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Promoter-proximal pausing by RNA polymerase II (Pol II) ensures gene-specific regulation and RNA quality control. Structural considerations suggested a requirement for initiation-factor eviction in elongation-factor engagement and pausing of transcription

The cyclin-dependent kinases (CDKs) that promote cell-cycle progression are targets for negative regulation by signals from damaged or unreplicated DNA, but also play active roles in response to DNA lesions. The requirement for activity in the face of DNA

Protein kinase C iota is required for various cell biological processes including epithelial tissue polarity and organ morphogenesis. To gain mechanistic insight into different roles of this kinase, it is essential to identify specific substrate proteins i

Mindfulness has gained widespread recognition for its benefits to mental health, cognitive performance, and wellbeing. However, the multifaceted nature of mindfulness, encompassing elements like attentional focus, emotional regulation, and present-moment awareness, complicates its definition and measurement. A key component that may underlie its broad benefits is equanimity - the ability to maintain an open and non-reactive attitude toward all sensory experiences. Empirical research suggests that mindfulness works through a combination of top-down attentional control and bottom-up sensory and emotional processes, and that equanimity's role in regulating those bottom-up processes drives the psychological and physiological benefits, making it a promising target for both theoretical and practical exploration. Given these findings, the development of interventions that specifically augment equanimity could improve the impact of mindfulness practices. Research into non-invasive brain stimulation (NIBS) suggests that it is a potential tool for altering neural circuits involved in mindfulness. However, most NIBS studies to date have focused on improving cognitive control systems, leaving equanimity relatively unexplored. Preliminary findings from focused ultrasound interventions targeting the posterior cingulate cortex (PCC) suggest that NIBS can directly facilitate equanimity by inhibiting self-referential processing in the default mode network (DMN) to promote a more present-centered state of awareness. Future research should prioritize the integration of NIBS with well-defined mindfulness training protocols, focusing on equanimity as a core target. This approach could provide a novel framework for advancing both contemplative neuroscience and clinical applications, offering new insights into the mechanisms of mindfulness and refining NIBS methodologies to support individualized, precision wellness interventions., (Copyright © 2024. Published by Elsevier Inc.)

