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Purpose of ReviewExcess sodium from dietary salt (NaCl) is linked to elevations in blood pressure (BP). However, salt sensitivity of BP varies widely between individuals and there are data suggesting that salt adversely affects target organs, irrespective of BP.Recent Findings High dietary salt has been shown to adversely affect the vasculature, heart, kidneys, skin, brain, and bone. Common mediators of the target organ dysfunction include heightened inflammation and oxidative stress. These physiological alterations may contribute to disease development over time. Despite the adverse effects of salt on BP and several organ systems, there is controversy surrounding lower salt intakes and cardiovascular outcomes.SummaryOur goal here is to review the physiology contributing to BP-independent effects of salt and address the controversy around lower salt intakes and cardiovascular outcomes. We will also address the importance of background diet in modulating the effects of dietary salt.

Despite decades of efforts to reduce sodium intake, excess dietary sodium remains commonplace, and contributes to increased cardiovascular morbidity and mortality independent of its effects on blood pressure. An increasing amount of research suggests that high-sodium diets lead to reduced nitric oxide-mediated endothelial function, even in the absence of a change in blood pressure. As endothelial dysfunction is an early step in the progression of cardiovascular diseases, the endothelium presents a target for interventions aimed at reducing the impact of excess dietary sodium. In this review, we briefly define endothelial function and present the literature demonstrating that excess dietary sodium results in impaired endothelial function. We then discuss the mechanisms through which sodium impairs the endothelium, including increased reactive oxygen species, decreased intrinsic antioxidant defenses, endothelial cell stiffening, and damage to the endothelial glycocalyx. Finally, we present selected research findings suggesting that aerobic exercise or increased intake of dietary potassium may counteract the deleterious vascular effects of a high-sodium diet.

Previous studies in individuals with mild cognitive impairment suggest that they may have altered systemic metabolic function at rest; however, metabolic function during aerobic exercise is not fully understood in this population. This study sought to determine whether individuals with amnestic mild cognitive impairment (aMCI) have lower rates of baseline and peak fat oxidation (FatOx) during a graded exercise test (GXT) compared with cognitively unimpaired control participants (CU). Twenty‐two (22) older adults with aMCI and 21 age‐ and sex‐matched adults completed a GXT to assess rates of substrate oxidation and peak oxygen consumption (VO2 peak). Rates of FatOx and carbohydrate oxidation (CHOOx) were assessed using VO2 and VCO2. Resting absolute (0.10 ± 0.03 vs. 0.09 ± 0.02 g/min, p = 0.126) and relative (1.5 ± 0.43 vs. 1.4 ± 0.44 mg/kg/min, p = 0.492) rates of FatOx, as well as resting absolute (0.51 ± 0.11 vs. 0.59 ± 0.15 g/min, p = 0.093) and relative (8.0 ± 2.3 vs. 7.5 ± 2.7 mg/kg/min, p = 0.126) rates of CHOOx were similar between groups. However, peak absolute rates of FatOx (0.33 ± 0.13 vs. 0.39 ± 0.10 g/min, p = 0.033) and CHOOx (1.9 ± 0.41 vs. 2.2 ± 0.49 g/min, p = 0.046) were significantly lower in the aMCI group. Time to fatigue (7.2 ± 2.0 vs. 8.7 ± 2.3 min, p = 0.033) and absolute VO2 peak (1.3 ± 0.34 vs. 1.6 ± 0.47 L/min, p = 0.024) were also significantly lower in the aMCI group. These findings suggest that absolute peak rates of whole‐body FatOx and CHOOx are reduced during aerobic exercise in older adults with aMCI.

The mechanisms for the benefits of Angiotensin Receptor Neprilysin Inhibition (ARNi) in heart failure patients with reduced ejection fraction (HFrEF) are likely beyond blood pressure reduction. Measures of vascular function such as arterial stiffness and endothelial function are strong prognostic markers of cardiovascular outcomes in HFrEF, yet the impact of ARNi on vascular health remains to be explored. We hypothesized that arterial stiffness and endothelial function would improve after 12 weeks of ARNi in HFrEF. We tested 10 stable HFrEF patients at baseline and following 12 weeks of ARNi [64 ± 9 years, Men/Women: 9/1, left ventricular ejection fraction (EF): 28 ± 6%] as well as 10 stable HFrEF patients that remained on conventional treatment (CON: 60 ± 7 years, Men/Women: 6/4, EF: 31 ± 5%; all p = NS). Arterial stiffness was assessed via carotid‐femoral pulse wave velocity (PWV) and endothelial function was assessed via brachial artery flow‐mediated dilation (FMD). PWV decreased after 12 weeks of ARNi (9.0 ± 2.1 vs. 7.1 ± 1.2 m/s; p < 0.01) but not in CON (7.0 ± 2.4 vs. 7.5 ± 2.3 m/s; p = 0.35), an effect that remained when controlling for reductions in mean arterial pressure (p < 0.01). FMD increased after 12 weeks of ARNi (2.2 ± 1.9 vs. 5.5 ± 2.1%; p < 0.001) but not in CON (4.8 ± 3.8 vs. 5.4 ± 3.4%; p = 0.34). Baseline PWV (p = 0.06) and FMD (p = 0.07) were not different between groups. These preliminary data suggest that 12 weeks of ARNi therapy may reduce arterial stiffness and improve endothelial function in HFrEF. Thus, the findings from this pilot study suggest that the benefits of ARNi are beyond blood pressure reduction and include improvements in vascular function. ARNi may improve vascular function in HFrEF when compared to conventional treatment.

