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The American Journal of Physiology: Regulatory, Integrative & Comparative Physiology has issued a call for papers on the topic of cardiovascular regulation during exercise, specifically focusing on the role of biological sex and the consequences of aging. The editors are seeking original research, short reports, and reviews that explore areas such as autonomic control of circulation, skeletal muscle, cerebral and cardiac blood flow, cardiac regulation, hemodynamic regulation, and thermal challenges. The aim is to better understand the sex-specific differences in cardiovascular responses to exercise and how they change throughout the lifespan. The call also emphasizes the need to consider the effects of aging, age-related diseases, and medications commonly prescribed to older adults on cardiovascular regulation during exercise. The editors encourage researchers to refer to recently published guidelines on the use of sex and gender in cardiovascular research. [Extracted from the article]

In part 1 of this Perspective, I discussed general principles of scientific peer review in the biomedical sciences aimed at earlystage investigators (i.e., graduate students, postdoctoral fellows, and junior faculty). Here in part 2, I share my thoughts specifically on the topic of peer review of manuscripts. I begin by defining manuscript peer review and discussing the goals and importance of the concept. I then describe the organizational structure of the process, including the two distinct stages involved. Next, I emphasize several important considerations for manuscript reviewers, both general points and key considerations when evaluating specific types of papers, including original research manuscripts, reviews, methods articles, and opinion pieces. I then advance some practical suggestions for developing the written critique document, offer advice for making an overall recommendation to the editor (i.e., accept, revise, reject), and describe the unique issues involved when assessing a revised manuscript. Finally, I comment on how best to gain experience in the essential academic research skill of manuscript peer review. In part 3 of the series, I will discuss the topic of reviewing grant applications submitted to research funding agencies. [ABSTRACT FROM AUTHOR]

The article highlights the eight Cardiovascular-Kidney Interactions in Health and Disease meeting at Amelia Island Plantation in Florida on May 27-30, 2005. The meeting was funded by the Cardiovascular-Kidney Institute of Georgetown University in Washington D. C. The three-day meeting featured original contributions on a broad range of topics including redox regulation and microvascular function, genetic and cellular regulation of vascular growth and function and growing points in hypertension and cardiovascular disease.

The transitional epithelial cells (urothelium) that line the lumen of the urinary bladder form a barrier between potentially harmful pathogens, toxins, and other bladder contents and the inner layers of the bladder wall. The urothelium, however, is not simply a passive barrier, as it can produce signaling factors, such as ATP, nitric oxide, prostaglandins, and other prostanoids, that can modulate bladder function. We investigated whether substances produced by the urothelium could directly modulate the contractility of the underlying urinary bladder smooth muscle. Force was measured in isolated strips of mouse urinary bladder with the urothelium intact or denuded. Bladder strips developed spontaneous tone and phasic contractions. In urothelium-intact strips, basal tone, as well as the frequency and amplitude of phasic contractions, were 25%, 32%, and 338% higher than in urothelium-denuded strips, respectively. Basal tone and phasic contractility in urothelium-intact bladder strips were abolished by the cyclooxygenase (COX) inhibitor indomethacin (10 µM) or the voltage-dependent Ca2+ channel blocker diltiazem (50 µM), whereas blocking neuronal sodium channels with tetrodotoxin (1 µM) had no effect. These results suggest that prostanoids produced in the urothelium enhance smooth muscle tone and phasic contractions by activating voltage-dependent Ca2+ channels in the underlying bladder smooth muscle. We went on to demonstrate that blocking COX inhibits the generation of transient pressure events in isolated pressurized bladders and greatly attenuates the afferent nerve activity during bladder filling, suggesting that urothelial prostanoids may also play a role in sensory nerve signaling. NEW & NOTEWORTHY: This paper provides evidence for the role of urothelial-derived prostanoids in maintaining tone in the urinary bladder during bladder filling, not only underscoring the role of the urothelium as more than a barrier but also contributing to active regulation of the urinary bladder. Furthermore, cyclooxygenase products greatly augment sensory nerve activity generated by bladder afferents during bladder filling and thus may play a role in perception of bladder fullness. [ABSTRACT FROM AUTHOR]

Editorial. Introduces the papers commemorating the American Physiological Society (APS) Legacy Project. Brief history of the organization; Conception and creation of the APS Legacy Project to increase awareness of and access to seminal papers; Panel formed to identify paradigm-shifting papers including physiologists Christian M. Bauer and Dale J. Benos.

Nonreproducibility in scientific investigations has been explained by inadequately reporting methodology, honest error, and even misconduct. We hypothesized that, within the field of animal physiology, the most parsimonious explanation for nonreproducibility is inadequate reporting of key methodological details. We further hypothesized that implementation of relatively recently released reporting guidelines has positively impacted journal article quality, as measured by completeness of the methodology descriptions. We analyzed 84 research articles published in five primarily organismal animal physiology journals in 2008-2010 (generally before current guidelines) and 2018-2020. Compliance for reporting 34 variables referring to biology, experiments, and data collection was assessed. Reporting compliance was just ~61% in 2008-2010, rising only slightly to 67.5% for 2018-2020. Only 21% of the reported variables showed significant differences across the period from 2008-2020. We conclude that, despite attempts by societies and journals to promote greater reporting compliance, such efforts have so far been relatively unsuccessful in the field of animal physiology. [ABSTRACT FROM AUTHOR]

Hagfishes are characterized by omo- and iono-conforming nature similar to marine invertebrates. Conventionally, hagfishes had been recognized as the most primitive living vertebrate that retains plesiomorphic features. However, some of the "ancestral" features of hagfishes, such as rudimentary eyes and the lack of vertebrae, have been proven to be deceptive. Similarly, by the principle of maximum parsimony, the unique body fluid regulatory strategy of hagfishes seems to be apomorphic, since the lamprey, another cyclostome, adopts osmo- and iono-regulatory mechanisms as in jawed vertebrates. Although hagfishes are unequivocally important in discussing the origin and evolution of the vertebrate osmoregulatory system, the molecular basis for the body fluid homeostasis in hagfishes has been poorly understood. In the present study, we explored this matter in the inshore hagfish, Eptatretus burgeri, by analyzing the transcriptomes obtained from the gill, kidney, and muscle of the animals acclimated to distinct environmental salinities. Together with the measurement of parameters in the muscular fluid compartment, our data indicate that the hagfish possesses an ability to conduct free amino acid (FAA)-based osmoregulation at a cellular level, which is in coordination with the renal and branchial FAA absorption. We also revealed that the hagfish does possess the orthologs of the known osmoregulatory genes and that the transepithelial movement of inorganic ions in the hagfish gill and kidney is more complex than previously thought. These observations pose a challenge to the conventional view that the physiological features of hagfishes have been inherited from the last common ancestor of the extant vertebrates. [ABSTRACT FROM AUTHOR]

