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Abstract The gradual deterioration of physiological systems with ageing makes it difficult to maintain skeletal muscle mass (sarcopenia), at least partly due to the presence of ‘anabolic resistance’, resulting in muscle loss. Sarcopenia can be transiently but markedly accelerated through periods of muscle disuse‐induced (i.e., unloading) atrophy due to reduced physical activity, sickness, immobilisation or hospitalisation. Periods of disuse are detrimental to older adults' overall quality of life and substantially increase their risk of falls, physical and social dependence, and early mortality. Disuse events induce skeletal muscle atrophy through various mechanisms, including anabolic resistance, inflammation, disturbed proteostasis and mitochondrial dysfunction, all of which tip the scales in favour of a negative net protein balance and subsequent muscle loss. Concerningly, recovery from disuse atrophy is more difficult for older adults than their younger counterparts. Resistance training (RT) is a potent anabolic stimulus that can robustly stimulate muscle protein synthesis and mitigate muscle losses in older adults when implemented before, during and following unloading. RT may take the form of traditional weightlifting‐focused RT, bodyweight training and lower‐ and higher‐load RT. When combined with sufficient dietary protein, RT can accelerate older adults' recovery from a disuse event, mitigate frailty and improve mobility; however, few older adults regularly participate in RT. A feasible and practical approach to improving the accessibility and acceptability of RT is through the use of resistance bands. Moving forward, RT must be prescribed to older adults to mitigate the negative consequences of disuse atrophy.

Abstract During pregnancy the immune system needs to maintain immune tolerance of the foetus while also responding to infection, which can cause premature activation of the inflammatory pathways leading to the onset of labour and preterm birth. The vaginal microbiome is an important modifier of preterm birth risk, with Lactobacillus dominance during pregnancy associated with term delivery while high microbial diversity is associated with an increased risk of preterm birth. Glycans on glycoproteins along the lower female reproductive tract are fundamental to microbiota-host interactions and the mediation of inflammatory responses. However, the specific glycan epitopes involved in these processes are not well understood. To address this, we conducted glycomic analyses of cervicovaginal fluid (CVF) from 36 pregnant women at high risk of preterm birth and 4 non-pregnant women. Our analysis of N- and O-glycans revealed a rich CVF glycome. While O-glycans were shown to be the main carriers of ABO blood group epitopes, the main features of N-glycans were the presence of abundant paucimannose and high mannose glycans, and a remarkable diversity of complex bi-, tri-, and tetra-antennary glycans decorated with fucose and sialic acid. We identified immuno-regulatory epitopes, such as Lewis antigens, and found that fucosylation was negatively correlated to pro-inflammatory factors, such as IL-1β, MMP-8, C3a and C5a, while glycans with only sialylated antennae were mainly positively correlated to those. Similarly, paucimannose glycans showed a positive correlation to pro-inflammatory factors. We revealed a high abundance of glycans which have previously been identified as hallmarks of cancer and viral glycosylation, such as Man8 and Man9 high mannose glycans. Although each pregnant woman had a unique glycomic profile, longitudinal studies showed that the main glycosylation features were consistent throughout pregnancy in women who delivered at term, whereas women who experienced extreme preterm birth exhibited sharp changes in the CVF glycome shortly before delivery. These findings shed light on the processes underlying the role of glycosylation in maintaining a healthy vaginal microbiome and associated host immune responses. In addition, these discoveries facilitate our understanding of the lower female reproductive tract which has broad implications for women’s health.

Abstract Background Fatigue is a common complication of stroke that has a significant impact on quality of life. The biological mechanisms that underly post-stroke fatigue are currently unclear, however, reactivation of latent viruses and their impact on systemic immune function have been increasingly reported in other conditions where fatigue is a predominant symptom. Epstein-Barr virus (EBV) in particular has been associated with fatigue, including in long-COVID and myalgic encephalomyelitis/chronic fatigue syndrome, but has not yet been explored within the context of stroke. Aims We performed an exploratory analysis to determine if there is evidence of a relationship between EBV reactivation and post-stroke fatigue. Methods In a chronic ischemic stroke cohort (> 5 months post-stroke), we assayed circulating EBV by qPCR and measured the titres of anti-EBV antibodies by ELISA in patients with high fatigue (FACIT-F 41). Statistical analysis between two-groups were performed by t-test when normally distributed according to the Shapiro-Wilk test, by Mann-Whitney test when the data was not normally distributed, and by Fisher’s exact test for categorical data. Results We observed a similar incidence of viral reactivation between people with low versus high levels of post-stroke fatigue (5 of 22 participants (24%) versus 6 of 22 participants (27%)). Although the amount of circulating EBV was similar, we observed an altered circulating anti-EBV antibody profile in participants with high fatigue, with reduced IgM against the Viral Capsid Antigen (2.244 ± 0.926 vs. 3.334 ± 2.68; P = 0.031). Total IgM levels were not different between groups indicating this effect was specific to anti-EBV antibodies (3.23 × 105 ± 4.44 × 104 high fatigue versus 4.60 × 105 ± 9.28 × 104 low fatigue; P = 0.288). Conclusions These data indicate that EBV is not more prone to reactivation during chronic stroke recovery in those with post-stroke fatigue. However, the dysregulated antibody response to EBV may be suggestive of viral reactivation at an earlier stage after stroke.

Abstract Acute myeloid leukaemia (AML) is a highly aggressive and devastating malignancy of the bone marrow and blood. For decades, intensive chemotherapy has been the frontline treatment for AML but has yielded only poor patient outcomes as exemplified by a 5-year survival rate of

Abstract In persons with a spinal cord injury (SCI), resistance training using neuromuscular electrical stimulation (NMES‐RT) increases lean mass in the lower limbs. However, whether protein supplementation in conjunction with NMES‐RT further enhances this training effect is unknown. In this randomized controlled pilot trial, 15 individuals with chronic SCI engaged in 3 times/week NMES‐RT, with (NMES+PRO, n = 8) or without protein supplementation (NMES, n = 7), for 12 weeks. Before and after the intervention, whole body and regional body composition (DXA) and fasting glucose and insulin concentrations were assessed in plasma. Adherence to the intervention components was ≥96%. Thigh lean mass was increased to a greater extent after NMES+PRO compared to NMES (0.3 (0.2, 0.4) kg; p

True abundance of lesser snow (Anser caerulescens caerulescens, Linnaeus 1758) and Ross's geese (Anser rossii, Cassin 1861, collectively referred to as “light geese”, in North America had been unknown in the 1980s. However, different indices of abundance suggested steady increases at the time. The Karrak Lake Research Station (KLRS) was established partly because it was not known if the breeding biology from more southern latitudes (the only information available at the time) was representative of more northern colonies where 90% of the midcontinent population of lesser snow geese nested. Visits in 1990 confirmed the continued importance of Karrak Lake and surrounding areas in Canada’s central Arctic to a large nesting concentration of both snow and Ross's geese documented previously. Key activities at KLRS were (1) colony-wide annual monitoring of nesting goose abundance and nesting performance and (2) large-scale marking efforts to monitor survival, range-wide abundance, distribution, and exploitation rate from hunter harvest and natural mortality rate. The scope of research expanded to include their interaction with local vegetation and other sympatric wildlife, including Arctic foxes (Vulpes lagopus, Linnaeus 1758), king eiders (Somateria spectabilis, Linnaeus 1758), long-tailed ducks (Clangula hyemalis, Linnaeus 1758), and cackling geese (Branta hutchinsii). Following exponential growth in the 1990s and 2000s, nesting populations of light geese at Karrak lake collapsed since 2012, presenting a unique opportunity to examine how local ecosystems recover and revert from heavy grazing by hyperabundant geese.