Storylines of Family Medicine is a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In 'IX: people and places-diverse populations and locations of care', authors address the following themes: 'LGBTQIA+health in family medicine', 'A family medicine approach to substance use disorders', 'Shameless medicine for people experiencing homelessness', '''Difficult" encounters-finding the person behind the patient', 'Attending to patients with medically unexplained symptoms', 'Making house calls and home visits', 'Family physicians in the procedure room', 'Robust rural family medicine' and 'Full-spectrum family medicine'. May readers appreciate the breadth of family medicine in these essays., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Recent reviews highlighted low-intensity transcranial focused ultrasound (TUS) as a promising new tool for non-invasive neuromodulation in basic and applied sciences. Our preregistered double-blind within-subjects study (N = 152) utilized TUS targeting the right prefrontal cortex, which, in earlier work, was found to positively enhance self-reported global mood, decrease negative states of self-reported emotional conflict (anxiety/worrying), and modulate related midfrontal functional magnetic resonance imaging activity in affect regulation brain networks. To further explore TUS effects on objective physiological and behavioral variables, we used a virtual T-maze task that has been established in prior studies to measure motivational conflicts regarding whether participants execute approach versus withdrawal behavior (with free-choice responses via continuous joystick movements) while allowing to record related electroencephalographic data such as midfrontal theta activity (MFT). MFT, a reliable marker of conflict representation on a neuronal level, was of particular interest to us since it has repeatedly been shown to explain related behavior, with relatively low MFT typically preceding approach-like risky behavior and relatively high MFT typically preceding withdrawal-like risk aversion. Our central hypothesis is that TUS decreases MFT in T-maze conflict situations and thereby increases approach and reduces withdrawal. Results indicate that TUS led to significant MFT decreases, which significantly explained increases in approach behavior and decreases in withdrawal behavior. This study expands TUS evidence on a physiological and behavioral level with a large sample size of human subjects, suggesting the promise of further research based on this distinct TUS-MFT-behavior link to influence conflict monitoring and its behavioral consequences. Ultimately, this can serve as a foundation for future clinical work to establish TUS interventions for emotional and motivational mental health., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Joseph L Sanguinetti is paid a salary and is a shareholder in Sanmai Technologies, PBC. Philipp Ziebell, Johannes Rodrigues, André Forster, John JB Allen, and Johannes Hewig have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Being able to control inner and environmental states is a basic need of living creatures. The perception of such control is based on the perceived ratio of outcome probabilities given the presence and the absence of agentic behavior. If an organism believes that options exist to change the probability of a given outcome, control perception (CP) may emerge. Nonetheless, regarding this model, not much is known about how the brain processes CP from this information. This study uses low-intensity transcranial focused ultrasound neuromodulation in a randomized-controlled double blind cross-over design to investigate the impact of the right inferior frontal gyrus of the lateral prefrontal cortex (lPFC) on this process. 39 healthy participants visited the laboratory twice (once in a sham, once in a neuromodulation condition) and rated their control perception regarding a classical control illusion task. EEG alpha and theta power density were analyzed in a hierarchical single trial-based mixed modeling approach. Results indicate that the litFUS neuromodulation changed the processing of stimulus probability without changing CP. Furthermore, neuromodulation of the right lPFC was found to modulate mid-frontal theta by altering its relationship with self-reported effort and worrying. While these data indicate lateral prefrontal sensitivity to stimulus probability, no evidence emerged for the dependency of CP on this processing., Competing Interests: Declaration of competing interest Author Sanguinetti is paid a salary and is a shareholder in Sanmai Technologies, PBC., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Variable heart rate during single-cycle inversion-recovery Late Gadolinium-Enhanced (LGE) scanning degrades image quality, which can be mitigated using Variable Inversion Times (VTIs) in real-time response to R-R interval changes. We investigate in vivo and in simulations an extension of a single-cycle VTI method previously applied in 3D LGE imaging, that now fully models the longitudinal magnetisation (fmVTI)., Methods: The VTI and fmVTI methods were used to perform 3D LGE scans for 28 3D LGE patients, with qualitative image quality scores assigned for left atrial wall clarity and total ghosting. Accompanying simulations of numerical phantom images were assessed in terms of ghosting of normal myocardium, blood, and myocardial scar., Results: The numerical simulations for fmVTI showed a significant decrease in blood ghosting (VTI: 410 ± 710, fmVTI: 68 ± 40, p < 0.0005) and scar ghosting (VTI: 830 ± 1300, fmVTI: 510 ± 730, p < 0.02). Despite this, there was no significant change in qualitative image quality scores, either for left atrial wall clarity (VTI: 2.0 ± 1.0, fmVTI: 1.8 ± 1.0, p > 0.1) or for total ghosting (VTI: 1.9 ± 1.0, fmVTI: 2.0 ± 1.0, p > 0.7)., Conclusions: Simulations indicated reduced ghosting with the fmVTI method, due to reduced Mz variability in the blood signal. However, other sources of phase-encode ghosting and blurring appeared to dominate and obscure this finding in the patient studies available., Competing Interests: Declaration of Competing Interest The authors declare there are no known competing interests to declare with regards to this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Successful sexual reproduction relies on the coordination of multiple biological systems, yet traditional concepts of biological sex often ignore the natural plasticity in morphology and physiology underlying sex. Most female mammals develop a patent (i.e., opened) vaginal entrance (introitus) prenatally or postnatally before or during puberty, usually under the influence of estrogens, and remain patent for the remainder of their lifespan 1 . An exception is the southern African giant pouched rat (Cricetomys ansorgei), whose vaginal introitus remains sealed well into adulthood 2 . Here, we explore this phenomenon and report that the reproductive organs and the vaginal introitus can undergo astounding and reversible transformation. Non-patency is characterized by reduced uterine size and the presence of a sealed vaginal introitus. Furthermore, the female urine metabolome shows that patent and non-patent females profoundly differ in their urine content, a reflection of differences in physiology and metabolism. Surprisingly, patency state did not predict fecal estradiol or progesterone metabolite concentrations. Exploring the plasticity that exists in reproductive anatomy and physiology can uncover that traits long considered 'fixed' in adulthood can become plastic under specific evolutionary pressures. Moreover, the barriers to reproduction that such plasticity creates present unique challenges to maximizing reproductive potential., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Closed-loop neuromodulation is presumed to be the logical evolution for improving the effectiveness of deep brain stimulation (DBS) treatment protocols (Widge et al., 2018). Identifying symptom-relevant biomarkers that provide meaningful feedback to stimulator devices is an important initial step in this direction. This report demonstrates a technique for assaying neural circuitry hypothesized to contribute to OCD and DBS treatment outcomes. We computed phase-lag connectivity between LFPs and EEGs in thirteen treatment-refractory OCD patients. Simultaneous recordings from scalp EEG and externalized DBS electrodes in the ventral capsule/ventral striatum (VC/VS) were collected at rest during the perioperative treatment stage. Connectivity strength between midfrontal EEG sensors and VC/VS electrodes correlated with baseline OCD symptoms and 12-month posttreatment OCD symptoms. Results are qualified by a relatively small sample size, and limitations regarding the conclusiveness of VS and mPFC as neural generators given some concerns about volume conduction. Nonetheless, findings are consistent with treatment-relevant tractography findings and theories that link frontostriatal hyperconnectivity to the etiopathogenesis of OCD. Findings support the continued investigation of connectivity-based assays for aiding in determination of optimal stimulation location, and are an initial step towards the identification of biomarkers that can guide closed-loop neuromodulation systems., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Most dairy cows develop a dominant follicle within two weeks postpartum, but 60% of these follicles fail to ovulate. In a previous study, we determined that cows destined to ovulate have higher LH pulse frequency and circulating estradiol. The latter characteristic provided a method for distinguishing ovulatory from nonovulatory follicles during development and we found that nonovulatory follicles have lower estradiol and androstenedione in their follicular fluid. We hypothesized that lower LH pulse frequency impairs androgen production by theca cells of nonovulatory cows, reducing their ability to make estradiol. In the present study, we applied our method for predicting follicle fate to collect dominant follicles from predicted ovulatory (n = 7) and nonovulatory (n = 3) follicles. Theca and granulosa cells were separated and cultured in the absence or presence of LH, FSH, and/or testosterone for three days, with daily collection of culture medium for steroid RIAs. Estradiol and progesterone production by granulosa cells were not different between ovulatory and nonovulatory follicles. By contrast, overall androstenedione production by theca cells from ovulatory follicles was significantly higher compared with nonovulatory follicles on all three days of culture and, as culture progressed, theca from nonovulatory follicles had increasingly poorer responses to LH. In the same cultures, the progesterone production by theca cells was similar in ovulatory and nonovulatory groups. In support of our hypothesis, the results show that estradiol production by granulosa cells from nonovulatory follicles is robust when androgen substrate is present, but that thecal androgen production in response to LH is impaired. This suggests that the initial defect in steroidogenesis in dominant follicles that fail to ovulate postpartum is lower production of androgen by theca cells., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The potential role of brief online studies in changing the types of research and theories likely to evolve is examined in the context of earlier changes in theory and methods in social and personality psychology, changes that favored low-difficulty, high-volume studies. An evolutionary metaphor suggests that the current publication environment of social and personality psychology is a highly competitive one, and that academic survival and reproduction processes (getting a job, tenure/promotion, grants, awards, good graduate students) can result in the extinction of important research domains. Tracking the prevalence of brief online studies, exemplified by studies using Amazon Mechanical Turk, in three top journals ( Journal of Personality and Social Psychology, Personality and Social Psychology Bulletin, Journal of Experimental Social Psychology) reveals a dramatic increase in their frequency and proportion. Implications, suggestions, and questions concerning this trend for the field and questions for its practitioners are discussed.

