Aerobic exercise training (AET) has emerged as a strategy to reduce cancer mortality, however, the mechanisms explaining AET on tumor development remain unclear. Tumors escape immune detection by generating immunosuppressive microenvironments and impaired T cell function, which is associated with T cell mitochondrial loss. AET improves mitochondrial content and function, thus we tested whether AET would modulate mitochondrial metabolism in tumor-infiltrating lymphocytes (TIL). Balb/c mice were subjected to a treadmill AET protocol prior to CT26 colon carcinoma cells injection and until tumor harvest. Tissue hypoxia, TIL infiltration and effector function, and mitochondrial content, morphology and function were evaluated. AET reduced tumor growth, improved survival, and decreased tumor hypoxia. An increased CD8+ TIL infiltration, IFN-γ and ATP production promoted by AET was correlated with reduced mitochondrial loss in these cells. Collectively, AET decreases tumor growth partially by increasing CD8+ TIL effector function through an improvement in their mitochondrial content and function.

The purpose of this study was firstly to examine the sensitivity of heart rate (HR)-based and subjective monitoring markers to intensified endurance training; and secondly, to investigate the validity of these markers to distinguish individuals in different fatigue states. A total of 24 recreational runners performed a 3-week baseline period, a 2-week overload period, and a 1-week recovery period. Performance was assessed before and after each period with a 3000m running test. Recovery was monitored with daily orthostatic tests, nocturnal HR recordings, questionnaires, and exercise data. The participants were divided into subgroups (overreached/OR, n = 8; responders/RESP, n = 12) based on the changes in performance and subjective recovery. The responses to the second week of the overload period were compared between the subgroups. RESP improved their baseline 3000 m time (p < 0.001) after the overload period (-2.5 ± 1.0%), and the change differed (p < 0.001) from OR (0.6 ± 1.2%). The changes in nocturnal HR (OR 3.2 ± 3.1%; RESP -2.8 ± 3.7%, p = 0.002) and HR variability (OR -0.7 ± 1.8%; RESP 2.1 ± 1.6%, p = 0.011) differed between the subgroups. In addition, the decrease in subjective readiness to train (p = 0.009) and increase in soreness of the legs (p = 0.04) were greater in OR compared to RESP. Nocturnal HR, readiness to train, and exercise-derived HR-running power index had ≥85% positive and negative predictive values in the discrimination between OR and RESP individuals. In conclusion, exercise tolerance can vary substantially in recreational runners. The results supported the usefulness of nocturnal HR and subjective recovery assessments in recognizing fatigue states.

The pial vasculature is the sole source of blood supply to the neocortex. The brain is contained within the skull, a vascularized bone marrow with a unique anatomical connection to the brain meninges. Recent developments in tissue clearing have enabled detailed mapping of the entire pial and calvarial vasculature. However, what are the absolute flow rate values of those vascular networks? This information cannot accurately be retrieved with the commonly used bioimaging methods. Here, we introduce Pia-FLOW, a unique approach based on large-scale transcranial fluorescence localization microscopy, to attain hemodynamic imaging of the whole murine pial and calvarial vasculature at frame rates up to 1,000 Hz and spatial resolution reaching 5.4 µm. Using Pia-FLOW, we provide detailed maps of flow velocity, direction, and vascular diameters which can serve as ground-truth data for further studies, advancing our understanding of brain fluid dynamics. Furthermore, Pia-FLOW revealed that the pial vascular network functions as one unit for robust allocation of blood after stroke.

To study neurovascular function in type 2 diabetes mellitus (T2DM), we established a high-fat diet/streptozotocin (HFD/STZ) rat model. Electrocorticography-laser speckle contrast imaging (ECoG-LSCI) revealed that the somatosensory-evoked potential (SSEP) amplitude and blood perfusion volume were significantly lower in the HFD/STZ group. Cortical spreading depression (CSD) velocity was used as a measure of neurovascular function, and the results showed that the blood flow velocity and the number of CSD events were significantly lower in the HFD/STZ group. In addition, to compare changes during acute hyperglycemia and hyperglycemia, we used intraperitoneal injection (IPI) of glucose to induce transient hyperglycemia. The results showed that CSD velocity and blood flow were significantly reduced in the IPI group. The significant neurovascular changes observed in the brains of rats in the HFD/STZ group suggest that changes in neuronal apoptosis may play a role in altered glucose homeostasis in T2DM.

