinct classes of membrane proteins that conduct ions across gated pores and are turned on by electrical or mechanical stimuli, respectively. Here, we describe an Hv channel (a.k.a voltage-dependent H+ channel) from the angiosperm plant A. thaliana that gates with a unique modality as it is turned on by an electrical stimulus only after exposure to a mechanical stimulus, a process that we call priming. The channel localizes in the vascular tissue and has homologs in vascular plants. We find that mechanical priming is not required for activation of non-angiosperm Hvs. Guided by AI-generated structural models of plant Hv homologs, we identify a set of residues playing a crucial role in mechanical priming. We propose that Hvs from angiosperm plants require priming because of a network of hydrophilic/charged residues that locks the channels in a silent resting conformation. Mechanical stimuli destabilize the network allowing the conduction pathway to turn on. In contrast to many other channels and receptors, Hv proteins are not thought to possess mechanisms such as inactivation or desensitization. Our findings demonstrate that angiosperm Hv channels are electrically silent until a mechanical stimulation turns on their voltage-dependent activity.

Emotional scene processing in biotypes of psychosis.

Social-emotional deficits in psychosis may be indexed by deviations in emotional scene processing, but event-related potential (ERP) studies indicate such deviations may not map cleanly to diagnostic categories. Neurobiologically defined psychosis subgroups offer an alternative that may better capture neurophysiological correlates of social-emotional deficits. The current study investigates emotional scene-elicited ERPs in Biotypes of psychosis in a large (N = 622), well-characterized sample. Electroencephalography was recorded in healthy persons (N = 129), Biotype-1 (N = 195), Biotype-2 (N = 131), and Biotype-3 (N = 167) psychosis cases. ERPs were measured from posterior and centroparietal scalp locations. Neural responses to emotional scenes were compared between healthy and psychosis groups. Multivariate group discrimination analyses resulted in two composite variates that differentiated groups. The first variate displayed large differences between low-cognition (Biotype-1, Biotype-2) and intact-cognition groups (Biotype-3, healthy persons). The second indicated a small-to-moderate distinction of Biotypes-2 and -3 from Biotype-1 and healthy persons. Two multivariate correlations were identified indicating associations between 1) self-reported emotional experience and generalized cognition and 2) socio-occupational functioning and late-stage emotional processing. Psychosis Biotypes displayed emotional processing deficits not apparent in DSM psychosis subgroups. Future translational research may benefit from exploring emotional scene processing in such neurobiologically-defined psychosis groups.

Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial.

The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan1-3. Caloric restriction (CR), defined as lessening caloric intake without depriving essential nutrients4, results in changes in molecular processes that have been associated with aging, including DNA methylation (DNAm)5-7, and is established to increase healthy lifespan in multiple species8,9. Here we report the results of a post hoc analysis of the influence of CR on DNAm measures of aging in blood samples from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, a randomized controlled trial in which n = 220 adults without obesity were randomized to 25% CR or ad libitum control diet for 2 yr (ref. 10). We found that CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in biological age estimates measured by various DNAm clocks including PhenoAge and GrimAge. Treatment effect sizes were small. Nevertheless, modest slowing of the pace of aging can have profound effects on population health11-13. The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies14-16 and contrasting with reports that biological aging may not be modifiable17. Ultimately, a conclusive test of the geroscience hypothesis will require trials with long-term follow-up to establish effects of intervention on primary healthy-aging endpoints, including incidence of chronic disease and mortality18-20.

MRI Detection of Carotid Intraplaque Hemorrhage and Postintervention Cognition.