Background: Jones fractures result in subsequent dysfunction and remain an issue for athletes., Purpose: To (1) describe the epidemiology, treatment, and impact of Jones fractures identified at the National Football League (NFL) Scouting Combine on players' early careers and (2) establish the value of computed tomography (CT) to determine bony healing after a fracture in prospective players., Study Design: Cohort study; Level of evidence, 3., Methods: All players who attended the combine between 2009 and 2015 were retrospectively reviewed to identify their history of Jones fractures. The playing position, treatment method, and number of missed collegiate games were recorded. The mean overall draft pick number, number of games started and played, snap percentage, and position-specific performance scores (fantasy score) over the first 2 years in the NFL were compared between players with fractures and controls. An imaging classification system was applied based on grading of each quadrant of the fifth metatarsal (plantar, dorsal, medial, lateral), with a score of 0 for not healed or 1 for healed., Results: Overall, the number of Jones fractures identified was 72 in 2285 athletes (3.2%), with all treated via intramedullary screw fixation. The mean overall draft pick number for players with fractures was 111.2 ± 67.9 compared with 99.0 ± 65.9 for controls ( P = .12). Performance scores for players with fractures were lower than those for controls across all positions, with a significant difference in running backs (2.6 vs 4.0, respectively; P < .001) and defensive linemen (1.4 vs 2.3, respectively; P = .02). The mean CT score was 2.5 ± 1.3. Of the 32 athletes who underwent imaging, 16 Jones fractures (50.0%) were healed or nearly healed, 12 (37.5%) were partially healed, and 4 (12.5%) showed little or no healing. The plantar cortex demonstrated the least healing (18/32; 56.3%), followed by the lateral cortex (15/32; 46.9%). Players with a mean score <1 were found to have fewer games started (2.7 ± 2.5) than those with 1 to 3 cortices healed (17.4 ± 10.4) or all cortices healed (8.7 ± 11.2)., Conclusion: Based on CT, 50% of all players with a previous Jones fracture demonstrated incomplete healing. Moreover, position-specific performance scores over the first 2 years of a player's career were lower across all positions for those with fractures compared with controls. Players with CT scores <1 were found to start fewer games and were drafted later than controls., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: T.O.C. receives royalties from Arthrex and Stryker, is a paid consultant for Arthrex and Stryker, is a paid speaker/presenter for Arthrex and Stryker, and receives research support from Arthrex. M.T.P. receives royalties from Arthrex and SLACK and is a paid consultant for Arthrex and the Joint Restoration Foundation (AlloSource).

The General Aggression Model (GAM) is a comprehensive, integrative, framework for understanding aggression. It considers the role of social, cognitive, personality, developmental, and biological factors on aggression. Proximate processes of GAM detail how person and situation factors influence cognitions, feelings, and arousal, which in turn affect appraisal and decision processes, which in turn influence aggressive or nonaggressive behavioral outcomes. Each cycle of the proximate processes serves as a learning trial that affects the development and accessibility of aggressive knowledge structures. Distal processes of GAM detail how biological and persistent environmental factors can influence personality through changes in knowledge structures. GAM has been applied to understand aggression in many contexts including media violence effects, domestic violence, intergroup violence, temperature effects, pain effects, and the effects of global climate change., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: At the annual National Football League (NFL) Scouting Combine, the medical staff of each NFL franchise performs a comprehensive medical evaluation of all athletes potentially entering the NFL. Currently, little is known regarding the overall epidemiology of injuries identified at the combine and their impact on NFL performance., Purpose: To determine the epidemiology of injuries identified at the combine and their impact on initial NFL performance., Study Design: Cohort study; Level of evidence, 3., Methods: All previous musculoskeletal injuries identified at the NFL Combine from 2009 to 2015 were retrospectively reviewed. Medical records and imaging reports were examined. Game statistics for the first 2 seasons of NFL play were obtained for all players from 2009 to 2013. Analysis of injury prevalence and overall impact on the draft status and position-specific performance metrics of each injury was performed and compared with a position-matched control group with no history of injury or surgery., Results: A total of 2203 athletes over 7 years were evaluated, including 1490 (67.6%) drafted athletes and 1040 (47.2%) who ultimately played at least 2 years in the NFL. The most common sites of injury were the ankle (1160, 52.7%), shoulder (1143, 51.9%), knee (1128, 51.2%), spine (785, 35.6%), and hand (739, 33.5%). Odds ratios (ORs) demonstrated that quarterbacks were most at risk of shoulder injury (OR, 2.78; P = .001), while running backs most commonly sustained ankle (OR, 1.39; P = .040) and shoulder injuries (OR, 1.55; P = .020) when compared with all other players. Ultimately, defensive players demonstrated a greater negative impact due to injury than offensive players, with multiple performance metrics significantly affected for each defensive position analyzed, whereas skilled offensive players (eg, quarterbacks, running backs) demonstrated only 1 metric significantly affected at each position., Conclusion: The most common sites of injury identified at the combine were (1) ankle, (2) shoulder, (3) knee, (4) spine, and (5) hand. Overall, performance in the NFL tended to worsen with injury history, with a direct correlation found between injury at a certain anatomic location and position of play. Defensive players tended to perform worse compared with offensive players if injury history was present., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: M.T.P. is a consultant for Arthrex and the Joint Restoration Foundation (Allosource) and receives royalties from Arthrex and SLACK Inc.

Male cuttlefish compete for females with a repertoire of visually dramatic behaviors. Laboratory experiments have explored this system in Sepia officinalis, but corroborative field data have eluded collection attempts by many researchers. While scuba diving in Turkey, we fortuitously filmed an intense sequence of consort/intruder behaviors in which the consort lost and then regained his female mate from the intruder. These agonistic bouts escalated in stages, leading to fast dramatic expression of the elaborate intense zebra display and culminating in biting and inking as the intruder male attempted a forced copulation of the female. When analyzed in the context of game theory, the patterns of fighting behavior were more consistent with mutual assessment than self-assessment of fighting ability. Additional observations of these behaviors in nature are needed to conclusively determine which models best represent conflict resolution, but our field observations agree with laboratory findings and provide a valuable perspective.

Unlike birds and insects, bats fly with wings composed of thin skin that envelops the bones of the forelimb and spans the area between the limbs, digits, and sometimes the tail. This skin is complex and unusual; it is thinner than typical mammalian skin and contains organized bundles of elastin and embedded skeletal muscles. These elements are likely responsible for controlling the shape of the wing during flight and contributing to the aerodynamic capabilities of bats. We examined the arrangement of two macroscopic architectural elements in bat wings, elastin bundles and wing membrane muscles, to assess the diversity in bat wing skin morphology. We characterized the plagiopatagium and dactylopatagium of 130 species from 17 families of bats using cross-polarized light imaging. This method revealed structures with distinctive relative birefringence, heterogeneity of birefringence, variation in size, and degree of branching. We used previously published anatomical studies and tissue histology to identify birefringent structures, and we analyzed their architecture across taxa. Elastin bundles, muscles, neurovasculature, and collagenous fibers are present in all species. Elastin bundles are oriented in a predominantly spanwise or proximodistal direction, and there are five characteristic muscle arrays that occur within the plagiopatagium, far more muscle than typically recognized. These results inform recent functional studies of wing membrane architecture, support the functional hypothesis that elastin bundles aid wing folding and unfolding, and further suggest that all bats may use these architectural elements for flight. All species also possess numerous muscles within the wing membrane, but the architecture of muscle arrays within the plagiopatagium varies among families. To facilitate present and future discussion of these muscle arrays, we refine wing membrane muscle nomenclature in a manner that reflects this morphological diversity. The architecture of the constituents of the skin of the wing likely plays a key role in shaping wings during flight., (© 2017 Anatomical Society.)