Recent investigation of a constitutively active ADAMTS13 variant (caADAMTS13) in murine models of acute ischaemic stroke (AIS) have revealed a potential anti-inflammatory mechanism of action contributing to its protective effect. However, it remains unclear whether these observations are a direct result of VWF proteolysis by caADAMTS13. We have implemented state of the art in vitro assays of neutrophil rolling and transmigration to quantify the impact of caADAMTS13 on these processes. Moreover, we have tested caADAMTS13 in two in vivo assays of neutrophil migration to confirm the impact of the treatment on the neutrophil response to sterile inflammation. Neutrophil rolling, over an interleukin-1β stimulated hCMEC/D3 monolayer, is directly inhibited by caADAMTS13, reducing the proportion of neutrophils rolling to 9.5 ± 3.8 % compared to 18.0 ± 4.5 % in untreated controls. Similarly, neutrophil transmigration recorded in real-time, was significantly suppressed in the presence of caADAMTS13 which reduced the number of migration events to a level like that in unstimulated controls (18.0 ± 4.5 and 15.8 ± 7.5 cells/mm2/h, respectively). Brain tissue from mice undergoing experimental focal cerebral ischaemia has indicated the inhibition of this process by caADAMTS13. This is supported by caADAMTS13’s ability to reduce neutrophil migration into the peritoneal cavity in an ischaemia-independent model of sterile inflammation, with the VWF-dependent mechanism by which this occurs being confirmed using a second experimental stroke model. These findings will be an important consideration in the further development of caADAMTS13 as a potential therapy for AIS and other thromboinflammatory pathologies, including cardiovascular disease.

ABSTRACT The global burden of infections due to the pathogenic fungus Cryptococcus is substantial in persons with low CD4+ T-cell counts. Previously, we deleted three chitin deacetylase genes from Cryptococcus neoformans to create a chitosan-deficient, avirulent strain, designated as cda1∆2∆3∆, which, when used as a vaccine, protected mice from challenge with virulent C. neoformans strain KN99. Here, we explored the immunological basis for protection. Vaccine-mediated protection was maintained in mice lacking B cells or CD8+ T cells. In contrast, protection was lost in mice lacking α/β T cells or CD4+ T cells. Moreover, CD4+ T cells from vaccinated mice conferred protection upon adoptive transfer to naive mice. Importantly, while monoclonal antibody-mediated depletion of CD4+ T cells just prior to vaccination resulted in complete loss of protection, significant protection was retained in mice depleted of CD4+ T cells after vaccination but prior to challenge. Vaccine-mediated protection was lost in mice genetically deficient in interferon-γ (IFNγ), tumor necrosis factor alpha (TNFα), or interleukin (IL)-23p19. A robust influx of leukocytes and IFNγ- and TNFα-expressing CD4+ T cells was seen in the lungs of vaccinated and challenged mice. Finally, a higher level of IFNγ production by lung cells stimulated ex vivo correlated with lower fungal burden in the lungs. Thus, while B cells and CD8+ T cells are dispensable, IFNγ and CD4+ T cells have overlapping roles in generating protective immunity prior to cda1∆2∆3∆ vaccination. However, once vaccinated, protection becomes less dependent on CD4+ T cells, suggesting a strategy for vaccinating HIV+ persons prior to loss of CD4+ T cells.IMPORTANCEThe fungus Cryptococcus neoformans is responsible for >100,000 deaths annually, mostly in persons with impaired CD4+ T-cell function such as AIDS. There are no approved human vaccines. We previously created a genetically engineered avirulent strain of C. neoformans, designated as cda1∆2∆3∆. When used as a vaccine, cda1∆2∆3∆ protects mice against a subsequent challenge with a virulent C. neoformans strain. Here, we defined components of the immune system responsible for vaccine-mediated protection. We found that while B cells and CD8+ T cells were dispensible, protection was lost in mice genetically deficient in CD4+ T cells and the cytokines IFNγ, TNFα, or IL-23. A robust influx of cytokine-producing CD4+ T cells was seen in the lungs of vaccinated mice following infection. Importantly, protection was retained in mice depleted of CD4+ T cells following vaccination, suggesting a strategy to protect persons who are at risk of future CD4+ T-cell dysfunction.

Abstract Background Biogeochemical processing of metals including the fabrication of novel nanomaterials from metal contaminated waste streams by microbial cells is an area of intense interest in the environmental sciences. Results Here we focus on the fate of Ce during the microbial reduction of a suite of Ce-bearing ferrihydrites with between 0.2 and 4.2 mol% Ce. Cerium K-edge X-ray absorption near edge structure (XANES) analyses showed that trivalent and tetravalent cerium co-existed, with a higher proportion of tetravalent cerium observed with increasing Ce-bearing of the ferrihydrite. The subsurface metal-reducing bacterium Geobacter sulfurreducens was used to bioreduce Ce-bearing ferrihydrite, and with 0.2 mol% and 0.5 mol% Ce, an Fe(II)-bearing mineral, magnetite (Fe(II)(III)2O4), formed alongside a small amount of goethite (FeOOH). At higher Ce-doping (1.4 mol% and 4.2 mol%) Fe(III) bioreduction was inhibited and goethite dominated the final products. During microbial Fe(III) reduction Ce was not released to solution, suggesting Ce remained associated with the Fe minerals during redox cycling, even at high Ce loadings. In addition, Fe L 2,3 X-ray magnetic circular dichroism (XMCD) analyses suggested that Ce partially incorporated into the Fe(III) crystallographic sites in the magnetite. The use of Ce-bearing biomagnetite prepared in this study was tested for hydrogen fuel cell catalyst applications. Platinum/carbon black electrodes were fabricated, containing 10% biomagnetite with 0.2 mol% Ce in the catalyst. The addition of bioreduced Ce-magnetite improved the electrode durability when compared to a normal Pt/CB catalyst. Conclusion Different concentrations of Ce can inhibit the bioreduction of Fe(III) minerals, resulting in the formation of different bioreduction products. Bioprocessing of Fe-minerals to form Ce-containing magnetite (potentially from waste sources) offers a sustainable route to the production of fuel cell catalysts with improved performance. Graphical Abstract

Abstract In the enduring challenge against disease, advancements in medical technology have empowered clinicians with novel diagnostic platforms. Whilst in some cases, a single test may provide a confident diagnosis, often additional tests are required. However, to strike a balance between diagnostic accuracy and cost-effectiveness, one must rigorously construct the clinical pathways. Here, we developed a framework to build multi-platform precision pathways in an automated, unbiased way, recommending the key steps a clinician would take to reach a diagnosis. We achieve this by developing a confidence score, used to simulate a clinical scenario, where at each stage, either a confident diagnosis is made, or another test is performed. Our framework provides a range of tools to interpret, visualize and compare the pathways, improving communication and enabling their evaluation on accuracy and cost, specific to different contexts. This framework will guide the development of novel diagnostic pathways for different diseases, accelerating the implementation of precision medicine into clinical practice.

