Effect of ice slurry ingestion on thermoregulatory responses during fixed-intensity cycling in humid and dry heat.

PURPOSE: This study examined the thermoregulatory response and ergogenic effects of ice slurry (ICE) ingestion in hot environments with high and low relative humidity (RH). METHODS: Eight males completed four trials in a crossover manner in dry (DRY: 34.7 ± 0.2 °C, 38 ± 2%RH) and humid heat (HUM: 34.8 °C ± 0.2 °C, 80 ± 1%RH). They ingested 8.0 g·kg-1 of ICE (0.0 °C) or 37.5 °C water (CON) during 30 min before exercise, and three aliquots (3.2 g·kg-1) of ICE or CON during 45-min cycling at 50%[Formula: see text]O2peak, followed by cycling to exhaustion at 80%[Formula: see text]O2peak (TTE). Body core temperature (Tcore), mean skin temperature (Tsk), heart rate (HR), thermal comfort, thermal sensation and rating of perceived exertion (RPE) were measured. RESULTS: Relative to CON, ICE improved TTE by 76.5 ± 96.5% in HUM and 21.3 ± 44.9% in DRY (p = 0.044). End-exercise Tcore was lower in ICE versus CON in DRY (37.8 ± 0.4 °C versus 38.1 ± 0.3 °C, p = 0.005) and HUM (38.8 ± 0.4 °C versus 39.3 ± 0.6 °C, p = 0.004). ICE decreased HR, heat storage and heat strain index only in DRY (p < 0.001-0.018). ICE improved thermal sensation and comfort in DRY and HUM (p < 0.001-0.011), attenuated RPE in HUM (p = 0.012) but not in DRY (p = 0.065). CONCLUSION: ICE tended to benefit performance in humid heat more than in dry heat. This is likely due to the reduced extent of hyperthermia in dry heat and the relative importance of sensory inputs in mediating exercise capacity.

The ER-Golgi transport of influenza virus through NS1-Sec13 association during virus replication.

IMPORTANCE: Influenza A virus is a respiratory virus that can cause complications such as acute bronchitis and secondary bacterial pneumonia. Drug therapies and vaccines are available against influenza, albeit limited by drug resistance and the non-universal vaccine administration. Hence there is a need for host-targeted therapies against influenza to provide an effective alternative therapeutic target. Sec13 was identified as a novel host interactor of influenza. Endoplasmic reticulum-to-Golgi transport is an important pathway of influenza virus replication and viral export. Specifically, Sec13 has a functional role in influenza replication and virulence.

Durable cross-protective neutralizing antibody responses elicited by lipid nanoparticle-formulated SARS-CoV-2 mRNA vaccines.

The advent of SARS-CoV-2 variants with defined mutations that augment pathogenicity and/or increase immune evasiveness continues to stimulate global efforts to improve vaccine formulation and efficacy. The extraordinary advantages of lipid nanoparticles (LNPs), including versatile design, scalability, and reproducibility, make them ideal candidates for developing next-generation mRNA vaccines against circulating SARS-CoV-2 variants. Here, we assess the efficacy of LNP-encapsulated mRNA booster vaccines encoding the spike protein of SARS-CoV-2 for variants of concern (Delta, Omicron) and using a predecessor (YN2016C isolated from bats) strain spike protein to elicit durable cross-protective neutralizing antibody responses. The mRNA-LNP vaccines have desirable physicochemical characteristics, such as small size (~78 nm), low polydispersity index (<0.13), and high encapsulation efficiency (>90%). We employ in vivo bioluminescence imaging to illustrate the capacity of our LNPs to induce robust mRNA expression in secondary lymphoid organs. In a BALB/c mouse model, a three-dose subcutaneous immunization of mRNA-LNPs vaccines achieved remarkably high levels of cross-neutralization against the Omicron B1.1.529 and BA.2 variants for extended periods of time (28 weeks) with good safety profiles for all constructs when used in a booster regime, including the YN2016C bat virus sequences. These findings have important implications for the design of mRNA-LNP vaccines that aim to trigger durable cross-protective immunity against the current and newly emerging variants.

Mild Behavioral Impairment and Cerebrovascular Profiles Are Associated with Early Cognitive Impairment in a Community-Based Southeast Asian Cohort.