Frontal electroencephalographic (EEG) alpha asymmetry is widely researched in studies of emotion, motivation, and psychopathology, yet it is a metric that has been quantified and analyzed using diverse procedures, and diversity in procedures muddles cross-study interpretation. The aim of this article is to provide an updated tutorial for EEG alpha asymmetry recording, processing, analysis, and interpretation, with an eye towards improving consistency of results across studies. First, a brief background in alpha asymmetry findings is provided. Then, some guidelines for recording, processing, and analyzing alpha asymmetry are presented with an emphasis on the creation of asymmetry scores, referencing choices, and artifact removal. Processing steps are explained in detail, and references to MATLAB-based toolboxes that are helpful for creating and investigating alpha asymmetry are noted. Then, conceptual challenges and interpretative issues are reviewed, including a discussion of alpha asymmetry as a mediator/moderator of emotion and psychopathology. Finally, the effects of two automated component-based artifact correction algorithms-MARA and ADJUST-on frontal alpha asymmetry are evaluated., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In cattle, primordial follicles form before birth. Fetal ovarian capacity to produce progesterone and estradiol is high before follicle formation begins and decreases around the time follicles first appear (around 90 days of gestation). However, mechanisms that regulate steroid production during this time remain unclear. We hypothesized that LH stimulates progesterone and androgen production and that FSH stimulates aromatization of androgens to estradiol. To test this, we cultured pieces from fetal bovine ovaries for 10 days without or with exogenous hormones and then measured the accumulation of steroids in the culture medium by RIA. LH (100 ng/mL) alone increased the accumulation of progesterone, androstenedione, testosterone and estradiol. FSH (100 ng/mL) alone increased both progesterone and estradiol accumulation, but had no effect on androgens. Exogenous testosterone (0.5 µM) alone greatly increased estradiol accumulation and the combination of testosterone + FSH, but not testosterone + LH, increased estradiol relative to testosterone alone. Interestingly, exogenous testosterone and estradiol decreased progesterone accumulation in a dose-dependent manner. Because the highest dose of estradiol (0.5 µM) decreased progesterone accumulation, but increased both pregnenolone and androstenedione in the same cultures, endogenous estradiol may be a paracrine regulator of steroid synthesis. Together, these results confirm our initial hypotheses and indicate that LH stimulates androgen production in fetal bovine ovaries via the Δ 5 pathway, whereas FSH stimulates aromatization of androgens to estradiol. These results are consistent with the two-cell, two-gonadotropin model of estradiol production by bovine preovulatory follicles, which suggests that the mechanisms regulating ovarian steroid production are established during fetal life., (© 2016 Society for Endocrinology.)

Importance: Limitations of current antidepressants highlight the need to identify novel treatments for major depressive disorder. A prior open trial found that a single session of whole-body hyperthermia (WBH) reduced depressive symptoms; however, the lack of a placebo control raises the possibility that the observed antidepressant effects resulted not from hyperthermia per se, but from nonspecific aspects of the intervention., Objective: To test whether WBH has specific antidepressant effects when compared with a sham condition and to evaluate the persistence of the antidepressant effects of a single treatment., Design, Setting, and Participants: A 6-week, randomized, double-blind study conducted between February 2013 and May 2015 at a university-based medical center comparing WBH with a sham condition. All research staff conducting screening and outcome procedures were blinded to randomization status. Of 338 individuals screened, 34 were randomized, 30 received a study intervention, and 29 provided at least 1 postintervention assessment and were included in a modified intent-to-treat efficacy analysis. Participants were medically healthy, aged 18 to 65 years, met criteria for major depressive disorder, were free of psychotropic medication use, and had a baseline 17-item Hamilton Depression Rating Scale score of 16 or greater., Interventions: A single session of active WBH vs a sham condition matched for length of WBH that mimicked all aspects of WBH except intense heat., Main Outcomes and Measures: Between-group differences in postintervention Hamilton Depression Rating Scale scores., Results: The mean (SD) age was 36.7 (15.2) years in the WBH group and 41.47 (12.54) years in the sham group. Immediately following the intervention, 10 participants (71.4%) randomized to sham treatment believed they had received WBH compared with 15 (93.8%) randomized to WBH. When compared with the sham group, the active WBH group showed significantly reduced Hamilton Depression Rating Scale scores across the 6-week postintervention study period (WBH vs sham; week 1: -6.53, 95% CI, -9.90 to -3.16, P < .001; week 2: -6.35, 95% CI, -9.95 to -2.74, P = .001; week 4: -4.50, 95% CI, -8.17 to -0.84, P = .02; and week 6: -4.27, 95% CI, -7.94 to -0.61, P = .02). These outcomes remained significant after evaluating potential moderating effects of between-group differences in baseline expectancy scores. Adverse events in both groups were generally mild., Conclusions and Relevance: Whole-body hyperthermia holds promise as a safe, rapid-acting, antidepressant modality with a prolonged therapeutic benefit., Trial Registration: clinicaltrials.gov Identifier: NCT01625546.

Theta oscillations in the EEG have been shown to reflect ongoing cognitive processes related to mental effort. Here, we show that the pattern of theta oscillation in response to varying cognitive demands reflects stable individual differences in the personality trait epistemic motivation: Individuals with high levels of epistemic motivation recruit relatively more cognitive resources in response to situations possessing high, compared to low, cognitive demand; individuals with low levels do not show such a specific response. Our results provide direct evidence for the theory of the construct need for cognition and add to our understanding of the neural processes underlying theta oscillations. More generally, we provide an explanation how individual differences in personality traits might be represented on a neural level.