The fungal infection, cryptococcosis, is responsible for >100,000 deaths annually. No licensed vaccines are available. We explored the efficacy and immune responses of subunit cryptococcal vaccines adjuvanted with Cationic Adjuvant Formulation 01 (CAF01). CAF01 promotes humoral and T helper (Th) 1 and Th17 immune responses and has been safely used in human vaccine trials. Four subcutaneous vaccines, each containing single recombinant Cryptococcus neoformans protein antigens, partially protected mice from experimental cryptococcosis. Protection increased, up to 100%, in mice that received bivalent and quadrivalent vaccine formulations. Vaccinated mice that received a pulmonary challenge with C. neoformans had an influx of leukocytes into the lung including robust numbers of polyfunctional CD4+ T cells which produced interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα), and interleukin (IL)-17 upon ex vivo antigenic stimulation. Cytokine-producing lung CD8+ T cells were also found, albeit in lesser numbers. A significant, durable IFNγ response was observed in the lungs, spleen, and blood. Moreover, IFNγ secretion following ex vivo stimulation directly correlated with fungal control in the lungs. Thus, we have developed multivalent cryptococcal vaccines which protect mice from experimental cryptococcosis using an adjuvant which has been safely tested in humans. These preclinical studies suggest a path towards human cryptococcal vaccine trials.

Abstract Since volcanic activity was first discovered on Io from Voyager images in 1979, changes on Io's surface have been monitored from both spacecraft and ground‐based telescopes. Here, we present the highest spatial resolution images of Io ever obtained from a ground‐based telescope. These images, acquired by the SHARK‐VIS instrument on the Large Binocular Telescope, show evidence of a major resurfacing event on Io's trailing hemisphere. When compared to the most recent spacecraft images, the SHARK‐VIS images show that a plume deposit from a powerful eruption at Pillan Patera has covered part of the long‐lived Pele plume deposit. Although this type of resurfacing event may be common on Io, few have been detected due to the rarity of spacecraft visits and the previously low spatial resolution available from Earth‐based telescopes. The SHARK‐VIS instrument ushers in a new era of high resolution imaging of Io's surface using adaptive optics at visible wavelengths.

Background: Primary prevention programs utilising traditional risk scores fail to identify all individuals who suffer acute cardiovascular events. We aimed to model the impact and cost effectiveness of incorporating a Polygenic risk scores (PRS) into the cardiovascular disease CVD primary prevention program in Australia, using a whole-of-system model. Methods: System dynamics models, encompassing acute and chronic CVD care in the Australian healthcare setting, assessing the cost-effectiveness of incorporating a CAD-PRS in the primary prevention setting. The time horizon was 10-years. Results: Pragmatically incorporating a CAD-PRS in the Australian primary prevention setting in middle-aged individuals already attending a Heart Health Check (HHC) who are determined to be at low or moderate risk based on the 5-year Framingham risk score (FRS), with conservative assumptions regarding uptake of PRS, could have prevented 2, 052 deaths over 10-years, and resulted in 24, 085 QALYs gained at a cost of $19, 945 per QALY with a net benefit of $724 million. If all Australians overs the age of 35 years old had their FRS and PRS performed, and acted upon, 12, 374 deaths and 60, 284 acute coronary events would be prevented, with 183, 682 QALYs gained at a cost of $18, 531 per QALY, with a net benefit of $5, 780 million. Conclusions: Incorporating a CAD-PRS in a contemporary primary prevention setting in Australia would result in substantial health and societal benefits and is cost-effective. The broader the uptake of CAD-PRS in the primary prevention setting in middle-aged Australians, the greater the impact and the more cost-effective the strategy.

Purpose: The aim of this umbrella review was to determine the impact of resistance training (RT) and individual RT prescription variables on muscle mass, strength, and physical function in healthy adults. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically searched and screened eligible systematic reviews reporting the effects of differing RT prescription variables on muscle mass (or its proxies), strength, and/or physical function in healthy adults aged >18 years. Results: We identified 44 systematic reviews that met our inclusion criteria. The methodological quality of these reviews was assessed using A Measurement Tool to Assess Systematic Reviews; standardized effectiveness statements were generated. We found that RT was consistently a potent stimulus for increasing skeletal muscle mass (4/4 reviews provide some or sufficient evidence), strength (4/6 reviews provided some or sufficient evidence), and physical function (1/1 review provided some evidence). RT load (6/8 reviews provided some or sufficient evidence), weekly frequency (2/4 reviews provided some or sufficient evidence), volume (3/7 reviews provided some or sufficient evidence), and exercise order (1/1 review provided some evidence) impacted RT-induced increases in muscular strength. We discovered that 2/3 reviews provided some or sufficient evidence that RT volume and contraction velocity influenced skeletal muscle mass, while 4/7 reviews provided insufficient evidence in favor of RT load impacting skeletal muscle mass. There was insufficient evidence to conclude that time of day, periodization, inter-set rest, set configuration, set end point, contraction velocity/time under tension, or exercise order (only pertaining to hypertrophy) influenced skeletal muscle adaptations. A paucity of data limited insights into the impact of RT prescription variables on physical function. Conclusion: Overall, RT increased muscle mass, strength, and physical function compared to no exercise. RT intensity (load) and weekly frequency impacted RT-induced increases in muscular strength but not muscle hypertrophy. RT volume (number of sets) influenced muscular strength and hypertrophy.

Abstract Familial hemiplegic migraine type-1 (FHM-1) is a form of migraine with aura caused by mutations in the P/Q-type (Cav2.1) voltage-gated calcium channel. Pregabalin, used clinically in the treatment of chronic pain and epilepsy, inhibits P/Q-type calcium channel activity and recent studies suggest that it may have potential for the treatment of migraine. Spreading Depolarization (SD) is a neurophysiological phenomenon that can occur during migraine with aura by propagating a wave of silenced neuronal function through cortex and sometimes subcortical brain structures. Here, utilizing an optogenetic stimulation technique optimized to allow for non-invasive initiation of cortical SD, we demonstrate that chronic pregabalin administration [12 mg/kg/day (s.c.)] in vivo increased the threshold for cortical spreading depolarization in transgenic mice harboring the clinically-relevant Cav2.1S218L mutation (S218L). In addition, chronic pregabalin treatment limited subcortical propagation of recurrent spreading depolarization events to the striatum and hippocampus in both wild-type and S218L mice. To examine contributing underlying mechanisms of action of chronic pregabalin, we performed whole-cell patch-clamp electrophysiology in CA1 neurons in ex vivo brain slices from mice treated with chronic pregabalin vs vehicle. In WT mice, chronic pregabalin produced a decrease in spontaneous excitatory postsynaptic current (sEPSC) amplitude with no effect on frequency. In contrast, in S218L mice chronic pregabalin produced an increase in sEPSC amplitude and decreased frequency. These electrophysiological findings suggest that in FHM-1 mice chronic pregabalin acts through both pre- and post-synaptic mechanisms in CA1 hippocampal neurons to elicit FHM-1 genotype-specific inhibitory action. The results highlight the potential of chronic pregabalin to limit recurrent SD to subcortical brain structures during pathophysiological events in both the genetically-normal and FHM-1 brain. The work further provides insights into FHM-1 pathophysiology and the potential for chronic pregabalin treatment to prevent SD in migraineurs.