Vagal afferents to the gastrointestinal tract are crucial for the regulation of food intake, signaling negative feedback that contributes to satiation and positive feedback that produces appetition and reward. Vagal afferents to the small intestinal mucosa contribute to this regulation by sensing luminal stimuli and reporting this information to the brain. These afferents respond to mechanical, chemical, thermal, pH, and osmolar stimuli, as well as to bacterial products and immunogens. Surprisingly, little is known about how these stimuli are transduced by vagal mucosal afferents or how their transduction is organized among these afferents' terminals. Furthermore, the effects of stimulus concentration ranges or physiological stimuli on vagal activity have not been examined for some of these stimuli. Also, detection of luminal stimuli has rarely been examined in rodents, which are most frequently used for studying small intestinal innervation. Here we review what is known about stimulus detection by vagal mucosal afferents and illustrate the complexity of this detection using nutrients as an exemplar. The accepted model proposes that nutrients bind to taste receptors on enteroendocrine cells (EECs), which excite them, causing the release of hormones that stimulate vagal mucosal afferents. However, evidence reviewed here suggests that although this model accounts for many aspects of vagal signaling about nutrients, it cannot account for all aspects. A major goal of this review is therefore to evaluate what is known about nutrient absorption and detection and, based on this evaluation, identify candidate mucosal cells and structures that could cooperate with EECs and vagal mucosal afferents in stimulus detection. [ABSTRACT FROM AUTHOR]

We sought to determine the effects of acute simulated altitude on the maximal lactate steady state (MLSS) and physiological responses to cycling at and 10 W above the MLSS-associated power output (PO) (MLSSp and MLSSp+10, respectively). Eleven (4 females) participants (means [SD]; 28 [4] yr; V̇ o 2max: 54.3 [6.9] mL·kg−1·min−1) acclimatized to ∼1,100 m performed 30-min constant PO trials in simulated altitudes of 0 m sea level (SL), 1,111 m mild altitude (MILD), and 2,222 m moderate altitude (MOD). MLSSp, defined as the highest PO with stable (<1 mM change) blood lactate concentration ([BLa]) between 10 and 30 min, was significantly lower in MOD (209 [54] W) compared with SL (230 [56] W; P < 0.001) and MILD (225 [58] W; P = 0.001), but MILD and SL were not different (P = 0.12). V̇ o 2 and V̇ co 2 decreased at higher simulated altitudes due to lower POs (P < 0.05), but other end-exercise physiological responses (e.g., [BLa], ventilation [V̇ e ], heart rate [HR]) were not different between conditions at MLSSp or MLSSp + 10 (P > 0.05). At the same absolute intensity (MLSSp for MILD), [BLa], HR, and V̇E and all perceptual variables were exacerbated in MOD compared with SL and MILD (P < 0.05). Maximum voluntary contraction, voluntary activation, and potentiated twitch forces were exacerbated at MLSSp + 10 relative to MLSSp within conditions (P < 0.05); however, condition did not affect performance fatiguability at the same relative or absolute intensity (P > 0.05). As MLSSp decreased in hypoxia, adjustments in PO are needed to ensure the same relative intensity across altitudes, but common indices of exercise intensity may facilitate exercise prescription and monitoring in hypoxia. NEW & NOTEWORTHY: This study demonstrates the power output and metabolic rate associated with the maximal lactate steady-state (MLSS) decline in response to simulated altitude; however, common indices of exercise intensity remained unchanged when cycling was performed at the work rate associated with MLSS at each simulated altitude. These results support previous studies that investigated the effects of hypoxia on alternative measures of the critical intensity of exercise and will inform exercise prescription/monitoring across altitudes. [ABSTRACT FROM AUTHOR]

Despite elite human free divers achieving incredible feats in competitive free diving, there has yet to be a study that compares consummate divers, (i.e. northern elephant seals) to highly conditioned free divers (i.e., elite competitive free-diving humans). Herein, we compare these two diving models and suggest that hematological traits detected in seals reflect species-specific specializations, while hematological traits shared between the two species are fundamental mammalian characteristics. Arterial blood samples were analyzed in elite human free divers (n = 14) during a single, maximal volitional apnea and in juvenile northern elephant seals (n = 3) during rest-associated apnea. Humans and elephant seals had comparable apnea durations (∼6.5 min) and end-apneic arterial P o 2 [humans: 40.4 ± 3.0 mmHg (means ± SE); seals: 27.1 ± 5.9 mmHg; P = 0.2]. Despite similar increases in arterial P co 2 (humans: 33 ± 5%; seals: 16.3 ± 5%; P = 0.2), only humans experienced reductions in pH from baseline (humans: 7.45 ± 0.01; seals: 7.39 ± 0.02) to end apnea (humans: 7.37 ± 0.01; seals: 7.38 ± 0.02; P < 0.0001). Hemoglobin P50 was greater in humans compared to elephant seals (29.9 ± 1.5 and 28.7 ± 0.6 mmHg, respectively; P = 0.046). Elephant seals overall had higher carboxyhemoglobin (COHb) levels (5.9 ± 2.6%) compared to humans (0.8 ± 1.2%; P < 0.0001); however, following apnea, COHb was reduced in seals (baseline: 6.1 ± 0.3%; end apnea: 5.6 ± 0.3%) and was slightly elevated in humans (baseline: 0.7 ± 0.1%; end apnea: 0.9 ± 0.1%; P < 0.0002, both comparisons). Our data indicate that during static apnea, seals have reduced hemoglobin P50, greater pH buffering, and increased COHb levels. The differences in hemoglobin P50 are likely due to the differences in the physiological environment between the two species during apnea, whereas enhanced pH buffering and higher COHb may represent traits selected for in elephant seals. NEW & NOTEWORTHY: This study uses similar methods and protocols in elite human free divers and northern elephant seals. Using highly conditioned divers (elite free-diving humans) and highly adapted divers (northern elephant seals), we explored which hematological traits are fundamentally mammalian and which may have been selected for. We found differences in P50, which may be due to different physiological environments between species, while elevated pH buffering and carbon monoxide levels might have been selected for in seals. [ABSTRACT FROM AUTHOR]