Some authors have argued that worry cues lateralization of frontal brain activity leftward, whereas other varieties of avoidance motivation cue lateralization of frontal brain activity rightward. By comparison, more right-than-left parietal activity correlates with anxious arousal. The purpose of the present report was to test two models of brain lateralization and anxiety: one model that proposed that worry correlates with more left-frontal activity and another model that proposed that avoidance motivation (including worry) correlates with more right-frontal activity. Undergraduate students were selected for worry, obsessive-compulsive symptoms, and trait anxiety using self-report questionnaires. A subset of participants also met DSM-IV criteria for Generalized Anxiety Disorder (GAD) or Obsessive-Compulsive Disorder (OCD). Alpha asymmetry and also a global-power-adjusted metric of alpha power were calculated from each participant's resting-state EEG. It was expected that participants with elevated worry and participants meeting criteria for GAD would show more left-than-right frontal activity. In contrast, participants with elevated trait anxiety, obsessive-compulsive symptoms, and those with an OCD diagnosis were expected to exhibit more right-than-left frontal activity. Participants with elevated worry, participants with a GAD diagnosis, and participants with elevated obsessive-compulsive symptoms, had more left frontal activity than low symptom individuals. Those with high scores on trait anxiety, but low worry, had greater right frontal and parietal activity compared to controls. The present results suggest that brain lateralization is not solely related to avoidance motivation, and suggest that facets of anxiety may cut across dimensions not well-represented by DSM-based categories., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Since the 1970s, researchers have studied the influence of exercise during pregnancy on offspring heart development. With the knowledge and current evidence of fetal programming effects, research has demonstrated that exercise is safe and beneficial for mother, fetus, and neonate. Predominantly, research has focused on maternal and fetal cardiac adaptations related to aerobic exercise during pregnancy; less is known regarding the effects of resistance or combination (aerobic and resistance) training during pregnancy. Ongoing research is focusing on fetal responses to different intensity, duration and modes of maternal exercise throughout pregnancy. This article will summarize our current state of knowledge regarding the influence of exercise intensity, duration, and modes during pregnancy on maternal and fetal cardiac responses., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Depression carries serious psychosocial, physical, and economic consequences for cancer survivors. Study goals were to characterize patterns and predictors of depressive symptoms and major depressive episodes in recently diagnosed breast cancer patients. Consecutively recruited women (N = 460) completed a validated interview (CIDI) and questionnaire measure (CES-D) of depression within 4 months after invasive breast cancer diagnosis and at six additional assessments across 12 months. Outcomes were major depressive episodes, continuous symptom scores, and latent symptom trajectory classes. Across 12 months, 16.6 % of women met criteria for a major depressive episode. Unemployment predicted depressive episodes after other correlates were controlled. Distinct trajectory classes were apparent: an estimated 38 % of women had chronically elevated symptoms (High trajectory), 20 % recovered from elevated symptoms (Recovery), and 43 % had lower symptoms (Low and Very Low trajectories). Although 96 % of episodes occurred in the High or Recovery classes, 66 % of women in the High trajectory did not have an episode. Women in the Low (vs High) trajectory were more likely to be older, retired, more affluent, and have fewer comorbid diseases and briefer oncologic treatment. Women in the Recovery trajectory (vs High) were more likely to be married and more affluent and have fewer comorbid diseases. Assuming available therapeutic resources, assessment of both depressive symptoms and episodes over several months after diagnosis is important. Identification of patients at risk for persistently high depressive symptoms (e.g., younger, longer treatment course) opens targeted opportunities to prevent and promote rapid recovery from depression.

The slender filefish is a master of adaptive camouflage and can change its appearance within 1-3 seconds. Videos and photographs of this animal's cryptic body patterning and behavior were collected in situ under natural light on a Caribbean coral reef. We present an ethogram of body patterning components that includes large- and small-scale spots, stripes and bars that confer a variety of cryptic patterns amidst a range of complex backgrounds. Field images were analyzed to investigate two aspects of camouflage effectiveness: (i) the degree of color resemblance between animals and their nearby visual stimuli and (ii) the visibility of each fish's actual body outline versus its illusory outline. Most animals more closely matched the color of nearby visual stimuli than that of the surrounding background. Three-dimensional dermal flaps complement the melanophore skin patterns by enhancing the complexity of the fish's physical skin texture to disguise its actual body shape, and the morphology of these structures was studied. The results suggest that the body patterns, skin texture, postures and swimming orientations putatively hinder both the detection and recognition of the fish by potential visual predators. Overall, the rapid speed of change of multiple patterns, color blending with nearby backgrounds, and the physically complicated edge produced by dermal flaps effectively camouflage this animal among soft corals and macroalgae in the Caribbean Sea.

Objectives: Major depression is associated with reduced cardiac vagal control, most commonly indexed by heart rate variability. To examine the dynamics of this abnormality, we examined within-participant covariation over time between brain activity, cardiac vagal control, and depressive symptoms in depressed patients treated with sertraline and in healthy volunteers., Methods: Patients with depression and nondepressed control participants were enrolled in a 12-week protocol. After Week 0 assessment, patients began treatment with sertraline. Neural activity and vagal control were measured for all participants at Weeks 0, 2, 6, and 12 using functional magnetic resonance imaging and synchronized electrocardiographic recordings. At each of the four assessments, a moving window analysis was used to estimate vagal control as assessed by respiratory sinus arrhythmia (RSA) from the electrocardiographic data, which was then regressed onto functional magnetic resonance imaging activity., Results: At baseline, patients showed reduced blood oxygen level-dependent RSA covariation compared with controls within multiple a priori brain regions associated with vagal control, collectively described as the medial visceromotor network (MVN). Sertraline treatment led to a significant increase in brain-RSA covariation for patients compared with controls, despite a lack of improvement in mean RSA., Conclusions: These data suggest a partial normalization of MVN dysfunction in depression during sertraline treatment. Specifically, results indicate a partial recovery of MVN function. However, this recovery was insufficient to cause a significant change in RSA levels. These results may help to explain both improvements with and limitations of sertraline treatment of depression.