The risk-factor-based prediction of atherosclerotic coronary artery disease (CAD) remains suboptimal, particularly in the absence of any of the standard modifiable cardiovascular risk factors (SMuRFs), making the discovery of biomarkers that correlate with atherosclerosis burden critically important. We hypothesized that cytokines and receptors associated with inflammation in CAD—tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), interleukin-18 (IL-18), and osteoprotegerin (OPG)—would be independently associated with CAD. To determine this, we measured the serum biomarker levels of 993 participants from the BioHEART study who had CT coronary angiograms that were scored for severity of stenosis and plaque composition. We found that the quartiles of TRAIL, OPG, and IL-18 were significantly associated with disease scores, and that the IL-18/TRAIL and OPG/TRAIL ratios demonstrated significant differences between no CAD vs. STEMI whereas only the OPG/TRAIL ratio showed differences between no CAD and obstructive CAD (stenosis > 50%). However, these associations did not persist after adjustment for age, sex, SMuRFs, and a family history of CAD. In conclusion, TRAIL, IL-18, and OPG and the derived ratios of IL-18/TRAIL and OPG/TRAIL demonstrate significant associations with raw disease scores and risk factors, but these markers are not discriminatory biomarkers for the prediction of CAD when incorporated into multi-variable risk models.

Abstract INTRODUCTION The Finnish Geriatric Intervention Study (FINGER) led to the global dementia risk reduction initiative: World‐Wide FINGERS (WW‐FINGERS). As part of WW‐FINGERS, the Australian AU‐ARROW study mirrors aspects of FINGER, as well as US‐POINTER. METHOD AU‐ARROW is a randomized, single‐blind, multisite, 2‐year clinical trial (n = 600; aged 55–79). The multimodal lifestyle intervention group will engage in aerobic exercise, resistance training and stretching, dietary advice to encourage MIND diet adherence, BrainHQ cognitive training, and medical monitoring and health education. The Health Education and Coaching group will receive occasional health education sessions. The primary outcome measure is the change in a global composite cognitive score. Extra value will emanate from blood biomarker analysis, positron emission tomography (PET) imaging, brain magnetic resonance imaging (MRI), and retinal biomarker tests. DISCUSSION The finalized AU‐ARROW protocol is expected to allow development of an evidence‐based innovative treatment plan to reduce cognitive decline and dementia risk, and effective transfer of research outcomes into Australian health policy. Highlights Study protocol for a single‐blind, randomized controlled trial, the AU‐ARROW Study. The AU‐ARROW Study is a member of the World‐Wide FINGERS (WW‐FINGERS) initiative. AU‐ARROW's primary outcome measure is change in a global composite cognitive score. Extra significance from amyloid PET imaging, brain MRI, and retinal biomarker tests. Leading to development of an innovative treatment plan to reduce cognitive decline.

BackgroundThe relationship between baseline perihematomal edema (PHE) and inflammation, and their impact on survival after intracerebral hemorrhage (ICH) are not well understood.ObjectiveAssess the association between baseline PHE, baseline C-reactive protein (CRP), and early death after ICH.MethodsAnalysis of pooled data from multicenter ICH registries. We included patients presenting within 24 h of symptom onset, using multifactorial linear regression model to assess the association between CRP and edema extension distance (EED), and a multifactorial Cox regression model to assess the association between CRP, PHE volume and 30-day mortality.ResultsWe included 1,034 patients. Median age was 69 (interquartile range [IQR] 59–79), median baseline ICH volume 11.5 (IQR 4.3–28.9) mL, and median baseline CRP 2.5 (IQR 1.5–7.0) mg/L. In the multifactorial analysis [adjusting for cohort, age, sex, log-ICH volume, ICH location, intraventricular hemorrhage (IVH), statin use, glucose, and systolic blood pressure], baseline log-CRP was not associated with baseline EED: for a 50% increase in CRP the difference in expected mean EED was 0.004 cm (95%CI 0.000–0.008, p = 0.055). In a further multifactorial analysis, after adjusting for key predictors of mortality, neither a 50% increase in PHE volume nor CRP were associated with higher 30-day mortality (HR 0.97; 95%CI 0.90–1.05, p = 0.51 and HR 0.98; 95%CI 0.93–1.03, p = 0.41, respectively).ConclusionHigher baseline CRP is not associated with higher baseline edema, which is also not associated with mortality. Edema at baseline might be driven by different pathophysiological processes with different effects on outcome.

Background: In South Africa, infants who are HIV-exposed are tested for HIV at birth and 10 weeks of age. The COVID-19 pandemic lockdown restrictions resulted in reduced access to healthcare services and uncertain impact on early infant HIV testing. Objectives: To describe the effects of the COVID-19 pandemic lockdown restrictions on early infant HIV testing and diagnosis in Cape Town, South Africa. Method: This retrospective cohort study compares HIV-exposed infants born during the first COVID-19 pandemic lockdown (2020) to those born in the same period the year before (2019). Laboratory and other data were abstracted from the Provincial Health Data Centre. Results: A total of 2888 infants were included: 1474 born in 2020 and 1413 in 2019. Compared to 2019, there was an increase in the 10-week HIV polymerase chain reaction (PCR) uptake in 2020 (71% vs. 60%, P 0.001). There was also an increase in the proportion of infants who demised without 10-week testing or were lost to follow-up in 2020 compared to 2019 (8% vs. 5%, P = 0.017). Differences detected in birth HIV PCR positivity rates between the two groups (1.1% vs. 0.5%, P = 0.17) did not reach statistical significance; however, a significant increase in vertical transmission of HIV by 10 weeks old was found in the 2020 cohort (1.2% vs. 0.5%. P = 0.046). Conclusion: Vertical transmission of HIV at 10 weeks increased in the Cape Town Metropolitan during the initial COVID-19 lockdown. There was also an increase in the proportion of deaths without testing by 10 weeks in the 2020 group.

Background: Careful administration of either spinal (intrathecal) or general anaesthesia probably has a greater impact on outcomes after hip fracture surgery than which method is used per se. Intraoperative hypotension is associated with poorer outcomes, but appears less prevalent using lower doses of spinal anaesthesia. Methods: In this observational single-centre study, intraoperative noninvasive blood pressure data were analysed from 280 patients undergoing unilateral hip fracture surgery after the administration of hyperbaric spinal bupivacaine 0.5%, 1.3 ml (0.65 mg). Results: Mean cohort mean arterial pressure (MAP) remained within 10% of baseline (spinal injection) MAP for 97/98 (99.0%) subsequent aggregated 1-min recording intervals. The prevalences of lowest MAP

Cryptococcus neoformans and C. gattii, the etiologic agents of cryptococcosis, cause over 100,000 deaths worldwide every year, yet no cryptococcal vaccine has progressed to clinical trials. In preclinical studies, mice vaccinated with an attenuated strain of C. neoformans deleted of three cryptococcal chitin deacetylases (Cn-cda1Δ2Δ3Δ) were protected against a lethal challenge with C. neoformans strain KN99. While Cn-cda1Δ2Δ3Δ extended the survival of mice infected with C. gattii strain R265 compared to unvaccinated groups, we were unable to demonstrate fungal clearance as robust as that seen following KN99 challenge. In stark contrast to vaccinated mice challenged with KN99, we also found that R265-challenged mice failed to induce the production of protection-associated cytokines and chemokines in the lungs. To investigate deficiencies in the vaccine response to R265 infection, we developed a KN99-R265 coinfection model. In unvaccinated mice, the strains behaved in a manner which mirrored single infections, wherein only KN99 disseminated to the brain and spleen. We expanded the coinfection model to Cn-cda1Δ2Δ3Δ-vaccinated mice. Fungal burden, cytokine production, and immune cell infiltration in the lungs of vaccinated, coinfected mice were indicative of immune evasion by C. gattii R265 as the presence of R265 neither compromised the immunophenotype established in response to KN99 nor inhibited clearance of KN99. Collectively, these data indicate that R265 does not dampen a protective vaccine response, but rather suggest that R265 remains largely undetected by the immune system.