BACKGROUND AND PURPOSE: Cognitive improvement has been reported after carotid revascularization and attributed to treating stenosis and correcting hypoperfusion. This study investigated the effect of carotid intraplaque hemorrhage on postintervention cognition. MATERIALS AND METHODS: In this institutional review board-approved single-center study, consecutive patients scheduled for carotid surgery were recruited for preoperative carotid MR imaging (MPRAGE) and pre- and postintervention cognitive testing using the Repeatable Battery for the Assessment of Neuropsychological Status. Pre- and postintervention scores were compared using t tests and multivariable linear regression. RESULTS: Twenty-three participants were included, with endarterectomy performed in 20 (87%) and angioplasty/stent placement, in 3 (13%). Overall, statistically significant improvements occurred in the pre- versus postintervention mean Total Scale score (92.1 [SD, 15.5] versus 96.1 [SD, 15.8], P = .04), immediate memory index (89.4 [SD, 18.2] versus 97.7 [SD, 14.9], P < .001), and verbal index (96.1 [SD, 14.1] versus 103.0 [SD, 12.0], P = .002). Intraplaque hemorrhage (+) participants (n = 11) had no significant improvement in any category, and the attention index significantly decreased (99.4 [SD, 18.0] versus 93.5 [SD, 19.4], P = .045). Intraplaque hemorrhage (-) participants (n = 12) significantly improved in the Total Scale score (86.4 [SD, 11.8] versus 95.5 [SD, 12.4], P = .004), immediate memory index (82.3 [SD, 14.6] versus 96.2 [SD, 14.1], P = .002), delayed memory index (94.3 [SD, 14.9] versus 102.4 [SD, 8.0], P = .03), and verbal index (94.3 [SD, 13.2] versus 101.5 [SD, 107.4], P = .009). Postintervention minus preintervention scores for intraplaque hemorrhage (+) versus (-) groups showed statistically significant differences in the Total Scale score (-0.4 [SD, 6.8] versus 8.0 [SD, 8.5], P = .02), attention index (-5.9 [SD, 8.5] versus 4.3 [SD, 11.9], P = .03), and immediate memory index (4.2 [SD, 6.7] versus 12.2 [SD, 10.2], P = .04). CONCLUSIONS: Cognitive improvement was observed after carotid intervention, and this was attributable to intraplaque hemorrhage (-) plaque. MR imaging detection of intraplaque hemorrhage status may be an important determinant of cognitive change after intervention.

Status and challenges for sustainable billfish fisheries in the Western Indian Ocean.

Billfish species (families Istiophoridae and Xiphiidae) are caught in artisanal, recreational, and commercial fisheries throughout the Western Indian Ocean region. However, data and information on the interactions among these fisheries and the ecology of billfish in the WIO are not well understood. Using an in-depth analysis of peer-reviewed articles, grey literature, observation studies, and authors' insider knowledge, we summarize the current state of knowledge on billfish fisheries in 10 countries. To describe historical and current trends, we examined fisheries statistics from governmental and non-governmental agencies, sportfishing clubs' reports, diaries of sportfishing captains, and the catch and effort databases of the Indian Ocean Tuna Commission. We highlight two key points. First, billfish fisheries in the Western Indian Ocean are highly diverse, comprising two distinct segments-coastal and oceanic. However, data are poor for most countries with significant gaps in information especially for sport and artisanal fisheries. Second, the evidence assembled showed that billfish species have immense social, cultural, and economic value. Swordfish are targeted by both large-scale and semi-industrial fisheries, while other billfish species, particularly marlin, are highly sought after by sport fisheries in most countries. Our paper provides a comprehensive review of billfish fisheries and available information in the context of the WIO underscoring the need to strengthen data collection and reporting, citizen science, and collaborative sustainable development and management of billfish. Supplementary Information: The online version contains supplementary material available at 10.1007/s11160-022-09725-8.

Treatment of Leptomeningeal Carcinomatosis Following Treatment of Cerebellar Metastasis of HER2+ (Human Epidermal Growth Factor Receptor 2 Positive) Breast Cancer: Case Report and Review of Literature.

Leptomeningeal carcinomatosis (LC) after metastasis of breast cancer is a rare occurrence with potentially devastating complications. Treatment options are limited, and there is a lack of literature on this topic. We report the case of a 38-year-old woman with estrogen/progesterone receptor negative (ER/PR-), human epidermal growth factor receptor 2 positive (HER2+) invasive ductal carcinoma of the left breast who underwent bilateral mastectomies with axillary lymph node dissection and chemotherapy treatment. The patient returned 11 months later with persistent headaches. Imaging and resection found cerebellar metastasis of the breast carcinoma. The brain metastasis was treated with further chemotherapy and stereotactic radiosurgery. Follow-up imaging showed the development of small lesions outside the radiation site. Metabolic studies were performed to determine if the new lesions were due to tumor recurrence or radiation necrosis, but the studies were inconclusive as to the etiology of these lesions. The patient later developed LC that was successfully treated with full resolution of the disease using intrathecal trastuzumab. There are currently no consensuses on treatment guidelines for treating LC. Here, we demonstrate successful treatment of LC from an ER/PR-, HER2+ breast carcinoma with intrathecal trastuzumab.

Root Coverage Predictability in the Treatment of Gingival Recessions on Mandibular Anterior Teeth.