The parahippocampal cortex and hippocampus are brain structures known to be involved in memory. However, the unique contribution of the parahippocampal cortex remains unclear. The current study investigates memory for object identity and memory of the configuration of objects in patients with small thermo-coagulation lesions to the hippocampus or the parahippocampal cortex. Results showed that in contrast to control participants and patients with damage to the hippocampus leaving the parahippocampal cortex intact, patients with lesions that included the right parahippocampal cortex (RPH) were severely impaired on a task that required learning the spatial configuration of objects on a computer screen; these patients, however, were not impaired at learning the identity of objects. Conversely, we found that patients with lesions to the right hippocampus (RH) or left hippocampus (LH), sparing the parahippocampal cortex, performed just as well as the control participants. Furthermore, they were not impaired on the object identity task. In the functional Magnetic Resonance Imaging (fMRI) experiment, healthy young adults performed the same tasks. Consistent with the findings of the lesion study, the fMRI results showed significant activity in the RPH in the memory for the spatial configuration condition, but not memory for object identity. Furthermore, the pattern of fMRI activity measured in the baseline control conditions decreased specifically in the parahippocampal cortex as a result of the experimental task, providing evidence for task specific repetition suppression. In summary, while our previous studies demonstrated that the hippocampus is critical to the construction of a cognitive map, both the lesion and fMRI studies have shown an involvement of the RPH for learning spatial configurations of objects but not object identity, and that this takes place independent of the hippocampus.

Frontal EEG asymmetry is a promising neurophysiological marker of depression risk. It predicts emotional response and negative affect hours to years later. Yet, inconsistencies in the literature may be due to differing methodological approaches between research groups. Within the past two years, a number of studies have shown this line of research may be strengthened by augmenting resting assessments with emotionally evocative tasks, utilizing optimal recording montages, and taking an integrative neuroscience approach that links frontal asymmetry to other indices of neural function. This review will focus on recent work in frontal asymmetry and depression with a particular focus on promising future directions and methodological considerations that may increase consistency between research groups.

This study assessed whether individual differences in self-oriented neural processing were associated with performance perceptions of minority students under stereotype threat. Resting electroencephalographic activity recorded in white and minority participants was used to predict later estimates of task errors and self-doubt on a presumed measure of intelligence. We assessed spontaneous phase-locking between dipole sources in left lateral parietal cortex (LPC), precuneus/posterior cingulate cortex (P/PCC), and medial prefrontal cortex (MPFC); three regions of the default mode network (DMN) that are integral for self-oriented processing. Results revealed that minorities with greater LPC-P/PCC phase-locking in the theta band reported more accurate error estimations. All individuals experienced less self-doubt to the extent they exhibited greater LPC-MPFC phase-locking in the alpha band but this effect was driven by minorities. Minorities also reported more self-doubt to the extent they overestimated errors. Findings reveal novel neural moderators of stereotype threat effects on subjective experience. Spontaneous synchronization between DMN regions may play a role in anticipatory coping mechanisms that buffer individuals from stereotype threat., (© The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

Objective: We tested the hypothesis that reduced rostral anterior cingulate cortex (rACC)-subcortical functional connectivity in depressed subjects might account for depression-related autonomic dysregulation., Methods: Ten healthy and ten depressed subjects categorized their immediate subjective emotional responses to picture sets while undergoing functional magnetic resonance imaging and electrocardiography. Using an rACC cluster commonly activated in both groups by emotion categorization as a seed region, we then performed voxel-wise functional connectivity analyses to examine rACC connectivity across the brain in depressed and control subjects., Results: rACC had significantly stronger connectivity with a region of the inferior pons in controls than in depressed subjects. Within-subjects differences in rACC-pons connectivity also significantly correlated with measures of both heart rate variability and depression severity., Conclusions: These findings support the hypothesis that autonomic dysregulation in depression may be associated with a functional disconnection between rACC and autonomic brainstem nuclei., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Psychophysiological theories suggest that individuals with anxiety disorders may evidence inflexibility in their autonomic activity at rest and when responding to stressors. In addition, theories of social anxiety disorder, in particular, highlight the importance of physical symptoms. Research on autonomic activity in childhood (social) anxiety disorders, however, is scarce and has produced inconsistent findings, possibly because of methodological limitations., Method: The present study aimed to account for limitations of previous studies and measured respiratory sinus arrhythmia (RSA) and heart rate (HR) using Actiheart heart rate monitors and software (Version 4) during rest and in response to a social and a non-social stressor in 60 anxious (30 socially anxious and 30 'other' anxious), and 30 nonanxious sex-and age-matched 7-12 year olds. In addition, the effect of state anxiety during the tasks was explored., Results: No group differences at rest or in response to stress were found. Importantly, however, with increases in state anxiety, all children, regardless of their anxiety diagnoses showed less autonomic responding (i.e., less change in HR and RSA from baseline in response to task) and took longer to recover once the stressor had passed., Limitations: This study focused primarily on parasympathetic arousal and lacked measures of sympathetic arousal., Conclusion: The findings suggest that childhood anxiety disorders may not be characterized by inflexible autonomic responding, and that previous findings to the contrary may have been the result of differences in subjective anxiety between anxious and nonanxious groups during the tasks, rather than a function of chronic autonomic dysregulation., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Regions of the medial visceromotor network (MVN) participate in concurrently regulating shifts in both affective state and cardiac vagal control in the attentional background, and this regulatory ability may be impaired in depression. We examined whether the relationship between changes in BOLD within MVN regions and changes in cardiac vagal control (VC) during affective state shifting changed with depression treatment. Ten depressed and ten control subjects performed an emotional counting Stroop task designed to trigger affective change in the attentional background while undergoing functional magnetic resonance imaging and concurrent electrocardiography (ECG) on four occasions: week 0 (pre-treatment) and weeks 2, 6 and 12 of treatment on sertraline. We measured the absolute value of change between adjacent emotional and neutral conditions in both VC and the BOLD signal in specific regions of the MVN. Over time consistent increases were observed in BOLD-VC magnitude correlations in depressed subjects in subgenual ACC and left DLPFC, which strongly correlated with depressive symptom improvement. Symptom improvement over time was also associated with decreases in the magnitude of both BOLD shifts and VC shifts within-subjects. This suggests that as depressive symptoms improve on sertraline, subgenual ACC and DLPFC may more efficiently regulate visceral states during affective state shifting., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

pFC is proposed to implement cognitive control via directed "top-down" influence over behavior. But how is this feat achieved? The virtue of such a descriptive model is contingent on a mechanistic understanding of how motor execution is altered in specific circumstances. In this report, we provide evidence that the well-known phenomenon of slowed RTs following mistakes (post-error slowing) is directly influenced by the degree of subthalamic nucleus (STN) activity. The STN is proposed to act as a brake on motor execution following conflict or errors, buying time so a more cautious response can be made on the next trial. STN local field potentials from nine Parkinson disease patients undergoing deep brain stimulation surgery were recorded while they performed a response conflict task. In a 2.5- to 5-Hz frequency range previously associated with conflict and error processing, the degree phase consistency preceding the response was associated with increasingly slower RTs specifically following errors. These findings provide compelling evidence that post-error slowing is in part mediated by a corticosubthalamic "hyperdirect" pathway for increased response caution.