Abstract Two major glycosaminoglycan types, heparan sulfate (HS) and chondroitin sulfate (CS), control many aspects of development and physiology in a type-specific manner. HS and CS are attached to core proteins via a common linker tetrasaccharide, but differ in their polymer backbones. How core proteins are specifically modified with HS or CS has been an enduring mystery. By reconstituting glycosaminoglycan biosynthesis in vitro, we establish that the CS-initiating N-acetylgalactosaminyltransferase CSGALNACT2 modifies all glycopeptide substrates equally, whereas the HS-initiating N-acetylglucosaminyltransferase EXTL3 is selective. Structure-function analysis reveals that acidic residues in the glycopeptide substrate and a basic exosite in EXTL3 are critical for specifying HS biosynthesis. Linker phosphorylation by the xylose kinase FAM20B accelerates linker synthesis and initiation of both HS and CS, but has no effect on the subsequent polymerisation of the backbone. Our results demonstrate that modification with CS occurs by default and must be overridden by EXTL3 to produce HS.

Abstract Evolution of human H3N2 influenza viruses driven by immune selection has narrowed the receptor specificity of the hemagglutinin (HA) to a restricted subset of human-type (Neu5Acα2-6 Gal) glycan receptors that have extended poly-LacNAc (Galβ1-4GlcNAc) repeats. This altered specificity has presented challenges for hemagglutination assays, growth in laboratory hosts, and vaccine production in eggs. To assess the impact of extended glycan receptors on virus binding, infection, and growth, we have engineered N-glycan extended (NExt) cell lines by overexpressing β3-Ν-acetylglucosaminyltransferase 2 in MDCK, SIAT, and hCK cell lines. Of these, SIAT-NExt cells exhibit markedly increased binding of H3 HAs and susceptibility to infection by recent H3N2 virus strains, but without impacting final virus titers. Glycome analysis of these cell lines and allantoic and amniotic egg membranes provide insights into the importance of extended glycan receptors for growth of recent H3N2 viruses and relevance to their production for cell- and egg-based vaccines.

Abstract Prostate cancer (PCa) development and progression relies on the programming of glucose and lipid metabolism, and this involves alterations in androgen receptor expression and signalling. Defining the molecular mechanism that underpins this metabolic programming will have direct significance for patients with PCa who have a poor prognosis. Here we show that there is a dynamic balance between sortilin and syndecan-1, that reports on different metabolic phenotypes. Using tissue microarrays, we demonstrated by immunohistochemistry that sortilin was highly expressed in low-grade cancer, while syndecan-1 was upregulated in high-grade disease. Mechanistic studies in prostate cell lines revealed that in androgen-sensitive LNCaP cells, sortilin enhanced glucose metabolism by regulating GLUT1 and GLUT4, while binding progranulin and lipoprotein lipase (LPL) to limit lipid metabolism. In contrast, in androgen-insensitive PC3 cells, syndecan-1 was upregulated, interacted with LPL and colocalised with β3 integrin to promote lipid metabolism. In addition, androgen-deprived LNCaP cells had decreased expression of sortilin and reduced glucose-metabolism, but increased syndecan-1 expression, facilitating interactions with LPL and possibly β3 integrin. We report a hitherto unappreciated molecular mechanism for PCa, which may have significance for disease progression and how androgen-deprivation therapy might promote castration-resistant PCa.

Microgravity in spaceflight produces headward fluid shifts which probably contribute to Spaceflight-Associated Neuro-Ocular Syndrome (SANS). Developing new methods to mitigate these shifts is crucial for preventing SANS. One possible strategy is the use of self-generated lower body negative pressure (LBNP). This study evaluates biological or physiological effects induced by bed rest to simulate adaptations to microgravity. Participants were tested during powered LBNP and dynamic self-generated (SELF) LBNP at 25 mmHg for 15 min. The results were compared to the physiologic responses observed in seated upright and supine positions without LBNP, which served as controls for normal gravitational effects on fluid dynamics. Eleven participants’ (five male, six female) heart rates, blood pressures, and cross-sectional areas (CSA) of left and right internal jugular veins (IJV) were monitored. Self-generated LBNP, which requires mild to moderate physical activity, significantly elevated heart rate and blood pressure (p < 0.01). Self-generated LBNP also significantly reduced right IJV CSA compared to supine position (p = 0.005), though changes on the left side were not significant (p = 0.365). While the effects of SELF and traditional LBNP on IJV CSA were largely similar, traditional LBNP significantly reduced IJV CSA on both sides. Given its low mass, volume, and power requirements, SELF LBNP is a promising countermeasure against SANS. Results from this study warrant longer-term studies of SELF LBNP under simulated spaceflight conditions.

Nest survival drives population demographics of most avian species. Researchers and managers have focused studies on investigating nest success in association with climate, land use change (e.g., agriculture), and predators in the Prairie and Arctic biomes. The Boreal Forest is also an important breeding area for ducks and it has undergone rapid land use change caused by industrial development (e.g., oil and gas; forestry). However, duck nesting ecology has received little attention in this biome. Therefore, we investigated nest survival of upland nesting ducks in the Western Boreal Forest of Alberta, Canada, from 2016–2018. We evaluated how daily nest survival rates (N = 96) were affected by a suite of natural and anthropogenic variables measured at the nest-site (microhabitat) and landscape level (macrohabitat). Nest survival was low (0.212 [85% CI: 0.152–0.282]) and comparable to nest survival estimates for ducks elsewhere in North America, including the Prairies. Nest survival increased with nest age and varied annually. At the microhabitat scale, nest survival increased with greater graminoid, forb, and shrub cover at the nest. At the macrohabitat scale, habitat influenced nest survival at coarse spatial scales with lower survival for nests with greater mineral wetland cover within 2500 m and greater survival with more forest cover within 5000 m. For anthropogenic variables, nests had greater survival with increased densities of pipelines and roads within 90 and 30 m of a nest, respectively. Contrary to our predictions, we did not find evidence that oil and gas development negatively affected duck nest survival. Comparisons with research on nest-site selection reveals both adaptive and maladaptive strategies for nest survival and suggests that some resources might be selected at an adaptive peak. Our findings highlight the importance of investigating the effects of anthropogenic disturbance at multiple scales and life history stages to gain a more nuanced understanding of species responses to land use change.

Abstract Resistance training is a method of enhancing strength, gait speed, mobility, and health. However, the external load required to induce these benefits is a contentious issue. A growing body of evidence suggests that when lower load resistance training [i.e., loads 70% of 1RM) training and in many cases can promote similar or even superior physiological adaptations. Such findings are important given that confidence with external loads and access to training facilities and equipment are commonly cited barriers to regular resistance training. Here, we review some of the mechanisms and physiological changes in response to lower load resistance training. We also consider the evidence for applying lower loads for those at risk of cardiovascular and metabolic diseases and those with reduced mobility. Finally, we provide practical recommendations, specifically that to maximize the benefits of lower load resistance training, high levels of effort and training in close proximity to concentric failure are required. Additionally, using lower loads 2–3 times per week with 3–4 sets per exercise, and loads no lower than 30% of 1RM can enhance muscle hypertrophy and strength adaptations. Consequently, implementing lower load resistance training can be a beneficial and viable resistance training method for a wide range of fitness- and health-related goals.