Rhythmic feeding behavior is critical for regulating phase and amplitude in the ≈24-h variation of heart rate (RR intervals), ventricular repolarization (QT intervals), and core body temperature in mice. We hypothesized changes in cardiac electrophysiology associated with feeding behavior were secondary to changes in core body temperature. Telemetry was used to record electrocardiograms and core body temperature in mice during ad libitum-fed conditions and after inverting normal feeding behavior by restricting food access to the light cycle. Light cycle-restricted feeding modified the phase and amplitude of 24-h rhythms in RR and QT intervals, and core body temperature to realign with the new feeding time. Changes in core body temperature alone could not account for changes in phase and amplitude in the ≈24-h variation of the RR intervals. Heart rate variability analysis and inhibiting β-adrenergic and muscarinic receptors suggested that changes in the phase and amplitude of 24-h rhythms in RR intervals were secondary to changes in autonomic signaling. In contrast, changes in QT intervals closely mirrored changes in core body temperature. Studies at thermoneutrality confirmed that the daily variation in QT interval, but not RR interval, primarily reflected daily changes in core body temperature (even in ad libitum-fed conditions). Correcting the QT interval for differences in core body temperature helped unmask QT interval prolongation after starting light cycle-restricted feeding and in a mouse model of long QT syndrome. We conclude feeding behavior alters autonomic signaling and core body temperature to regulate phase and amplitude in RR and QT intervals, respectively. NEW & NOTEWORTHY: We used time-restricted feeding and thermoneutrality to demonstrate that different mechanisms regulate the 24-h rhythms in heart rate and ventricular repolarization. The daily rhythm in heart rate reflects changes in autonomic input, whereas daily rhythms in ventricular repolarization reflect changes in core body temperature. This novel finding has major implications for understanding 24-h rhythms in mouse cardiac electrophysiology, arrhythmia susceptibility in transgenic mouse models, and interpretability of cardiac electrophysiological data acquired in thermoneutrality. [ABSTRACT FROM AUTHOR]

The stress-induced cardiovascular response is based on the defensive reaction in mammals. It has been shown that the sympathetic vasomotor pathway of acute psychological stress is indirectly mediated via neurons in the rostroventral medulla (RVM) from the hypothalamic stress center. In this study, direct projections to the RVM and distribution of neuroexcitatory marker c-Fos-expressed neurons were investigated during social defeat stress (SDS) in conscious rats. The experimental rat that was injected with a neural tracer, FluoroGold (FG) into the unilateral RVM, was exposed to the SDS. Double-positive neurons of both c-Fos and FG were locally distributed in the lateral/ventrolateral periaqueductal gray matter (l/vl PAG) in the midbrain. These results suggest that the neurons in the l/vl PAG contribute to the defensive reaction evoked by acute psychological stress, such as the SDS. During the SDS period, arterial pressure (AP) and heart rate (HR) showed sustained increases in the rat. Therefore, we performed chemical stimulation by excitatory amino acid microinjection within the l/vl PAG and measured cardiovascular response and sympathetic nerve activity in some anesthetized rats. The chemical stimulation of neurons in the l/vl PAG caused significant increases in arterial pressure and renal sympathetic nerve activity. Taken together, our results suggest that neurons in the l/vl PAG are a possible candidate for the cardiovascular descending pathway that modulates sympathetic vascular resistance evoked by acute psychological stress, like the SDS. NEW & NOTEWORTHY: The sympathetic vasomotor pathway of an acute psychological stress-induced cardiovascular response is mediated via neurons in the RVM indirectly from the hypothalamus. In this study, we showed the relaying area of the efferent sympathetic vasomotor pathway from the hypothalamus to the RVM. The results suggested that the pressor response during psychological stress is mediated via neurons in the lateral/ventrolateral PAG to the RVM. [ABSTRACT FROM AUTHOR]

Hypoxia is a pivotal factor in the pathophysiology of various clinical conditions, including obstructive sleep apnea, which has a strong association with cardiovascular diseases like hypertension, posing significant health risks. Although the precise mechanisms linking hypoxemia-associated clinical conditions with hypertension remains incompletely understood, compelling evidence suggests that hypoxia induces plasticity of the neurocirculatory control system. Despite variations in experimental designs and the severity, frequency, and duration of hypoxia exposure, evidence from animal and human models consistently demonstrates the robust effects of hypoxemia in triggering reflex-mediated sympathetic activation. Both acute and chronic hypoxia alters neurocirculatory regulation and, in some circumstances, leads to sympathetic outflow and elevated blood pressures that persist beyond the hypoxic stimulus. Dysregulation of autonomic control could lead to adverse cardiovascular outcomes and increase the risk of developing hypertension. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is associated with reduced whole body sweating during exercise-heat stress. However, it is unclear if this impairment is related to exercise intensity and whether it occurs uniformly across body regions. We evaluated whole body (direct calorimetry) and local (ventilated-capsule technique; chest, back, forearm, thigh) sweat rates in physically active men with type 2 diabetes [T2D; aged 59 (7) yr; V_ O2peak 32.3 (7.6) mL·kg-1·min-1; n = 26; HbA1c 5.1%-9.1%] and without diabetes [Control; aged 61 (5) yr; V_ O2peak 37.5 (5.4) mL·kg-1·min-1; n = 26] during light-(~40% V_ O2peak), moderate- (~50% V_ O2peak), and vigorous- (~65% V_ O2peak) intensity exercise (elicited by fixing metabolic heat production at ~150, 200, 250 W·m-2, respectively) in 40°C, ~17% relative humidity. Whole body sweating was ~11% (T2D: Control mean difference [95% confidence interval]: -37 [-63, -12] g·m-2·h-1) and ~13% (-50 [-76, -25] g·m-2·h-1) lower in the T2D compared with the Control group during moderate- and vigorous- (P = 0.001) but not light-intensity exercise (-21 [-47, 4] g·m-2·h-1; P = 0.128). Consequently, the diabetes-related reductions in whole body sweat rate were 2.3 [1.6, 3.1] times greater during vigorous relative to light exercise (P < 0.001). Furthermore, these diabetes-related impairments in local sweating were region-specific during vigorous-intensity exercise (group x region interaction: P = 0.024), such that the diabetes-related reduction in local sweat rate at the trunk (chest, back) was 2.4 [1.2, 3.7] times greater than that at the limbs (thigh, arm). In summary, when assessed under hot, dry conditions, diabetes-related impairments in sweating are exercise intensity-dependent and greater at the trunk compared with the limbs. NEW & NOTEWORTHY This study evaluates the influence of exercise intensity on decrements in whole body sweating associated with type 2 diabetes. Furthermore, it investigates whether diabetes-related sweating impairments were exhibited uniformly or heterogeneously across body regions. We found that whole body sweating was attenuated in the type 2 diabetes group relative to control participants during moderate- and vigorous-intensity exercise but not light-intensity exercise; impairments were largely mediated by reduced sweating at the trunk rather than the limbs. [ABSTRACT FROM AUTHOR]