Obsessive-Compulsive Disorder (OCD) is characterized by intrusive thoughts (i.e. obsessions) and future-oriented worrisome cognitions that are associated with behavioral ritualistic compensations (i.e. compulsions) and anxious arousal. Research has found an enhanced error-related negativity (ERN) among those with OCD in choice response tasks such as the flankers task, but not in probabilistic learning tasks. To date, research has not directly investigated whether the ERN effect observed in individuals with OCD is specific to the central features of OCD (obsessions and compulsions), or is related more closely to the worry or anxiety observed in this disorder. This study compared groups with relatively pure symptom profiles on OC, worry, and anxiety symptoms (e.g. high on OC, low on worry and anxiety) relative to a "typical" OC presentation group (e.g. high OC, mild to high worry and anxiety) and a non-anxious non-worry Control group, in both flankers and probabilistic learning tasks. For the flankers task, only the Worry group had a significantly enhanced ERN relative to controls. For the probabilistic learning task, the OC typical group had significantly enhanced ERN amplitude on suboptimal choices relative to controls. Across tasks, the experimental groups had significantly enhanced activity on error/suboptimal choices relative to the OC specific group. The results highlight the role of worry across both tasks, and to a lesser extent anxiety and OC symptoms, in performance-monitoring processes., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Interactions of ionic liquids (ILs) with water are of great interest for many potential IL applications. 1-Ethyl-3-methylimidazolium (emim) acetate, in particular, has shown interesting interactions with water including hydrogen bonding and even chemical exchange. Previous studies have shown the unusual behavior of emim acetate when in the presence of 0.43 mole fraction of water, and a combination of NMR techniques is used herein to investigate the emim acetate-water system and the unusual behavior at 0.43 mole fraction of water. NMR relaxometry techniques are used to describe the effects of water on the molecular motion and interactions of emim acetate with water. A discontinuity is seen in nuclear relaxation behavior at the concentration of 0.43 mole fraction of water, and this is attributed to the formation of a hydrogen bonded network. EXSY measurements are used to determine the exchange rates between the H2 emim proton and water, which show a complex dependence on the concentration of the mixture. The findings support and expand our previous results, which suggested the presence of an extended hydrogen bonding network in the emim acetate-water system at concentrations close to 0.50 mole fraction of H2O.

The capability model of frontal electroencephalographic (EEG) asymmetry suggests that brain activity during emotional challenge will be a more powerful indicator of predispositions toward psychopathology than activity observed at rest. EEG data were assessed during a resting baseline and a facial emotion task, wherein individuals with (n = 143) and without (n = 163) lifetime major depressive disorder (MDD) made approach (angry and happy) and withdrawal (afraid and sad) facial expressions. EEG asymmetry during emotional challenge was a more powerful indicator of MDD status than resting asymmetry for average, Cz, and linked mastoid references, results in support of the capability model. However, current-source-density (CSD) transformed asymmetry was indicative of lifetime MDD status under resting and task-elicited conditions. Findings suggest that CSD-transformed data may be more robust indicators of trait frontal EEG asymmetry., (Copyright © 2014 Society for Psychophysiological Research.)

Facial expressions are an important aspect of social interaction, conveying not only information regarding emotional states, but also regarding intentions, personality, and complex social characteristics. The present research investigates how a smiling, compared to a nonsmiling, expression impacts decision making and underlying cognitive and emotional processes in economic bargaining. Our results using the ultimatum game show that facial expressions have an impact on decision making as well as the feedback-related negativity following the offer. Furthermore, a moderating effect of sex on decision making was observed, with differential effects of facial expressions from male compared to female proposers. It is concluded that predictions of bargaining behavior must account for aspects of social interactions as well as sex effects to obtain more precise estimates of behavior., (Copyright © 2014 Society for Psychophysiological Research.)

A major component of cephalopod adaptive camouflage behavior has rarely been studied: their ability to change the three-dimensionality of their skin by morphing their malleable dermal papillae. Recent work has established that simple, conical papillae in cuttlefish (Sepia officinalis) function as muscular hydrostats; that is, the muscles that extend a papilla also provide its structural support. We used brightfield and scanning electron microscopy to investigate and compare the functional morphology of nine types of papillae of different shapes, sizes and complexity in six species: S. officinalis small dorsal papillae, Octopus vulgaris small dorsal and ventral eye papillae, Macrotritopus defilippi dorsal eye papillae, Abdopus aculeatus major mantle papillae, O. bimaculoides arm, minor mantle, and dorsal eye papillae, and S. apama face ridge papillae. Most papillae have two sets of muscles responsible for extension: circular dermal erector muscles arranged in a concentric pattern to lift the papilla away from the body surface and horizontal dermal erector muscles to pull the papilla's perimeter toward its core and determine shape. A third set of muscles, retractors, appears to be responsible for pulling a papilla's apex down toward the body surface while stretching out its base. Connective tissue infiltrated with mucopolysaccharides assists with structural support. S. apama face ridge papillae are different: the contraction of erector muscles perpendicular to the ridge causes overlying tissues to buckle. In this case, mucopolysaccharide-rich connective tissue provides structural support. These six species possess changeable papillae that are diverse in size and shape, yet with one exception they share somewhat similar functional morphologies. Future research on papilla morphology, biomechanics and neural control in the many unexamined species of octopus and cuttlefish may uncover new principles of actuation in soft, flexible tissue.

Commercial off-the-shelf digital cameras are inexpensive and easy-to-use instruments that can be used for quantitative scientific data acquisition if images are captured in raw format and processed so that they maintain a linear relationship with scene radiance. Here we describe the image-processing steps required for consistent data acquisition with color cameras. In addition, we present a method for scene-specific color calibration that increases the accuracy of color capture when a scene contains colors that are not well represented in the gamut of a standard color-calibration target. We demonstrate applications of the proposed methodology in the fields of biomedical engineering, artwork photography, perception science, marine biology, and underwater imaging.