Abstract Background The clinical manifestation of COVID-19 is associated with infection and inflammation of the lungs, but there is evidence to suggest that COVID-19 may also affect the structure and function of the cardiovascular system. At present, it is not fully understood to what extent COVID-19 impacts cardiovascular function in the short- and long-term following infection. The aim of the present study is twofold: (i) to define the effect of COVID-19 on cardiovascular function (i.e. arterial stiffness, cardiac systolic and diastolic function) in otherwise healthy individuals and (ii) to evaluate the effect of a home-based physical activity intervention on cardiovascular function in people with a history of COVID-19. Methods This prospective, single-centre, observational study will recruit 120 COVID-19-vaccinated adult participants aged between 50 and 85 years, i.e. 80 with a history of COVID-19 and 40 healthy controls without a history of COVID-19. All participants will undergo baseline assessments including 12-lead electrocardiography, heart rate variability, arterial stiffness, rest and stress echocardiography with speckle tracking imaging, spirometry, maximal cardiopulmonary exercise testing, 7-day physical activity and sleep measures and quality of life questionnaires. Blood samples will be collected to assess the microRNA expression profiles, cardiac and inflammatory biomarkers, i.e. cardiac troponin T; N-terminal pro B-type natriuretic peptide; tumour necrosis factor alpha; interleukins 1, 6 and 10; C-reactive protein; d-dimer; and vascular endothelial growth factors. Following baseline assessments, COVID-19 participants will be randomised 1:1 into a 12-week home-based physical activity intervention aiming to increase their daily number of steps by 2000 from baseline. The primary outcome is change in left ventricular global longitudinal strain. Secondary outcomes are arterial stiffness, systolic and diastolic function of the heart, functional capacity, lung function, sleep measures, quality of life and well-being (depression, anxiety, stress and sleep efficiency). Discussion The study will provide insights into the cardiovascular implications of COVID-19 and their malleability with a home-based physical activity intervention. Trial registration ClinicalTrials.gov NCT05492552. Registered on 7 April 2022.

Introduction: Kidney blood oxygenation level dependent (BOLD) magnetic resonance imaging (MRI) has shown great promise in evaluating relative oxygen availability. This method is quite efficacious in evaluating acute responses to physiological and pharmacologic maneuvers. Its outcome parameter, R2∗ is defined as the apparent spin-spin relaxation rate measured in the presence of magnetic susceptibility differences and it is measured using gradient echo MRI. Although associations between R2∗ and renal function decline have been described, it remains uncertain to what extent R2∗ is a true reflection of tissue oxygenation. This is primarily because of not taking into account the confounding factors, especially fractional blood volume (fBV) in tissue. Methods: This case-control study included 7 healthy controls and 6 patients with diabetes and chronic kidney disease (CKD). Using data before and after administration of ferumoxytol, a blood pool MRI contrast media, the fBVs in kidney cortex and medulla were measured. Results: This pilot study independently measured fBV in kidney cortex (0.23 ± 0.03 vs. 0.17 ± 0.03) and medulla (0.36 ± 0.08 vs. 0.25 ± 0.03) in a small number of healthy controls (n = 7) versus CKD (n = 6). These were then combined with BOLD MRI measurements to estimate oxygen saturation of hemoglobin (StO2) (0.87 ± 0.03 vs. 0.72 ± 0.10 in cortex; 0.82 ± 0.05 vs. 0.72 ± 0.06 in medulla) and partial pressure of oxygen in blood (bloodPO2) (55.4 ± 6.5 vs. 38.4 ± 7.6 mm Hg in cortex; 48.4 ± 6.2 vs. 38.1 ± 4.5 mm Hg in medulla) in control versus CKD. The results for the first time demonstrate that cortex is normoxemic in controls and moderately hypoxemic in CKD. In the medulla, it is mildly hypoxemic in controls and moderately hypoxemic in CKD. Whereas fBV, StO2, and bloodPO2 were strongly associated with estimated glomerular filtration rate (eGFR), R2∗ was not. Conclusion: Our results support the feasibility of quantitatively assessing oxygen availability using noninvasive quantitative BOLD MRI that could be translated to the clinic.

Abstract Objectives CAR‐T cells are being investigated as a novel immunotherapy for glioblastoma, but clinical success has been limited. We recently described fibroblast activation protein (FAP) as an ideal target antigen for glioblastoma immunotherapy, with expression on both tumor cells and tumor blood vessels. However, CAR‐T cells targeting FAP have never been investigated as a therapy for glioblastoma. Methods We generated a novel FAP targeting CAR with CD3ζ and CD28 signalling domains and tested the resulting CAR‐T cells for their lytic activity and cytokine secretion function in vitro (using real‐time impedance, flow cytometry, imaging and bead‐based cytokine assays), and in vivo (using a xenograft mimicking the natural heterogeneity of human glioblastoma). Results FAP‐CAR‐T cells exhibited target specificity against model cell lines and potent cytotoxicity against patient‐derived glioma neural stem cells, even when only a subpopulation expressed FAP, indicating a bystander killing mechanism. Using co‐culture assays, we confirmed FAP‐CAR‐T cells mediate bystander killing of antigen‐negative tumor cells, but only after activation by FAP‐positive target cells. This bystander killing was at least partially mediated by soluble factors and amplified by IL‐2 which activated the non‐transduced fraction of the CAR‐T product. Finally, a low dose of intravenously administered FAP‐CAR‐T cells controlled, without overt toxicity, the growth of subcutaneous tumors created using a mixture of antigen‐negative and antigen‐positive glioblastoma cells. Conclusions Our findings advance FAP as a leading candidate for clinical CAR‐T therapy of glioblastoma and highlight under‐recognised antigen nonspecific mechanisms that may contribute meaningfully to the antitumor activity of CAR‐T cells.

Age is a key risk factor for cardiovascular disease, including atherosclerosis. However, pathophysiological disease processes in the arteries are not an inevitable feature of aging. Large cohort studies with arterial phenotyping along with clinical and demographic data are essential to better understand factors related to the susceptibility or resilience to age-related vascular pathophysiology in humans. This review explores the mechanisms by which vascular structure and function alters with age, and how these changes relate to cardiovascular pathophysiology and disease. Features of vascular aging in the coronary arteries have historically been difficult to quantify pre-mortem due to their size and location. However, non-invasive imaging modalities including CT Coronary Angiogram are now being used to assess coronary vascular age, and further advances in imaging analysis such as the CT Fat Attenuation Index will help provide further measurement of features associated with coronary vascular aging. Currently, markers of vascular aging are not used as therapeutic targets in routine clinical practice, but non-pharmacological interventions including aerobic exercise and low salt diet, as well as anti-hypertensives have been demonstrated to reduce arterial stiffness. Advances in imaging technology, both in acquisition and advanced analysis, as well as harmonisation of measurements for researchers across the globe will be invaluable in understanding what constitutes healthy vascular aging and in identifying features of vascular aging that are associated with coronary artery disease and its adverse outcomes. Assessing such images in large cohorts can facilitate improved definitions of resilient and susceptible phenotypes to vascular aging in the coronary arteries. This is a critical step in identifying further risk factors and biomarkers within these groups and driving forward the development of novel therapies aimed at slowing or stopping age-related vascular changes in the coronary arteries.