In pilot work, we showed that somatic nerve transfers can restore motor function in long-term decentralized dogs. We continue to explore the effectiveness of motor reinnervation in 30 female dogs. After anesthesia, 12 underwent bilateral transection of coccygeal and sacral (S) spinal roots, dorsal roots of lumbar (L)7, and hypogastric nerves. Twelve months postdecentralization, eight underwent transfer of obturator nerve branches to pelvic nerve vesical branches, and sciatic nerve branches to pudendal nerves, followed by 10 mo recovery (ObNT-ScNT Reinn). The remaining four were euthanized 18 mo postdecentralization (Decentralized). Results were compared with 18 Controls. Squat-and-void postures were tracked during awake cystometry. None showed squat-and-void postures during the decentralization phase. Seven of eight ObNT-ScNT Reinn began showing such postures by 6 mo postreinnervation; one showed a return of defecation postures. Retrograde dyes were injected into the bladder and urethra 3 wk before euthanasia, at which point, roots and transferred nerves were electrically stimulated to evaluate motor function. Upon L2-L6 root stimulation, five of eight ObNT-ScNT Reinn showed elevated detrusor pressure and four showed elevated urethral pressure, compared with L7-S3 root stimulation. After stimulation of sciatic-to-pudendal transferred nerves, three of eight ObNT-ScNT Reinn showed elevated urethral pressure; all showed elevated anal sphincter pressure. Retrogradely labeled neurons were observed in L2-L6 ventral horns (in laminae VI, VIII, and IX) of ObNT-ScNT Reinn versus Controls in which labeled neurons were observed in L7-S3 ventral horns (in lamina VII). This data supports the use of nerve transfer techniques for the restoration of bladder function. NEW & NOTEWORTHY This data supports the use of nerve transfer techniques for the restoration of bladder function. [ABSTRACT FROM AUTHOR]

Animal models have been critical in building evidence that the prenatal experience and intrauterine environment are capable of exerting profound and permanent effects on metabolic health through developmental programming of obesity. However, despite physiological and evolutionary similarities, nonhuman primate models are relatively rare. The common marmoset monkey (Callithrix jacchus) is a New World monkey that has been used as a biomedical model for well more than 50 years and has recently been framed as an appropriate model for exploring early-life impacts on later health and disease. The spontaneous, multifactorial, and early-life development of obesity in the common marmoset make it a valuable research model for advancing our knowledge about the role of the prenatal and placental mechanisms involved in developmental programming of obesity. This paper provides a brief overview of obesity in the common marmoset, followed by a discussion of marmoset reproduction and placental characteristics. We then discuss the occurrence and utility of variable intrauterine environments in developmental programming in marmosets. Evidence of developmental programming of obesity will be given, and finally, we put forward future directions and innovations for including the placenta in developmental programming of obesity in the common marmoset. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate how aging affects blood flow and structure of the brain. It was hypothesized older individuals would have lower gray matter volume (GMV), resting cerebral blood flow (CBF0), and depressed responses to isometabolic and neurometabolic stimuli. In addition, increased carotid-femoral pulse-wave velocity (PWV), carotid intima-media thickness (IMT), and decreased brachial flow-mediated dilation (FMD) would be associated with lower CBF0, cerebrovascular reactivity (CVR), and GMV. Brain scans (magnetic resonance imaging) and cardiovascular examinations were conducted in young (age = 24 ± 3 yr, range = 22–28 yr; n = 13) and old (age = 71 ± 4 yr; range = 67–82 yr, n = 14) participants, and CBF0, CVR [isometabolic % blood oxygen level-dependent (BOLD) in response to a breath hold (BH)], brain activation patterns during a working memory task (neurometabolic %BOLD response to N-back trial), GMV, PWV, IMT, and FMD were measured. CBF0 and to a lesser extent CVRBH were lower in the old group (P 0.050); however, the increase in the %BOLD response to the memory task was not blunted (P 0.2867). Age-related differential activation patterns during the working memory task were characterized by disinhibition of the default mode network in the old group (P < 0.0001). Linear regression analyses revealed PWV, and IMT were negatively correlated with CBF0, CVRBH, and GMV across age groups, but within the old group alone only the relationships between PWV-CVRBH and IMT-GMV remained significant (P 0.0183). These findings suggest the impacts of age on cerebral % BOLD responses are stimulus specific, brain aging involves alterations in cerebrovascular and possibly neurocognitive control, and arterial stiffening and wall thickening may serve a role in cerebrovascular aging. NEW & NOTEWORTHY Cerebral perfusion was lower in old versus young adults. %Blood oxygen level-dependent (BOLD) responses to an isometabolic stimulus and gray matter volume were decreased in old versus young adults and associated with arterial stiffening and wall thickening. The increased %BOLD response to a neurometabolic stimulus appeared unaffected by age; however, the old group displayed disinhibition of the default mode network during the stimulus. Thus, age-related alterations in cerebral %BOLD responses were stimulus specific and related to arterial remodeling. [ABSTRACT FROM AUTHOR]