INTRODUCTION: Mandibular anterior teeth are most frequently affected by gingival recession. However, data regarding mucogingival treatment aimed at root coverage in this specific location are limited. OBJECTIVE: The purpose of this study was to systematically review the scientific literature and to use the meta-analytic approach to address the following focused question: "What is the effectiveness of different surgical approaches on clinical and patient-related outcomes in the treatment of buccal gingival recessions on mandibular anterior teeth?" METHODS: Studies were located by searching 3 electronic databases (Medline, Scopus, and Cochrane databases) and cross-referencing. Randomized and nonrandomized studies including at least 1 arm involving the use of pedicle flaps and/or free soft tissue grafts in the treatment of gingival recessions (recession type [RT] 1 and RT2) located on the buccal aspects of mandibular centrals, laterals and canines, were included in the analysis. Primary outcome was mean root coverage (mRC), expressed in percentage, based on a 3- to 12-mo follow-up observation. A Bayesian single-arm network meta-analysis was performed to identify a treatment hierarchy of the different surgical techniques. RESULTS: Sixteen studies, with a total of 23 arms, were included in the quantitative analysis. The greatest mRC is associated with laterally positioned flap (LPF) + connective tissue graft (CTG) (91.2%) and tunnel (TUN) + CTG (89.4%), whereas LPF alone, coronally advanced flap (CAF) + CTG, and free gingival graft (FGG) showed lower mRC (79.1%, 78.9%, and 68.5% respectively). TUN + CTG provides significantly greater mRC compared to CAF+CTG. No difference among the procedures could be observed in terms of keratinized tissue width gain. CONCLUSIONS: Treatment hierarchy generated by an arm-based network meta-analysis model suggested that tunnel and laterally positioned flap, both in combination with connective tissue graft, may provide the greatest mean root coverage in the treatment of mandibular anterior recessions. KNOWLEDGE TRANSFER STATEMENT: The results of the present systematic review can be used by clinicians when deciding which approach to adopt when treating buccal gingival recessions on mandibular anterior teeth. In particular, procedures based on a laterally positioned flap or a tunneling technique, both in combination with connective tissue graft, seem to be the most predictable therapeutic decision.

Recent advances in positron emission particle tracking: a comparative review.

Positron emission particle tracking (PEPT) is a technique which allows the high-resolution, three-dimensional imaging of particulate and multiphase systems, including systems which are large, dense, and/or optically opaque, and thus difficult to study using other methodologies. In this work, we bring together researchers from the world's foremost PEPT facilities not only to give a balanced and detailed overview and review of the technique but, for the first time, provide a rigorous, direct, quantitative assessment of the relative strengths and weaknesses of all contemporary PEPT methodologies. We provide detailed explanations of the methodologies explored, including also interactive code examples allowing the reader to actively explore, edit and apply the algorithms discussed. The suite of benchmarking tests performed and described within the document is made available in an open-source repository for future researchers.

Effect of stage of lactation and dietary starch content on endocrine-metabolic status, blood amino acid concentrations, milk yield, and composition in Holstein dairy cows.

Milk yield and composition are modified by level and chemical characteristics of dietary energy and protein. Those factors determine nutrient availability from a given diet, and once absorbed, they interact with the endocrine system and together determine availability of metabolites to the mammary gland. Four multiparous dairy cows in early lactation and subsequently in late lactation were fed 2 diets for 28 d in a changeover design that provided, within the same stage of lactation, similar amounts of rumen fermentable feed with either high (HS) or low starch (LS). All diets had similar dietary crude protein (15.5% dry matter) and rumen-undegradable protein (∼40% of crude protein) content. Profiles of AA were calculated to be similar to that of casein. On d 28, [1-13C] Leu was infused into one jugular vein with blood samples taken at 0, 2, 4, 6, and 8 h, and cows milked at 0, 2, 4, 5, 6, 7, and 8 h from start of infusion. Isotopic enrichments of plasma Leu, keto-isocaproic acid, and milk casein were determined for calculation of Leu kinetics. Data were subjected to ANOVA using the MIXED procedure of SAS (SAS Institute Inc.), with time as repeated factor and cow as the random effect. Dry matter intake within each stage of lactation was similar between groups. Feeding LS resulted in lower blood glucose and greater ratio of bovine somatotropin to insulin. This response was associated with greater blood concentrations of nonesterified fatty acids and ß-hydroxybutyrate, which might have contributed to greater milk fat content in LS-fed cows. Except for His, average concentrations of all AA in blood were higher in late than early lactation. Diet did not alter average plasma concentrations of AA. However, for most of the essential AA (particularly branched-chain), the HS diet led to a marked decrease in concentrations after the forage meal, resulting in significant differences between dietary groups in early lactation. In early-lactating cows fed HS, a greater reduction in plasma concentrations at 8 h relative to pre-feeding values (time zero) was observed for Met, Lys, and His, resulting in decreases of 27.9%, 33.6%, and 38.5%, respectively. A higher bovine somatotropin/insulin ratio in early lactation and in cows fed LS could possibly have led to greater breakdown and, consequently, higher AA flux from peripheral tissues. In LS-fed cows, higher mobilization of body fat and protein was confirmed by the greater body weight loss in both stages of lactation. Higher irreversible loss of [1-13C] Leu in early lactation suggested lower protein retention in peripheral tissues during early compared with late lactation. Milk yield, protein output, and composition were similar between groups at both stages of lactation, whereas milk coagulation was faster (lower curd firming rate) and with higher curd firmness in response to feeding HS in late lactation. Overall, data indicated that rate of carbohydrate fermentability in the rumen can modify the availability of metabolites to the mammary gland and consequently modify milk protein coagulation.