Optimal dietary intake of omega-3 long-chain polyunsaturated fatty acids (n3-LCPUFAs) is critical to human health across the lifespan. However, omega-3 index (O3I) determination is not routinely assessed due to complicated procedures for n3-LCPUFA analysis from the phospholipid (PL) fraction of erythrocytes. Herein, a high-throughput method for lipidomics based on multisegment injection-nonaqueous capillary electrophoresis-mass spectrometry was applied to identify circulating PLs as surrogate biomarkers of O3I in two randomized placebo-controlled trials. An untargeted lipidomic data workflow using a subgroup analysis of serum extracts from sunflower oil versus high-dose fish oil (FO)-supplemented participants revealed that ingested n3-LCPUFAs were primarily distributed as their phosphatidylcholines (PCs) relative to other PL classes. In both high-dose FO (5.0 g/day) and EPA-only trials (3.0 g/day), PC (16:0_20:5) was the most responsive PL, whereas PC (16:0_22:6) was selective to DHA-only supplementation. We also demonstrated that the sum concentration of both these PCs in fasting serum or plasma samples was positively correlated to the O3I following FO (r = 0.708, P = 1.02 × 10−11, n = 69) and EPA- or DHA-only supplementation (r = 0.768, P = 1.01 × 10−33, n = 167). Overall, DHA was more effective in improving the O3I (ΔO3I = 4.90 ± 1.33%) compared to EPA (ΔO3I = 2.99 ± 1.19%) in young Canadian adults who had a poor nutritional status with an O3I (3.50 ± 0.68%) at baseline. Our method enables the rapid assessment of the O3I by directly measuring two circulating PC species in small volumes of blood, which may facilitate screening applications for population and precision health.

Current SARS-CoV-2 variants evade immune responses induced by approved vaccines. In this study, the authors find that a recombinant prefusion-stabilized Beta spike protein vaccine confers broad neutralization capacity in mice and non-human primates as well as protective antibody and immune memory responses.

Abstract Vaccination with glucan particles (GP) containing the Cryptococcus neoformans chitin deacetylases Cda1 and Cda2 protect mice against experimental cryptococcosis. Here, immunological correlates of vaccine-mediated protection were explored. Studies comparing knockout and wild-type mice demonstrated CD4+ T cells are crucial, while B cells and CD8+ T cells are dispensable. Protection was abolished following CD4+ T cell depletion during either vaccination or infection but was retained if CD4+ T cells were only partially depleted. Vaccination elicited systemic and durable antigen-specific immune responses in peripheral blood mononuclear cells (PBMCs), spleens, and lungs. Following vaccination and fungal challenge, robust T-helper (Th) 1 and Th17 responses were observed in the lungs. Protection was abrogated in mice congenitally deficient in interferon (IFN) γ, IFNγ receptor, interleukin (IL)-1β, IL-6, or IL-23. Thus, CD4+ T cells and specific proinflammatory cytokines are required for GP-vaccine-mediated protection. Importantly, retention of protection in the setting of partial CD4+ T depletion suggests a pathway for vaccinating at-risk immunocompromised individuals.

ABSTRACT Inhalation of airborne conidia of the ubiquitous fungus Aspergillus fumigatus commonly occurs but invasive aspergillosis is rare except in profoundly immunocompromised persons. Severe influenza predisposes patients to invasive pulmonary aspergillosis by mechanisms that are poorly defined. Using a post-influenza aspergillosis model, we found that superinfected mice had 100% mortality when challenged with A. fumigatus conidia on days 2 and 5 (early stages) of influenza A virus infection but 100% survival when challenged on days 8 and 14 (late stages). Influenza-infected mice superinfected with A. fumigatus had increased levels of the pro-inflammatory cytokines and chemokines interleukin (IL)-6, tumor necrosis factor (TNF)α, interferon (IFN)β, IL-12p70, IL-1α, IL-1β, CXC motif chemokine ligand 1 (CXCL1), granulocyte-colony-stimulating factor (G-CSF), macrophage inflammatory protein (MIP)-1α, MIP-1β, regulated upon activation, normal T cell expressed and presumably secreted (RANTES), and monocyte chemoattractant protein (MCP)-1. Surprisingly, on histopathological analysis, superinfected mice did not have greater lung inflammation compared with mice infected with influenza alone. Mice infected with influenza had dampened neutrophil recruitment to the lungs following subsequent challenge with A. fumigatus, but only if the fungal challenge was executed during the early stages of influenza infection. However, influenza infection did not have a major effect on neutrophil phagocytosis and killing of A. fumigatus conidia. Moreover, minimal germination of conidia was seen on histopathology even in the superinfected mice. Taken together, our data suggest that the high mortality rate seen in mice during the early stages of influenza-associated pulmonary aspergillosis is multifactorial with a greater contribution from dysregulated inflammation than microbial growth. IMPORTANCE Severe influenza is a risk factor for fatal invasive pulmonary aspergillosis; however, the mechanistic basis for the lethality is unclear. Utilizing an influenza-associated pulmonary aspergillosis (IAPA) model, we found that mice infected with influenza A virus followed by Aspergillus fumigatus had 100% mortality when superinfected during the early stages of influenza but survived at later stages. While superinfected mice had dysregulated pulmonary inflammatory responses compared to controls, they had neither increased inflammation nor extensive fungal growth. Although influenza-infected mice had dampened neutrophil recruitment to the lungs following subsequent challenge with A. fumigatus, influenza did not affect the ability of neutrophils to clear the fungi. Our data suggest that the lethality seen in our model of IAPA is multifactorial with dysregulated inflammation being a greater contributor than uncontrollable microbial growth. If confirmed in humans, our findings provide a rationale for clinical studies of adjuvant anti-inflammatory agents in the treatment of IAPA.

Although several reports have hypothesized that exercise may increase skeletal muscle protein lactylation, empirical evidence in humans is lacking. Thus, we adopted a multi-faceted approach to examine if acute and subchronic resistance training (RT) altered skeletal muscle protein lactylation levels. In mice, we also sought to examine if surgical ablation-induced plantaris hypertrophy coincided with increases in muscle protein lactylation. To examine acute responses, participants’ blood lactate concentrations were assessed before, during, and after eight sets of an exhaustive lower body RT bout (n = 10 trained college-aged men). Vastus lateralis biopsies were also taken before, 3-h post, and 6-h post-exercise to assess muscle protein lactylation. To identify training responses, another cohort of trained college-aged men (n = 14) partook in 6 weeks of lower-body RT (3x/week) and biopsies were obtained before and following the intervention. Five-month-old C57BL/6 mice were subjected to 10 days of plantaris overload (OV, n = 8) or served as age-matched sham surgery controls (Sham, n = 8). Although acute resistance training significantly increased blood lactate responses ∼7.2-fold (p < 0.001), cytoplasmic and nuclear protein lactylation levels were not significantly altered at the post-exercise time points, and no putative lactylation-dependent mRNA was altered following exercise. Six weeks of RT did not alter cytoplasmic protein lactylation (p = 0.800) despite significantly increasing VL muscle size (+3.5%, p = 0.037), and again, no putative lactylation-dependent mRNA was significantly affected by training. Plantaris muscles were larger in OV versus Sham mice (+43.7%, p < 0.001). However, cytoplasmic protein lactylation was similar between groups (p = 0.369), and nuclear protein lactylation was significantly lower in OV versus Sham mice (p < 0.001). The current null findings, along with other recent null findings in the literature, challenge the thesis that lactate has an appreciable role in promoting skeletal muscle hypertrophy.