The estrous cycle is known to modify food, fluid, and electrolyte intake behaviors and energy homeostasis in various species, in part through fluctuations in estrogen levels. Simultaneously, commonly commercially available rodent dietary formulations greatly vary in soy protein content, and thereby the delivery of biologically active phytoestrogens. To explore the interactions among the estrous cycle, sodium, fluid, and caloric seeking behaviors, and energy homeostasis, young adult C57BL/6J female mice were maintained on a soy protein-free 2920x diet and provided water, or a choice between water and 0.15 mol/L NaCl drink solution. Comprehensive metabolic phenotyping was performed using a multiplexed Promethion (Sable Systems International) system, and estrous stages were determined via daily vaginal cytology. When provided food and water, estrous cycling had no major modulatory effects on intake behaviors or energy balance. When provided a saline solution drink choice, significant modulatory effects of the transition from diestrus to proestrus were observed upon fluid intake patterning, locomotion, and total energy expenditure. Access to saline increased total daily sodium consumption and aspects of energy expenditure, but these effects were not modified by the estrous stage. Collectively, these results indicate that when supplied a phytoestrogen-free diet, the estrous cycle has minor modulatory effects on ingestive behaviors and energy balance in C57BL/6J mice that are sensitive to sodium supply. [ABSTRACT FROM AUTHOR]

Although body fluid volume control by the kidneys may be classified as a long-term arterial pressure (AP) control system, it does not necessarily follow that the urine flow (UF) response to changes in AP is slow. We quantified the dynamic characteristics of the UF response to short-term AP changes by changing mean AP between 60 mmHg and 100 mmHg every 10 s according to a binary white noise sequence in anesthetized rats (n = 8 animals). In a baro-on trial (the carotid sinus baroreflex was enabled), the UF response represented the combined synergistic effects of pressure diuresis (PD) and neurally mediated antidiuresis (NMA). In a baro-fix trial (the carotid sinus pressure was fixed at 100 mmHg), the UF response mainly reflected the effect of PD. The UF step response was quantified using the sum of two exponential decay functions. The fast and slow components had time constants of 6.5 ± 3.6 s and 102 ± 85 s (means ± SD), respectively, in the baro-on trial. Although the gain of the fast component did not differ between the two trials (0.49 ± 0.21 vs. 0.66 ± 0.22 lL·min-1·kg-1·mmHg-1), the gain of the slow component was greater in the baro-on than in the baro-fix trial (0.51 ± 0.14 vs. 0.09 ± 0.39 lL·min-1·kg-1·mmHg-1, P = 0.023). The magnitude of NMA relative to PD was calculated to be 32.2 ± 29.8%. In conclusion, NMA contributed to the slow component, and its magnitude was approximately one-third of that of the effect of PD. [ABSTRACT FROM AUTHOR]

The article comments on two papers published within the issue that demonstrate that brain-derived neurotrophic factor (BDNF) acts as a prototypic catabolic factor when injected into the hypothalamic paraventricular nucleus (PVN). According to the author, the papers add to the growing body of data that demonstrate that BDNF can act at a specific site as a catabolic agent. The author adds that the papers also show that PVN BDNF injections act with different temporal patterns.

Vitamin B12 deficiency has been shown to affect bone mass in rodents and negatively impact bone formation in humans. In this study using mouse models, we define the effect of B12 supplementation in the wild-type mother and B12 deficiency in a mouse genetic model (Gif-/- mice) during gestation on bone and muscle architecture and mechanical properties in the offspring. Analysis of bones from 4-wk-old offspring of the wild-type mother following vehicle or B12 supplementation during gestation (from embryonic day 0.5 to 20.5) showed an increase in bone mass caused by an isolated increase in bone formation in the B12-supplemented group compared with vehicle controls. Analysis of the effect of B12 deficiency in the mother in a mouse genetic model (Gif-/- mice) on the long bone architecture of the offspring showed a compromised cortical and trabecular bone mass, which was completely prevented by a single injection of B12 in the B12-deficient Gif-/- mothers. Biomechanical analysis of long bones of the offspring born from B12-supplemented wild-type mothers showed an increase in bone strength, and conversely, offspring born from B12-deficient Gif-/- mothers revealed a compromised bone strength, which could be rescued by a single injection of B12 in the B12-deficient Gif-/- mother. Muscle structure and function analysis however revealed no significant effect on muscle mass, structure, and grip strength of B12 deficiency or supplementation in Gif-/- mice compared with littermate controls. Together, these results demonstrate the beneficial effect of maternally derived B12 in the regulation of bone structure and function in the offspring. [ABSTRACT FROM AUTHOR]

The hypoxia-inducible factor (HIF) is considered key in the transcriptional response to low oxygen. Yet, the role of HIF in the absence of oxygen (anoxia) and in preparation for reoxygenation remains unclear. Recent studies suggest that mounting a HIF response may be counterproductive for anoxia survival. We here studied one of the champions of anoxia survival, the crucian carp (Carassius carassius), and hypothesized that expression of prolyl hydroxylase domains (PHDs; the upstream regulators of HIF) are upregulated to circumvent an energy-costly activation of HIF in anoxia and to prepare for reoxygenation. We measured whole brain mRNA and protein levels of the three isoforms PHD1, PHD2, and PHD3, coded for by multiple paralogs of the genes egln2, egln1, and egln3, using quantitative PCR and Western blotting in the brain of crucian carps exposed to 5 days normoxia or anoxia, and 5 days anoxia followed by 3 or 24 h of reoxygenation. The mRNA levels of most egln paralogs were increased in anoxia and upon reoxygenation, with egln3 showing the largest increase in mRNA level (up to 17-fold) and highest relative mRNA abundance (up to 75% of expressed egln). The protein level of all PHDs was maintained in anoxia and increased upon reoxygenation. We then explored PHD distribution in different brain regions and found PHD immunoreactivity to be associated with axonal branches and showing region-specific changes during anoxia-reoxygenation. Our results support an overall upregulation of egln under prolonged anoxia and PHDs upon reoxygenation in crucian carp, likely aimed at suppressing HIF responses, although regional differences are apparent in such a complex organ as the brain. [ABSTRACT FROM AUTHOR]