Chronic kidney disease (CKD) is an independent risk factor for the development of cardiovascular disease and is characterized by reduced nitric oxide (NO) bioavailability and vascular dysfunction, typically assessed using brachial artery flow‐mediated dilation (FMD). It has been previously reported that passive leg movement (PLM)‐induced hyperemia, an assessment of lower extremity vascular function, is highly dependent on NO, but has not yet been utilized to assess vascular function in patients with CKD. The purpose of this study was to comprehensively assess vascular function in patients with CKD using PLM, in addition to the traditional FMD technique. Assessment of vascular function via PLM and FMD was performed on 12 patients (CKD, 66 ± 3 years) and 16 age‐matched healthy controls (CON, 60 ± 2 years). Blood velocity and artery diameters during PLM and FMD were measured using duplex ultrasound of the femoral and brachial arteries, respectively. Habitual physical activity, assessed by accelerometry, was performed in a subset of each group. CKD patients had reduced peak leg blood flow (LBF) (384 ± 39 vs. 569 ± 77 mL/min, P < 0.05) and change in LBF from baseline to peak (∆peakLBF) (143 ± 22 vs. 249 ± 34 mL/min, P < 0.05) during PLM compared to CON. Additionally, PLM responses were significantly associated with kidney function and physical activity levels. As anticipated, FMD was significantly attenuated in CKD patients (5.2 ± 1.1 vs. 8.8 ± 1.2%, P < 0.05). In conclusion, both upper and lower extremity measures of vascular function indicate impairment in CKD patients when compared to controls. PLM appears to be a novel and feasible approach to assessing lower extremity vascular function in CKD. This study sought to determine whether lower extremity vascular dysfunction, as assessed by passive leg movement (PLM), is impaired in patients with chronic kidney diseae (CKD). As hypothesized, we observed a significantly diminished hyperemic response during PLM in CKD patients, suggesting impaired blood flow regulation and vascular dysfunction within the lower‐limb vasculature. We identified significant relationships between the hyperemic responses during PLM and kidney function, potentially providing insight on the dynamic relationship between kidney health, endothelial function, and risk of CVD development in older adults. Furthermore, we identified relationships between the magnitude of PLM hyperemia and habitual physical activity levels in all subjects. Taken together, these findings provide evidence of a widespread reduction in vascular responsiveness in patients with CKD which may be linked to the physical inactivity which is commonly reported in this population.

Declining national rates of current tobacco use to an all-time low of 15.1% represents a public health victory. Undermining this progress, however, are smoking rates of up to 50% among high-risk, low-income populations. Current FDA-approved treatments for nicotine dependence are ineffective with between 70-95% of treatment-seekers relapsing within the first year of attempted abstinence. Thus, identification of novel intervention targets to optimize response to currently available treatments for nicotine dependence is a critical next step. One such target may be sleep insomnia. Insomnia is a clinically verified nicotine withdrawal symptom but, to date, addressing insomnia or other sleep disturbance symptoms as an adjunctive smoking cessation therapy has yet to be fully considered. To this end, this manuscript presents a narrative review of: (1) sleep continuity and architecture in smokers versus nonsmokers; (2) effects of nicotine abstinence on sleep; (3) possible mechanisms linking sleep with smoking cessation outcomes; (4) plausible adjunctive sleep therapies to promote smoking cessation; (5) possible treatments for unhealthy sleep in smokers; and (6) directions for future research. Taken together, this will provide conceptual support for sleep therapy as an adjunctive treatment for smoking cessation. This narrative literature review presents a comprehensive discussion of the relationship between habitual sleep and cigarette smoking. The extent to which unhealthy sleep in smokers may be a viable intervention target for promoting response to smoking cessation treatment is considered. Ultimately, this review provides conceptual support for sleep therapy as an adjunctive treatment for smoking cessation.