Plasticity during the critical period is important for the functional maturation of cortical neurons. While characteristics of plasticity are diverse among cortical layers, it is unknown whether critical period timing is controlled by a common or unique molecular mechanism among them. We here clarified layer-specific regulation of the critical period timing of ocular dominance plasticity in the primary visual cortex. Mice lacking the endocannabinoid synthesis enzyme diacylglycerol lipase-α exhibited precocious critical period timing, earlier maturation of inhibitory synaptic function in layers 2/3 and 4, and impaired development of the binocular matching of orientation selectivity exclusively in layer 2/3. Activation of cannabinoid receptor restored ocular dominance plasticity at the normal critical period in layer 2/3. Suppression of GABAA receptor rescued precocious ocular dominance plasticity in layer 4. Therefore, endocannabinoids regulate critical period timing and maturation of visual function partly through the development of inhibitory synaptic functions in a layer-dependent manner.

Respiration is an invaluable signal that facilitates the real-time observation of physiological dynamics. In recent years, the advancement of noncontact measurement technology has gained momentum in capturing physiological activities in natural settings. This technology is anticipated to be found not only in humans but also in nonhuman primates. Currently, the predominant noncontact approach for nonhuman animals involves measuring vital signs through subtle variations in skin color. However, this approach is limited when addressing areas of the body covered with hair or when working in outdoor settings under fluctuating sunlight. To overcome this issue, we focused on noncontact respiratory measurements using millimeter-wave radar. Millimeter-wave radar systems, which employ millimeter waves that can penetrate animal fur and estimate respiration-derived periodic body motion, exhibit minimal susceptibility to sunlight interference. Thus, this method shows potential for conducting noncontact vital measurements in natural and outdoor settings. In this study, we validated a millimeter-wave radar methodology for capturing respiration in outdoor-housed rhesus macaques (Macaca mulatta). The radar was positioned beyond the captive enclosure and maintained at a distance >5 m from the target. Millimeter waves were transmitted to the target, and the reflected waves were used to estimate skin surface displacement associated with respiration. The results revealed periodic skin surface displacement, and the estimated respiratory rates weres within the reported range of respiratory rates for rhesus macaques. These results suggest the potential applicability of millimeter-wave radar for noncontact respiration monitoring in outdoor-living macaques without anesthesia or immobilization. The continued advancement of noncontact vital measurement technology will contribute to understanding primate mental and physical dynamics during their daily life.

Ischemic stroke can cause depolarized brain waves, termed peri-infarct depolarization (PID). Here, we evaluated whether topiramate, a neuroprotective drug used to treat epilepsy and alleviate migraine, has the potential to reduce PID. We employed a rat model of photothrombotic ischemia that can reliably and reproducibly induce PID and developed a combined electrocorticography-laser speckle contrast imaging (ECoG-LSCI) platform to monitor neuronal activity and cerebral blood flow (CBF) simultaneously. Topiramate administration after photothrombotic ischemia did not rescue CBF but significantly restored somatosensory evoked potentials in the forelimb area of the primary somatosensory cortex. Moreover, infarct volume was investigated by 2,3,5-triphenyltetrazolium chloride (TTC) staining, and neuronal survival was evaluated by Nissl staining. Mechanistically, the levels of inflammatory markers, such as ED1 (CD68), Iba-1, and GFAP, decreased significantly after topiramate administration, as did BDNF expression, while the expression of NeuN and Bcl-2/Bax increased, which is indicative of reduced inflammation and improved neuroprotection.

High salt (HS) consumption is a risk factor for multiple autoimmune disorders via disturbing immune homeostasis. Nevertheless, the exact mechanisms by which HS exacerbates rheumatoid arthritis (RA) pathogenesis remain poorly defined. Herein, we found that heightened phosphorylation of PDPK1 and SGK1 upon HS exposure attenuated FoxO1 expression to enhance the glycolytic capacity of CD4 T cells, resulting in strengthened Th17 but compromised Treg program. GSK2334470 (GSK), a dual PDPK1/SGK1 inhibitor, effectively mitigated the HS-induced enhancement in glycolytic capacity and the overproduction of IL-17A. Therefore, administration of GSK markedly alleviated HS-exacerbated RA progression in collagen-induced arthritis (CIA) model. Collectively, our data indicate that HS consumption subverts Th17/Treg homeostasis through the PDPK1-SGK1-FoxO1 signaling, while GSK could be a viable drug against RA progression in clinical settings.