Exercise intolerance is a hallmark symptom of heart failure and to a large extent stems from reductions in cardiac output that occur due to the inherent ventricular dysfunction coupled with enhanced muscle metaboreflex-induced functional coronary vasoconstriction, which limits increases in coronary blood flow. This creates a further mismatch between O2 delivery and O2 demand, which may activate the cardiac sympathetic afferent reflex (CSAR), causing amplification of the already increased sympathetic activity in a positive-feedback fashion. We used our chronically instrumented conscious canine model to evaluate if chronic ablation of afferents responsible for the CSAR would attenuate the gain of muscle metaboreflex before and after induction of heart failure. After afferent ablation, the gain of the muscle metaboreflex control of mean arterial pressure was significantly reduced before (-239.5 ± 16 to -95.2 ± 8 mmHg/L/min) and after the induction of heart failure (-185.6 ± 14 to -95.7 ± 12 mmHg/L/min). Similar results were observed for the strength (gain) of muscle metaboreflex control of heart rate, cardiac output, and ventricular contractility. Thus, we conclude that the CSAR contributes significantly to the strength of the muscle metaboreflex in normal animals with heart failure serving as an effective positive-feedback amplifier thereby further increasing sympathetic activity. [ABSTRACT FROM AUTHOR]

Lifestyle modification including exercise training is often the first line of defense in the treatment of obesity and hypertension (HTN), however, little is known regarding how these potentially compounding disease states impact vasodilatory and hemodynamic responses at baseline and exercise. Therefore, this study sought to compare the impact of obesity on vascular function and hemodynamics at baseline and during handgrip (HG) exercise among individuals with HTN. Non-obese (13M/7F, 56±16 yr, 25±4 kg/m²) and obese (17M/4F, 50±7 yr, 35±4 kg/m²) middle-aged individuals with HTN forwent antihypertensive medication use for ≤2 wk before assessment of vascular function by brachial artery flow-mediated dilation (FMD) and exercise hemodynamics during progressive HG exercise at 15-30-45% maximal voluntary contraction (MVC). FMD was not different between Non-Obese (4.1±1.7%) and Obese (5.2±1.9%, P = 0.11). Systolic blood pressure (SBP) was elevated by ~15% during the supine baseline and during HG exercise in the obese group. The blood flow response to HG exercise at 30% and 45% MVC was ~20% greater (P < 0.05) in the obese group but not different after normalizing for the higher, albeit, nonsignificant differences in workloads (MVC: obese: 24±5 kg, non-obese: 21±5 kg, P = 0.11). Vascular conductance and the brachial artery shear-induced vasodilatory response during HG were not different between groups (P > 0.05). Taken together, despite elevated SBP during HG exercise, obesity does not lead to additional impairments in vascular function and peripheral exercising hemodynamics in patients with HTN. Obesity may not be a contraindication when prescribing exercise for the treatment of HTN among middle-aged adults, however, the elevated SBP should be appropriately monitored. NEW & NOTEWORTHY This study examined vascular function and handgrip exercise hemodynamics in obese and nonobese individuals with hypertension. Obesity, when combined with hypertension, was neither associated with additional vascular function impairments at baseline nor peripheral hemodynamics and vasodilation during exercise compared with nonobese hypertension. Interestingly, systolic blood pressure and pulse pressure were greater in the obese group during supine baseline and exercise. These findings should not be ignored and may be particularly important for rehabilitation strategies. [ABSTRACT FROM AUTHOR]

In addition to its role in substrate selection (carbohydrate vs. fat) for oxidative metabolism in muscle, acetylcarnitine production may be an important modulator of the energetic pathway by which ATP is produced. A combination of noninvasive magnetic resonance spectroscopy measures of cytosolic acetylcarnitine and ATP production pathways was used to investigate the link between [acetylcarnitine] and energy production in vivo. Intracellular metabolites were measured in the vastus lateralis muscle of eight males (mean: 28.4 yr, range: 25-35) during 8 min of incremental, dynamic contractions (0.5 Hz, 2-min stages at 6%, 9%, 12%, and 15% maximal torque) that increased [acetylcarnitine] approximately fivefold from resting levels. ATP production via oxidative phosphorylation, glycolysis, and the creatine kinase reaction was calculated based on phosphorus metabolites and pH. Spearman rank correlations indicated that postcontraction [acetylcarnitine] was positively associated with both absolute (mM) and relative (% total ATP) glycolytic ATP production (rs = 0.95, P = 0.001; rs = 0.93, P = 0.002), and negatively associated with relative (ss = 0.81, P = 0.02) but not absolute (rs = 0.14, P = 0.75) oxidative ATP production. Thus, acetylcarnitine accumulated more when there was a greater reliance on "nonoxidative" glycolysis and a relatively lower contribution from oxidative phosphorylation, reflecting the fate of pyruvate in working skeletal muscle. Furthermore, these data indicate striking interindividual variation in responses to the energy demand of submaximal contractions. Overall, the results of this preliminary study provide novel evidence of the coupling in vivo between ATP production pathways and the carnitine system. NEW & NOTEWORTHY Production of acetylcarnitine from acetyl-CoA and free carnitine may be important for energy pathway regulation in contracting skeletal muscle. Noninvasive magnetic resonance spectroscopy was used to investigate the link between acetylcarnitine and energy production in the vastus lateralis muscle during dynamic contractions (n = 8 individuals). A positive correlation between acetylcarnitine accumulation and "nonoxidative" glycolysis and an inverse relationship with oxidative phosphorylation, provides novel evidence of the coupling between ATP production and the carnitine system in vivo. [ABSTRACT FROM AUTHOR]