Abstract While numerous targeted therapies have been recently adopted to improve the treatment of hematologic malignancies, acquired or intrinsic resistance poses a significant obstacle to their efficacy. Thus, there is increasing need to identify novel, targetable pathways to further improve therapy for these diseases. The integrated stress response is a signaling pathway activated in cancer cells in response to both dysregulated growth and metabolism, and also following exposure to many therapies that appears one such targetable pathway for improved treatment of these diseases. In this review, we discuss the role of the integrated stress response in the biology of hematologic malignancies, its critical involvement in the mechanism of action of targeted therapies, and as a target for pharmacologic modulation as a novel strategy for the treatment of hematologic malignancies.

A heterologous protein expression platform in a culturable methanogen Methanococcus maripaludis is developed to study the methyl-coenzyme M reductase from uncultured archaea.

Abstract Human cervicovaginal fluid (CVF) is a complex, functionally important and glycan rich biological fluid, fundamental in mediating physiological events associated with reproductive health. Using a comprehensive glycomic strategy we reveal an extremely rich and complex N-glycome in CVF of pregnant and non-pregnant women, abundant in paucimannose and high mannose glycans, complex glycans with 2–4 N-Acetyllactosamine (LacNAc) antennae, and Poly-LacNAc glycans decorated with fucosylation and sialylation. N-glycosylation profiles were observed to differ in relation to pregnancy status, microbial composition, immune activation, and pregnancy outcome. Compared to CVF from women experiencing term birth, CVF from women who subsequently experienced preterm birth showed lower sialylation, which correlated to the presence of a diverse microbiome, and higher fucosylation, which correlated positively to pro-inflammatory cytokine concentration. This study is the first step towards better understanding the role of cervicovaginal glycans in reproductive health, their contribution to the mechanism of microbial driven preterm birth, and their potential for preventative therapy.

Changes in glycoprotein expression are correlates of disease, but secreted glycoproteins cannot be accurately traced to their cell line of origin. Here, the authors develop a strategy to chemically tag and profile glycoproteins in a cell line-specific manner in co-culture systems and in vivo.

Abstract The compound β‐hydroxy‐β‐methyl butyrate (HMB) is proposed to increase or mitigate the loss of skeletal muscle and improve muscle function. We undertook a review of systematic reviews of HMB supplementation to promote gains or mitigate muscle loss in ageing and clinical populations. Following PRISMA guidelines, we searched for systematic reviews reporting the effect of HMB in our target populations. Dual‐energy X‐ray absorptiometry (DXA) measured lean soft‐tissue mass (LSTM) was accepted as a proxy for muscle. We identified 15 systematic reviews that met our inclusion criteria, which were independently evaluated. The methodological quality of the reviews was assessed using A Measurement Tool to Assess Systematic Reviews (AMSTAR), and standardized effectiveness statements were generated. Five of 15 studies found some evidence that HMB augmented LSTM; the remaining 10 studies reported some evidence favouring no difference (6/10 studies) or insufficient evidence to determine an effect (4/10 studies). Of the 12 studies that evaluated strength, 4/12 found some evidence, 5/12 found some evidence of no effect with one article finding some evidence in favour of patients in peri‐hospitalized and no evidence for those that are community‐dwelling, 4/12 had insufficient evidence to determine an effect, and 1/12 had insufficient evidence. No]study reported a positive effect of HMB on physical function; however, 2/10 studies found some evidence favouring no effect, and 7/10 studies reported insufficient evidence to determine an effect. The effectiveness of HMB supplementation in augmenting LSTM was heterogeneous, with most reviews finding no effect or inconclusive evidence to determine an effect. Most reviews concluded that HMB supplementation did not affect strength outcome measures or studies were inconclusive. The current evidence is insufficient to assess the impact of HMB supplementation on functional outcome measures. Our analysis shows minor, inconsistent support for HMB as part of an oral nutritional supplement or as a stand‐alone supplement (or combined with other amino acids) to increase or promote retention of LSTM, improve strength, and no evidence that it improves physical function in older persons or clinical populations.

A surgical method in mice can selectively remove dorsal root ganglia (DRG) at specific spinal levels without interfering with other nerves, providing insight on thoracolumbar vs. lumbosacral DRG contributions to pain signalling and behaviour.

Abstract Background We determined the short‐term (i.e. 4 days) impacts of disuse atrophy in relation to muscle protein turnover [acute fasted‐fed muscle protein synthesis (MPS)/muscle protein breakdown (MPB) and integrated MPS/estimated MPB]. Methods Healthy men (N = 9, 22 ± 2 years, body mass index 24 ± 3 kg m−2) underwent 4 day unilateral leg immobilization. Vastus lateralis (VL) muscle thickness (MT) and extensor strength and thigh lean mass (TLM) were measured. Bilateral VL muscle biopsies were collected on Day 4 at t = −120, 0, 90, and 180 min to determine integrated MPS, estimated MPB, acute fasted‐fed MPS (l‐[ring‐13C6]‐phe), and acute fasted tracer decay rate representative of MPB (l‐[15N]‐phe and l‐[2H8]‐phe). Protein turnover cell signalling was measured by immunoblotting. Results Immobilization decreased TLM [pre: 7477 ± 1196 g, post: 7352 ± 1209 g (P 0.05). Conclusions Human skeletal muscle disuse atrophy is driven by declines in MPS, not increases in MPB. Pro‐anabolic therapies to mitigate disuse atrophy would likely be more effective than therapies aimed at attenuating protein degradation.

Abstract Potential benefits of precision medicine in cardiovascular disease (CVD) include more accurate phenotyping of individual patients with the same condition or presentation, using multiple clinical, imaging, molecular and other variables to guide diagnosis and treatment. An approach to realising this potential is the digital twin concept, whereby a virtual representation of a patient is constructed and receives real-time updates of a range of data variables in order to predict disease and optimise treatment selection for the real-life patient. We explored the term digital twin, its defining concepts, the challenges as an emerging field, and potentially important applications in CVD. A mapping review was undertaken using a systematic search of peer-reviewed literature. Industry-based participants and patent applications were identified through web-based sources. Searches of Compendex, EMBASE, Medline, ProQuest and Scopus databases yielded 88 papers related to cardiovascular conditions (28%, n = 25), non-cardiovascular conditions (41%, n = 36), and general aspects of the health digital twin (31%, n = 27). Fifteen companies with a commercial interest in health digital twin or simulation modelling had products focused on CVD. The patent search identified 18 applications from 11 applicants, of which 73% were companies and 27% were universities. Three applicants had cardiac-related inventions. For CVD, digital twin research within industry and academia is recent, interdisciplinary, and established globally. Overall, the applications were numerical simulation models, although precursor models exist for the real-time cyber-physical system characteristic of a true digital twin. Implementation challenges include ethical constraints and clinical barriers to the adoption of decision tools derived from artificial intelligence systems.