Background: Mild behavioral impairment (MBI) is one of the earliest observable changes when a person experiences cognitive decline and could be an early manifestation of underlying Alzheimer's disease neuropathology. Limited attention has been given to investigating the clinical applicability of behavioral biomarkers for detection of prodromal dementia. Objective: This study compared the prevalence of self-reported MBI and vascular risk factors in Southeast Asian adults to identify early indicators of cognitive impairment and dementia. Methods: This cohort study utilized baseline data from the Biomarkers and Cognition Study, Singapore (BIOCIS). 607 participants were recruited and classified into three groups: cognitively normal (CN), subjective cognitive decline (SCD), and mild cognitive impairment (MCI). Group comparisons of cognitive-behavioral, neuroimaging, and blood biomarkers data were applied using univariate analyses. Multivariate logistic regression analyses were conducted to investigate the association between cerebrovascular disease, vascular profiles, and cognitive impairment. Results: SCD had significantly higher depression scores and poorer quality of life (QOL) compared to CN. MCI had significantly higher depression scores; total MBI symptoms, MBI-interest, MBI-mood, and MBI-beliefs; poorer sleep quality; and poorer QOL compared to CN. Higher Staals scores, glucose levels, and systolic blood pressure were significantly associated with MCI classification. Fasting glucose levels were significantly correlated with depression, anxiety, MBI-social, and poorer sleep quality. Conclusions: The results reflect current research that behavioral changes are among the first symptoms noticeable to the person themselves as they begin to experience cognitive decline. Self-reported questionnaires may aid in early diagnoses of prodromal dementia. Behavioral changes and diabetes could be potential targets for preventative healthcare for dementia.

Macrophage IL-1ß contributes to tumorigenesis through paracrine AIM2 inflammasome activation in the tumor microenvironment.

Intracellular recognition of self and non-self -nucleic acids can result in the initiation of effective pro-inflammatory and anti-tumorigenic responses. We hypothesized that macrophages can be activated by tumor-derived nucleic acids to induce inflammasome activation in the tumor microenvironment. We show that tumor conditioned media (CM) can induce IL-1ß production, indicative of inflammasome activation in primed macrophages. This could be partially dependent on caspase 1/11, AIM2 and NLRP3. IL-1ß enhances tumor cell proliferation, migration and invasion while coculture of tumor cells with macrophages enhances the proliferation of tumor cells, which is AIM2 and caspase 1/11 dependent. Furthermore, we have identified that DNA-RNA hybrids could be the nucleic acid form which activates AIM2 inflammasome at a higher sensitivity as compared to dsDNA. Taken together, the tumor-secretome stimulates an innate immune pathway in macrophages which promotes paracrine cancer growth and may be a key tumorigenic pathway in cancer. Broader understanding on the mechanisms of nucleic acid recognition and interaction with innate immune signaling pathway will help us to better appreciate its potential application in diagnostic and therapeutic benefit in cancer.

A Nonexercise Estimate of Cardiorespiratory Fitness Using a Symptom Questionnaire and Clinical Variables.

PURPOSE: Cardiorespiratory fitness (CRF) has recently been recognized as a risk factor for mortality, but it is not routinely measured in clinical settings. The purpose of this study was to assess a nonexercise method to estimate CRF (eCRF) and its association with mortality in a clinically referred population. METHODS: A symptom tool, termed the Veterans Specific Activity Questionnaire (VSAQ), and nonexercise clinical variables were obtained from 1545 clinically referred subjects (60 ± 13 yr), and followed for a mean of 5.6 ± 4.2 yr. The VSAQ along with nonexercise clinical and historical variables was used to develop a multivariate model to predict achieved CRF from maximal exercise testing. Proportional hazards analysis was used to assess the association between measured and eCRF and all-cause mortality. RESULTS: The eCRF model was significantly associated with achieved CRF (multiple R = 0.67, P < .001). Mean achieved CRF from maximal treadmill testing and eCRF were similar (8.6 ± 5.0 metabolic equivalents [METs] vs 8.7 ± 4.7 METs respectively, P = .27). Achieved CRF and eCRF performed similarly for predicting mortality. After full adjustment, each 1 MET higher increment in achieved CRF and eCRF was associated with 19% and 26% reductions in mortality risk, respectively. Compared with the lowest fit group (<5 METs), the highest CRF groups (>11 METs) had 88% and 87% lower risks for mortality for achieved CRF and eCRF, respectively. CONCLUSIONS: A multivariable nonexercise model featuring a symptom questionnaire combined with clinical variables that are readily available during a typical clinical encounter had a reasonably strong association with achieved CRF and exhibited prognostic characteristics that were similar to achieved CRF.

The Dentate Gyrus Classifies Cortical Representations of Learned Stimuli.

Animals must discern important stimuli and place them onto their cognitive map of their environment. The neocortex conveys general representations of sensory events to the hippocampus, and the hippocampus is thought to classify and sharpen the distinctions between these events. We recorded populations of dentate gyrus granule cells (DG GCs) and lateral entorhinal cortex (LEC) neurons across days to understand how sensory representations are modified by experience. We found representations of odors in DG GCs that required synaptic input from the LEC. Odor classification accuracy in DG GCs correlated with future behavioral discrimination. In associative learning, DG GCs, more so than LEC neurons, changed their responses to odor stimuli, increasing the distance in neural representations between stimuli, responding more to the conditioned and less to the unconditioned odorant. Thus, with learning, DG GCs amplify the decodability of cortical representations of important stimuli, which may facilitate information storage to guide behavior.