Moderate-to-heavy episodic ("binge") drinking is the most common form of alcohol consumption in the United States. Alcohol at binge drinking concentrations reduces brain artery diameter in vivo and in vitro in many species including rats, mice, and humans. Despite the critical role played by brain vessels in maintaining neuronal function, there is a shortage of methodologies to simultaneously assess neuron and blood vessel function in deep brain regions. Here, we investigate cerebrovascular responses to ethanol by choosing a deep brain region that is implicated in alcohol disruption of brain function, the hippocampal CA1, and describe the process for obtaining simultaneous imaging of pyramidal neuron activity and diameter of nearby microvessels in freely moving mice via a dualcolor miniscope. Recordings of neurovascular events were performed upon intraperitoneal injection of saline versus 3 g/kg ethanol in the same mouse. In male mice, ethanol mildly increased the amplitude of calcium signals while robustly decreasing their frequency. Simultaneously, ethanol decreased microvessel diameter. In females, ethanol did not change the amplitude or frequency of calcium signals from CA1 neurons but decreased microvessel diameter. A linear regression of ethanol-induced reduction in number of active neurons and microvessel constriction revealed a positive correlation (R = 0.981) in females. Together, these data demonstrate the feasibility of simultaneously evaluating neuronal and vascular components of alcohol actions in a deep brain area in freely moving mice, as well as the sexual dimorphism of hippocampal neurovascular responses to alcohol. [ABSTRACT FROM AUTHOR]

The article offers information on editorial policies of the journal and also provides ethical information to readers regarding submission of articles associated with experiments and research involving animal and human subjects.

The author reflects on the current condition of American Journal of Physiology (AJP) after one year that he joined the publication. He reminisces the challenges that he had to face in assuming the post in the publication. He also mentions the contribution made by Scott Powers and of the editorial team which includes Quentin Pittman, David Pollock and others. The author also reports the current condition of the journal and other future plans.

Editorial. Comments on the historical significance of three American Physiological Society papers that are available online. "Emotional simulation of adrenal secretion," by Walter B. Cannon and D. De de la Paz; "The emergency of the adrenal medulla in pain and the major emotions" and "Studies on the conditions of activity in endocrine glands. V. The isolated heart as an indicator of adrenal secretion induced by pain, asphyxia and excitement," by W.B. Cannon.

The article discusses the ethical policies and procedures of the "American Journal of Physiology: Regulatory, Integrative and Comparative Physiology." It notes that each author is expected to have made an important scientific contribution to the study of physiology. It also presents the policies in the presentation of funding sources, duplication of publication, plagiarism and falsification.

As we approach the centenary of the term "comparative physiology," we reexamine its role in modern biology. Finding inspiration in Krogh's classic 1929 paper, we first look back to some timeless contributions to the field. The obvious and fascinating variation among animals is much more evident than is their shared physiological unity, which transcends both body size and specific adaptations. The "unity in diversity" reveals general patterns and principles of physiology that are invisible when examining only one species. Next, we examine selected contemporary contributions to comparative physiology, which provides the context in which reductionist experiments are best interpreted. We discuss the sometimes surprising insights provided by two comparative "athletes" (pronghorn and rattlesnakes), which demonstrate 1) animals are not isolated molecular mechanisms but highly integrated physiological machines, a single "rate-limiting" step may be exceptional; and 2) extremes in nature are rarely the result of novel mechanisms, but rather employ existing solutions in novel ways. Furthermore, rattlesnake tailshaker muscle effectively abolished the conventional view of incompatibility of simultaneous sustained anaerobic glycolysis and oxidative ATP production. We end this review by looking forward, much as Krogh did, to suggest that a comparative approach may best lend insights in unraveling how skeletal muscle stores and recovers mechanical energy when operating cyclically. We discuss and speculate on the role of the largest known protein, titin (the third muscle filament), as a dynamic spring capable of storing and recovering elastic recoil potential energy in skeletal muscle. [ABSTRACT FROM AUTHOR]

The diving physiology of aquatic animals at sea began 50 years ago with studies of the Weddell seal. Even today with the advancements in marine recording and tracking technology, only a few species are suitable for investigation. The first experiments were in McMurdo Sound, Antarctica. In this paper are examples of what was learned in Antarctica and elsewhere. Some methods employed relied on willingness of Weddell seals and emperor penguins to dive under sea ice. Diving depth and duration were obtained with a time depth recorder. Some dives were longer than an hour and as deep as 600 m. From arterial blood samples, lactate and nitrogen concentrations were obtained. These results showed how Weddell seals manage their oxygen stores, that they become reliant on a positive contribution of anaerobic metabolism during a dive duration of more than 20 min, and that nitrogen blood gases remain so low that lung collapse must occur at about 25 to 50 m. This nitrogen level was similar to that determined in elephant seals during forcible submersion with compression to depths greater than 100 m. These results led to further questions about diving mammal's terminal airway structure in the lungs. Much of the strengthening of the airways is not for avoiding the "bends," by enhancing lung collapse at depth, but for reducing the resistance to high flow rates during expiration. The most exceptional examples are the small whales that maintain high expiratory flow rates throughout the entire vital capacity, which represents about 90% of their total lung capacity. [ABSTRACT FROM AUTHOR]

Neuronal stimulation by light is a novel approach in the emerging field of optogenetics, where genetic engineering is used to introduce light-activated chan-nels. However, light is also capable of stimulating neurons even in the absence of genetic modifications through a range of physical and biological mechanisms. As a result, rigorous design of optogenetic experiments needs to take note of alterna-tive and parallel effects of light illumination of neuronal tissues. Thus all matters relating to light penetration are critical to the development of studies using light-activated proteins. This paper discusses ways to quantify light, light penetra-tion in tissue, as well as light stimulation of neurons in physiological conditions. We also describe the direct effect of light on neurons investigated at different sites. [ABSTRACT FROM AUTHOR]

Editorial. Examines the historical significance of the study "Effect of mean circulatory filling pressure and other peripheral circulatory factors on cardiac output," by A.C. Gluton et al and published in a 1955 issue of the "American Journal of Physiology". Emphasis on venous return as a determinant of cardiac output; Systematic analysis of the various factors that nfluence venous return; Effect of increased mean circulatory filling pressure on the venous return.