Single-cell analysis of human triple-negative breast cancer revealed heterogeneous macrophage populations with opposing phenotypes - proinflammatory and proresolution of inflammation. Paradoxically, both subsets accumulated in therapy-refractory residual tumors but showed inverse correlations across patients, suggesting mutually exclusive resistance mechanisms. Inflammatory macrophages localized preferentially to epithelial-like tumors, whereas proresolution macrophages were enriched in mesenchymal-like tumors. Mouse models faithfully recapitulated these patterns. After chemoimmunotherapy, mesenchymal-like tumors expanded proresolution macrophages through phagocytosis/efferocytosis, ω-3 fatty acid uptake, and resolvin production. Macrophage-secreted C1q emerged as a principal antagonist of T cell function by targeting mitochondria and inducing metabolic dysfunction. By contrast, epithelial-like tumors accumulated inflammatory macrophages and neutrophils that produced prostaglandins via ω-6 fatty acid pathways. Knocking down ELOVL5 - an elongase involved in ω-3 and ω-6 metabolism - mitigated both neutrophil- and macrophage-mediated immunosuppression. These distinct axes, driven by dysregulated inflammation and resolution programs, converged to undermine therapy-induced immunosurveillance; however, targeting their shared upstream regulators may overcome these resistance mechanisms.

Abstract Study Objectives Vascular dysfunction is a hypothesized mechanism linking poor sleep habits to an increased incidence of cardiovascular diseases (CVDs). However, the vascular profile associated with free-living sleep duration and sleep regularity has not been well elucidated, particularly in young adults. Thus, this study aimed to evaluate the associations between mean sleep duration, regularity in sleep duration, and peripheral vascular function in young adult college students. Methods Fifty-one healthy undergraduate students (20 ± 1 years) completed 14 days of 24-hour wrist actigraphy and subsequent vascular assessments. Macrovascular function was measured using brachial artery flow-mediated dilation (FMD) while microvascular function was measured via passive leg movement (PLM). Results Mean sleep duration was unrelated to FMD and PLM. Conversely, more irregular sleep duration (14-day sleep duration standard deviation [SD]) was unfavorably associated with all three measures of PLM-induced hyperemia (peak leg blood flow [LBF], p = 0.01; change in LBF from baseline to peak, p < 0.01; LBF area under the curve, p < 0.01), and remained significant in regression models which adjusted for sex, body mass index, blood pressure, physical activity, alcohol and caffeine consumption, and sleep duration (all p < 0.05). When using a median split to dichotomize “low” and “high” sleep duration SD groups, those demonstrating high variability in sleep duration exhibited ~45% lower PLM responses compared with those demonstrating low variability. Conclusions Irregular sleep duration is associated with poorer microvascular function as early as young adulthood. These findings support the growing body of evidence that irregular sleep patterns may be an independent and modifiable risk factor for CVD.

• Caustis blakei produces an intriguing morphological adaptation by inducing dauciform roots in response to phosphorus (P) deficiency. We tested the hypothesis that these hairy, swollen lateral roots play a similar role to cluster roots in the exudation of organic chelators and ectoenzymes known to aid the chemical mobilization of sparingly available soil nutrients, such as P. • Dauciform-root development and exudate composition (carboxylates and acid phosphatase activity) were analysed in C. blakei plants grown in nutrient solution under P-starved conditions. The distribution of dauciform roots in the field was determined in relation to soil profile depth and matrix. • The percentage of dauciform roots of the entire root mass was greatest at the lowest P concentration ([P]) in solution, and was suppressed with increasing solution [P], while in the field dauciform roots were predominately located in the upper soil horizons, and decreased with increasing soil depth. Citrate was the major carboxylate released in an exudative burst from mature dauciform roots, which also produced elevated levels of acid phosphatase activity. Malonate was the dominant internal carboxylate present, with the highest concentration in young dauciform roots. • The high concentration of carboxylates and phosphatases released from dauciform roots, combined with their prolific distribution in the organic surface layer of nutrient-impoverished soils, provides an ecophysiological advantage for enhancing nutrient acquisition.

Solid tumours induce systemic immunosuppression that involves myeloid and T cells. B cell-related mechanisms remain relatively understudied. Here we discover two distinct patterns of tumour-induced B cell abnormality (TiBA; TiBA-1 and TiBA-2), both associated with abnormal myelopoiesis in the bone marrow. TiBA-1 probably results from the niche competition between pre-progenitor-B cells and myeloid progenitors, leading to a global reduction in downstream B cells. TiBA-2 is characterized by systemic accumulation of a unique early B cell population, driven by interaction with excessive neutrophils. Importantly, TiBA-2-associated early B cells foster the systemic accumulation of exhaustion-like T cells. Myeloid and B cells from the peripheral blood of patients with triple-negative breast cancer recapitulate the TiBA subtypes, and the distinct TiBA profile correlates with pathologic complete responses to standard-of-care immunotherapy. This study underscores the inter-patient diversity of tumour-induced systemic changes and emphasizes the need for treatments tailored to different B and myeloid cell abnormalities. Hao, Shen and colleagues identify and characterize two distinct types of myeloid–B cell interaction that may signal solid tumour-induced immunosuppression and can correlate with complete responses to immunotherapy in patients with breast cancer.