Evaluation of an online toolkit for carers of people with a life-limiting illness at the end-of-life: health professionals' perspectives.

Carers of people with a life-limiting illness report unmet information, practical, and emotional support needs, and are often unaware of services available to help improve preparedness, wellbeing, and reduce strain. CarerHelp is the first e-health toolkit that focuses on the information and support needs of carers of people with a life-limiting illness at the end-of-life, using a pathway approach. This study investigated the usefulness of CarerHelp, from the perspective of health professionals who care for these people. Through a 10-min online survey, health professionals provided feedback about their user experience and perceived usefulness of the website. Their expert opinion was sought to ascertain whether CarerHelp could increase carers' preparedness and confidence to support the person for whom they are caring and thereby improve carers' own psychological wellbeing. Health professionals also evaluated whether CarerHelp adequately raised awareness of support services available. CarerHelp was perceived as a useful resource for increasing preparedness for the caring role, including physical tasks and emotional support. Health professionals reported that CarerHelp would increase carers' knowledge of services, confidence to care and ability for self-care. Health professionals endorsed CarerHelp as a useful information source, guide for support, and would promote CarerHelp to clients and their families.

HIFs: New arginine mimic inhibitors of the Hv1 channel with improved VSD-ligand interactions.

The human voltage-gated proton channel Hv1 is a drug target for cancer, ischemic stroke, and neuroinflammation. It resides on the plasma membrane and endocytic compartments of a variety of cell types, where it mediates outward proton movement and regulates the activity of NOX enzymes. Its voltage-sensing domain (VSD) contains a gated and proton-selective conduction pathway, which can be blocked by aromatic guanidine derivatives such as 2-guanidinobenzimidazole (2GBI). Mutation of Hv1 residue F150 to alanine (F150A) was previously found to increase 2GBI apparent binding affinity more than two orders of magnitude. Here, we explore the contribution of aromatic interactions between the inhibitor and the channel in the presence and absence of the F150A mutation, using a combination of electrophysiological recordings, classic mutagenesis, and site-specific incorporation of fluorinated phenylalanines via nonsense suppression methodology. Our data suggest that the increase in apparent binding affinity is due to a rearrangement of the binding site allowed by the smaller residue at position 150. We used this information to design new arginine mimics with improved affinity for the nonrearranged binding site of the wild-type channel. The new compounds, named "Hv1 Inhibitor Flexibles" (HIFs), consist of two "prongs," an aminoimidazole ring, and an aromatic group connected by extended flexible linkers. Some HIF compounds display inhibitory properties that are superior to those of 2GBI, thus providing a promising scaffold for further development of high-affinity Hv1 inhibitors.

Improving image quality in transcranial magnetic resonance guided focused ultrasound using a conductive screen.

Transcranial Magnetic Resonance guided Focused Ultrasound (TcMRgFUS) has been proven to be an effective treatment for some neurological disorders such as essential and Parkinson's tremor. However, magnetic resonance guidance at 3 Tesla (3T) frequencies and using the large hemispherical transducers required for TcMRgFUS results in artifactual low-signal bands that pass through key regions of the brain. The purpose of this work was to investigate the use of a circular conductive Radio Frequency (RF) screen, that is bent to have a 12 cm radius in one direction and positioned near the top or back of the head, to reduce or remove these artifactual low-signal bands in TcMRgFUS. The impact of using an RF screen to remove these low signal bands was studied in both imaging experiments and electromagnetic simulations. Hydrophone measurements of the acoustic transparency of the bronze 2 mm diameter square mesh screen used in the imaging studies were compared with temperature measurements with and without the screen in heating studies in the TcMRgFUS system. The imaging and simulation studies both show that for the different screen configurations studied in this work, RF screen removes the low-signal bands and increases both homogeneity and signal-to-noise ratio (SNR) throughout the region of the brain. Hydrophone and heating studies indicate that even a 2 mm wire mesh provides minimal attenuation to the ultrasound beam. Simulation results also suggest that a 1 cm mesh will provide adequate artifact suppression with even less ultrasound attenuation. An RF screen that disrupts the natural waveguide nature of the transducer in the 3T MR environment can change the electromagnetic field profile to reduce unwanted artifacts and provide an imaging region which has more homogeneity and higher SNR throughout the brain.