This commentary critically examines the long-standing emphasis on amyloid-β (Aβ)-based therapies in Alzheimer\'s disease (AD), despite numerous clinical trial failures. It highlights the urgency to reassess research methodologies and challenges the initiation of anti-Aβ trials in preclinical stages of the disease without conclusive proofs of their safety and efficacy. Instead, a comprehensive approach that considers Aβ\'s physiological roles and addresses AD complex nature is suggested, encouraging the idea that clinical trial failures may result from targeting the wrong mechanism. Evidence-based scientific research is needed to advance with AD treatment, moving beyond the current conception of Aβ hypothesis.

This paper examines the significant contribution of Dr. Valentín Grandis and Dr. Virgilio Ducceschi to the founding and development of experimental physiology at the Faculty of Medical Sciences of the National University of Córdoba (UNC), Argentina. Although the most notable contribution to the field of experimental physiology in Argentina is attributed to Bernardo Alberto Houssay, this study highlights the importance of the previous and fundamental efforts of Grandis and Ducceschi, two Italian professors whose work in Buenos Aires and Córdoba laid the foundations for research and teaching in this discipline. The paper details how, in 1904, the arrival of Valentin Grandis at the UNC marked the formal beginning of the teaching and practice of experimental physiology at the institution, followed by the incorporation of Virgilio Ducceschi, who continued and expanded Grandis\' legacy. The work of these two Italian masters involved not only the installation of a state-of-the-art laboratory but also the establishment of a solid academic and scientific foundation that would influence future generations of Argentine physicians and researchers. Through a detailed analysis of their biographies, scientific contributions, and the impact of their work, this paper illustrates how Grandis and Ducceschi were key figures in the development of medical science in Argentina, particularly in the field of experimental physiology. Furthermore, the study highlights the importance of their educational approach and their ability to train disciples who would continue their research, thus ensuring the permanence of their legacy at the National University of Córdoba and in Argentine science in general. In conclusion, this paper vindicates and celebrates the contributions of Valentín Grandis and Virgilio Ducceschi to the initiation of research and experimentation in physiology and biological chemistry at the UNC, highlighting their importance in the advancement of medicine and science in Argentina.
Este trabajo examina el significativo aporte de los doctores Valentín Grandis y Virgilio Ducceschi a la fundación y desarrollo de la fisiología experimental en la Facultad de Ciencias Médicas de la Universidad Nacional de Córdoba (UNC), Argentina. A pesar de que la contribución más notable en el campo de la fisiología experimental en Argentina se atribuye a Bernardo Alberto Houssay, este estudio destaca la importancia de los esfuerzos previos y fundamentales de Grandis y Ducceschi, dos profesores italianos cuyo trabajo en Buenos Aires y Córdoba sentó las bases para la investigación y la enseñanza de esta disciplina.   El trabajo detalla cómo, en 1904, la llegada de Valentín Grandis a la UNC marcó el inicio formal de la enseñanza y práctica de la fisiología experimental en la institución, seguida por la incorporación de Virgilio Ducceschi, quien continuó y expandió el legado de Grandis. La labor de estos dos maestros italianos no solo involucró la instalación de un laboratorio de vanguardia sino también el establecimiento de una sólida base académica y científica que influiría en generaciones futuras de médicos e investigadores argentinos.   A través de un análisis detallado de sus biografías, contribuciones científicas, y el impacto de su trabajo, este documento ilustra cómo Grandis y Ducceschi fueron figuras clave en el desarrollo de la ciencia médica en Argentina, particularmente en el ámbito de la fisiología experimental. Además, el estudio resalta la importancia de su enfoque educativo y su capacidad para formar discípulos que continuarían sus investigaciones, asegurando así la permanencia de su legado en la Universidad Nacional de Córdoba y en la ciencia argentina en general.   En conclusión, el presente trabajo reivindica y celebra las contribuciones de Valentín Grandis y Virgilio Ducceschi al inicio de la investigación y experimentación en fisiología y química biológica en la UNC, subrayando su importancia en el avance de la medicina y la ciencia en Argentina.