Traditional theories of perception posit that only objects access semantics; abutting, patently shapeless grounds do not. Surprisingly, this assumption has been untested until now. In two experiments, participants classified silhouettes as depicting meaningful real-world or meaningless novel objects while event-related potentials (ERPs) were recorded. The borders of half of the novel objects suggested portions of meaningful objects on the ground side. Participants were unaware of these meaningful objects because grounds are perceived as shapeless. In Experiment 1, in which silhouettes were presented twice, N400 ERP repetition effects indicated that semantics were accessed for novel silhouettes that suggested meaningful objects in the ground and for silhouettes that depicted real-world objects, but not for novel silhouettes that did not suggest meaningful objects in the ground. In Experiment 2, repetition was manipulated via matching prime words. This experiment replicated the effect observed in Experiment 1. These experiments provide the first neurophysiological evidence that semantic access can occur for the apparently shapeless ground side of a border.

Selective breeding of dogs by humans has generated extraordinary diversity in body size. A number of multibreed analyses have been undertaken to identify the genetic basis of this diversity. We analyzed four loci discovered in a previous genome-wide association study that used 60,968 SNPs to identify size-associated genomic intervals, which were too large to assign causative roles to genes. First, we performed fine-mapping to define critical intervals that included the candidate genes GHR, HMGA2, SMAD2, and STC2, identifying five highly associated markers at the four loci. We hypothesize that three of the variants are likely to be causative. We then genotyped each marker, together with previously reported size-associated variants in the IGF1 and IGF1R genes, on a panel of 500 domestic dogs from 93 breeds, and identified the ancestral allele by genotyping the same markers on 30 wild canids. We observed that the derived alleles at all markers correlated with reduced body size, and smaller dogs are more likely to carry derived alleles at multiple markers. However, breeds are not generally fixed at all markers; multiple combinations of genotypes are found within most breeds. Finally, we show that 46%-52.5% of the variance in body size of dog breeds can be explained by seven markers in proximity to exceptional candidate genes. Among breeds with standard weights <41 kg (90 lb), the genotypes accounted for 64.3% of variance in weight. This work advances our understanding of mammalian growth by describing genetic contributions to canine size determination in non-giant dog breeds.

Background: Premenstrual dysphoric disorder (PMDD) is a chronic condition that significantly affects a woman's well-being on a monthly basis. Although co-occurrence of PMDD and major depressive disorder (MDD) is common, most studies examine whether women with PMDD are at risk for depression and investigations of PMDD in depressed women are scant. Therefore, the present study examined rates of PMDD in young depressed women., Methods: PMDD was assessed using a structured clinical interview (SCID-PMDD) in a sample of 164 young women with (n=85) and without (n=79) any history of depression., Results: Rates of PMDD were elevated among women with MDD in this sample. This result held true regardless of participants' MDD status (current, lifetime or past history-only symptoms of MDD) and regardless of whether all or most DSM-IV-TR PMDD criteria were met., Limitations: Sample size in the present study was relatively small, and daily diary data were not available to confirm a PMDD diagnosis., Conclusions: The current study highlights the need for clinicians to assess for PMDD in young female patients with major depression. Depressed women experiencing the added physical and psychological burden of PMDD may have a more severe disease course, and future studies will need to identify appropriate treatments for this subset of depressed women., (Published by Elsevier B.V.)

Background: We tested the hypothesis that subgenual anterior cingulate cortex (sgACC) participates in concurrently regulating shifts in both affective state and cardiac vagal control., Methods: Eleven healthy adults and 8 depressed subjects performed the Emotional Counting Stroop task in alternating 15-second blocks of emotion words and neutral words while undergoing functional magnetic resonance imaging (fMRI) and electrocardiography (ECG). We measured the absolute value of change between adjacent 15-second blocks in both cardiac vagal control and the BOLD signal in specific regions of interest., Results: Strong positive correlations were observed in healthy control participants between changes in cardiac vagal control and changes in BOLD signal intensity in sgACC (BA25) (right: r=.67, p<.02; left r=.69, p<.02), as well as other key structures in the medial visceromotor network. Depressed subjects showed no significant correlations between cardiac vagal control and BOLD signal intensity within BA25 or any other brain region examined. During the transition from depression-specific emotion blocks to neutral blocks, the correlation between BOLD signal change in BA25 and cardiac vagal control change was significantly greater in controls than in depressed subjects (p<.04)., Conclusions: Findings in healthy volunteers suggest that sgACC participates in affective state shifting. The latter function appears to be altered in depressed individuals, and may have implications for the unvarying mood and vagal dysfunction associated with depression., Limitations: Limitations include a small sample size, an inability to disentangle afferent versus efferent contributions to the results, and the lack of a whole-brain analysis., (Published by Elsevier B.V.)

The ovarian follicular reserve has been linked to fertility in cattle. Young adult cattle with low vs. high numbers of antral follicles ≥ 3 mm in diameter in follicular waves also have fewer preantral follicles and decreased fertility. This underscores the importance of understanding the factors that regulate early follicular development and establish the ovarian follicular reserve, but little is known about how the follicular reserve is first established. In ruminants and humans, follicles form during fetal life, but there is a gap (about 50 d in cattle) between the appearance of the first primordial follicles and the first growing, primary follicles. In this review we present evidence that in cattle, fetal ovarian steroids (i.e., estradiol and progesterone) are negative regulators of both follicle formation and of the acquisition by newly formed follicles of the capacity to activate (i.e., initiate growth). The results indicate that capacity to activate is linked to the completion of meiotic prophase I by the oocyte. The inhibitory effects of estradiol on follicle activation were found to be reversible and correlated with inhibition of the progression of meiotic prophase I. Fetal bovine ovaries produce steroid hormones and production varies considerably during gestation and in a pattern consistent with the hypothesis that they inhibit follicle formation and capacity of newly formed follicles to activate in vivo. However, little was known about how steroid production is regulated. In our studies, both LH and FSH stimulated progesterone and estradiol production by ovarian pieces in vitro. The addition of testosterone to the culture medium enhanced estradiol production, especially when FSH was also present, but inhibited progesterone production, even in the presence of gonadotropins. Evidence is also presented for effects of maternal nutrition and health and for potential effects of estrogenic endocrine-disrupting chemicals on the size of the ovarian follicular reserve established during fetal life. In summary, fetal ovarian steroids may be important regulators of the early stages of follicular development in cattle. Therefore, external factors that alter steroid production or action may affect the size of the ovarian follicular reserve.