The biological clock is an invisible "clock" in the organism, which can regulate behavior, physiology, and biochemical reactions. However, the relationship between clock genes and energy metabolism in postexercise skeletal muscle is not well known. The purpose of this study was to determine the mechanisms through which peripheral clock genes regulate energy metabolism in skeletal muscle. We analyzed the rhythm of mRNA expression of the clock genes Bmal1 and Clock in skeletal muscle following heavyload exercise and measured related indicators of mitochondrial structure and function. We obtained the following experimental results. First, heavy-load exercise induced loss of circadian rhythm of Bmal1 between ZT0 and ZT24, and the circadian rhythm of Clock was not restored between ZT0 and ZT72. Second, analysis of mitochondrial morphology in group E showed abnormal swelling and ridge structure damage at ZT0, which recovered somewhat at ZT24 and ZT48, and the damage had essentially disappeared by ZT72. Third, the expression of NAMPT/NAD þ/SIRT1 signaling axis proteins in group E was abnormal at ZT0, the content of NAMPT and the activity of SIRT1 significantly increased, and the content of NAD þ significantly decreased. Fourth, the expression of BMAL1 and PGC-1a in group E significantly increased, whereas the ATP and ADP content, as well as the activities of COXII and COXIV, were significantly changed. Finally, the colocalization of BMAL1 and SIRT1 in group E was significantly upregulated at ZT0. These results suggest that the skeletal muscle clock gene Bmal1 may regulate the energy metabolism level of skeletal muscle after exercise through the NAMPT/NAD þ/SIRT1 signaling pathway. [ABSTRACT FROM AUTHOR]

Prostaglandins (PGs) serve as signaling molecules that regulate various physiological processes, including inflammation, immune response, blood clotting, and reproduction. The aim of this study was to investigate the immunolocalizations and expression patterns of prostaglandin-E2 (PGE2), cyclooxygenase (COX)-1, and COX-2, as well as its receptor subtypes 4 (EP4) in the scent glands of muskrats (Ondatra zibethicus) during the breeding and nonbreeding periods. There were significant seasonal differences in the scent glandular mass, with higher values in the breeding season and relatively low in the nonbreeding season. PGE2, EP4, COX-1, and COX-2 have been immunolocalized in the scent glandular and epithelial cells in both breeding and nonbreeding seasons, whereas no immunostaining was observed in the interstitial cells. The protein and mRNA expression levels of EP4, COX-1, and COX-2 were higher in the scent glands of the breeding season than those of the nonbreeding season. The mean mRNA levels of EP4, COX-1, and COX-2 were positively correlated with the scent glandular weights. The circulating follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), and PGE2, as well as scent glandular PGE2 and dihydrotestosterone (DHT) concentrations, were also significantly higher in the breeding season. In addition, the transcriptomic study in the scent glands identified that differentially expressed genes might be related to fatty carboxylic monocarboxylic acid, steroidogenic- related pathways, and prostanoid metabolic processes. These findings suggested that prostaglandin-E2 might play an essential autocrine or paracrine role in regulating seasonal changes in the scent glandular functions of the muskrats. [ABSTRACT FROM AUTHOR]

To investigate the role of glial cells in the regulation of glucoprivic responses in rats, a chemogenetic approach was used to activate astrocytes neighboring catecholamine (CA) neurons in the ventromedial medulla (VLM) where A1 and C1 CA cell groups overlap (A1/C1). Previous results indicate that activation of CA neurons in this region is necessary and sufficient for feeding and corticosterone release in response to glucoprivation. However, it is not known whether astrocyte neighbors of CA neurons contribute to glucoregulatory responses. Hence, we made nanoinjections of AAV5-GFAP-hM3D(Gq)-mCherry to selectively transfect astrocytes in the A1/C1 region with the excitatory designer receptor exclusively activated by designer drugs (DREADDs), hM3D (Gq). After allowing time for DREADD expression, we evaluated the rats for increased food intake and corticosterone release in response to low systemic doses of the antiglycolytic agent, 2-deoxy-D-glucose (2DG), alone and in combination with the hM3D (Gq) activator clozapine-N-oxide (CNO). We found that DREADD-transfected rats ate significantly more food when 2DG and CNO were coadministered than when either 2DG or CNO was injected alone. We also found that CNO significantly enhanced 2DG-induced FOS expression in the A1/C1 CA neurons, and that corticosterone release also was enhanced when CNO and 2DG were administered together. Importantly, CNO-induced activation of astrocytes in the absence of 2DG did not trigger food intake or corticosterone release. Our results indicate that during glucoprivation, activation of VLM astrocytes cells markedly increases the sensitivity or responsiveness of neighboring A1/C1 CA neurons to glucose deficit, suggesting a potentially important role for VLM astrocytes in glucoregulation. [ABSTRACT FROM AUTHOR]

The present paper provides an overview of adaptive changes in brain structure and learning abilities during hibernation as a behavioral strategy used by several mammalian species to minimize energy expenditure under current or anticipated inhospitable environmental conditions. One cellular mechanism that contributes to the regulated suppression of metabolism and thermogenesis during hibernation is reversible phosphorylation of enzymes and proteins, which limits rates of flux through metabolic pathways. Reversible phosphorylation during hibernation also affects synaptic membrane proteins, a process known to be involved in synaptic plasticity. This mechanism of reversible protein phosphorylation also affects the microtubule-associated protein tau, thereby generating a condition that in the adult human brain is associated with aggregation of tau protein to paired helical filaments (PHFs), as observed in Alzheimer's disease. Here, we put forward the concept that phosphorylation of tau is a neuroprotective mechanism to escape NMDA-mediated hyperexcitability of neurons that would otherwise occur during slow gradual cooling of the brain. Phosphorylation of tau and its subsequent targeting to subsynaptic sites might, thus, work as a kind of "master switch," regulating NMDA receptor-mediated synaptic gain in a wide array of neuronal networks, thereby enabling entry into torpor. If this condition lasts too long, however, it may eventually turn into a pathological trigger, driving a cascade of events leading to neurodegeneration, as in Alzheimer's disease or other "tauopathies". [ABSTRACT FROM AUTHOR]