Sex differences in behavior, cognitive, and physiological recovery following methamphetamine administration.

Intact executive functions are required for proper performance of cognitive tasks and relies on balance of excitatory and inhibitory (E/I) transmission in the medial prefrontal cortex (mPFC). Hypofrontality is a state of decreased activity in the mPFC and is seen in several neuropsychiatric conditions, including substance use disorders. People who chronically use methamphetamine (meth) develop hypofrontality and concurrent changes in cognitive processing across several domains. Despite the fact that there are sex difference in substance use disorders, few studies have considered sex as a biological variable regarding meth-mediated hypoactivity in mPFC and concurrent cognitive deficits. Hypofrontality along with changes in cognition are emulated in rodent models following repeated meth administration. Here, we used a meth sensitization regimen to study sex differences in a Temporal Order Memory (TOM) task following short (7 days) or prolonged (28 days) periods of abstinence. GABAergic transmission, GABAA receptor (GABAAR) and GABA Transporter (GAT) mRNA expression in the mPFC were evaluated with patch-clamp recordings and RT-qPCR, respectively. Both sexes sensitized to the locomotor activating effects of meth, with the effect persisting in females. After short abstinence, males and females had impaired TOM and increased GABAergic transmission. Female rats recovered from these changes after prolonged abstinence, whereas male rats showed enduring changes. In general, meth appears to elicit an overall decrease in GABAAR expression after short abstinence; whereas GABA transporters are decreased in meth female rats after prolonged abstinence. These results show sex differences in the long-term effects of repeated meth exposure and suggest that females have neuroprotective mechanisms that alleviate some of the meth-mediated cognitive deficits.

Peptides and primate personality: Central and peripheral oxytocin and vasopressin levels and social behavior in two baboon species (Papio hamadryas and Papio anubis).

The neurohormones oxytocin (OT) and arginine vasopressin (AVP) are involved in social behaviors and psychiatric conditions. However, more research on nonhuman primates with complex social behaviors is needed. We studied two closely-related primate species with divergent social and mating systems; hamadryas baboons (Papio hamadryas, n=38 individuals) and anubis baboons (Papio anubis, n=46). We measured OT in cerebrospinal fluid (CSF, n=75), plasma (n=81) and urine (n=77), and AVP in CSF (n=45), and we collected over 250 hours of focal behavioral observations. Using Bayesian multivariate models, we found no clear species difference in hormone levels; the strongest support was for hamadryas having higher CSF OT levels than anubis (posterior probability [PP] for females = 0.75, males = 0.84). Looking at nine specific behaviors, OT was associated with affiliative behaviors (approach, proximity, grooming, PP ∼ 0.85 - 1.00), albeit inconsistently across sources of measurement (CSF, plasma, and urine, which were uncorrelated with each other). Most behaviors had low repeatability (R ∼ 0 - 0.2), i.e. they did not exhibit stable between-individual differences (or "personality"), and different behaviors did not neatly coalesce into higher-order factors (or "behavioral syndromes"), which cautions against the use of aggregate behavioral measures and highlights the need to establish stable behavioral profiles when testing associations with baseline hormone levels. In sum, we found some associations between peptides and social behavior, but also many null results, OT levels from different sources were uncorrelated, and our behavioral measures did not indicate clear individual differences in sociability.

Estrogen receptor beta signaling enhances extinction memory recall for heroin-conditioned cues in a sex- and region-specific manner.

Return to use, or relapse, is a major challenge in the treatment of opioid use disorder (OUD). Relapse can be precipitated by several factors, including exposure to drug-conditioned cues. Identifying successful treatments to mitigate cue-induced relapse has been challenging, perhaps due to extinction memory recall (EMR) deficits. Previously, inhibition of estradiol (E2) signaling in the basolateral amygdala (BLA) impaired heroin-cue EMR. This effect was recapitulated by antagonism of BLA estrogen receptors (ER) in a sex-specific manner such that blocking ERα in males, but ERß in females, impaired EMR. However, it is unclear whether increased E2 signaling, in the BLA or systemically, enhances heroin-cue EMR. We hypothesized that ERß agonism would enhance heroin-cue EMR in a sex- and region-specific manner. To determine the capacity of E2 signaling to improve EMR, we pharmacologically manipulated ERß across several translationally designed experiments. First, male and female rats acquired heroin or sucrose self-administration. Next, during a cued extinction session, we administered diarylpropionitrile (DPN, an ERß agonist) and tested anxiety-like behavior on an open field. Subsequently, we assessed EMR in a cue-induced reinstatement test and, finally, measured ERß expression in several brain regions. Across all experiments, females took more heroin and sucrose than males and had greater responses during heroin-cued extinction. Administration of DPN in the BLA enhanced EMR in females only, driven by ERß's impacts on memory consolidation. Interestingly, however, systemic DPN administration improved EMR for heroin cues in both sexes across several different tests, but did not impact sucrose-cue EMR. Immunohistochemical analysis of ERß expression across several different brain regions showed that females only had greater expression of ERß in the basal nucleus of the BLA. Here, in several preclinical experiments, we demonstrated that ERß agonism enhances heroin-cue EMR and has potential utility in combatting cue-induced relapse.

Morbidity and neurodevelopmental outcomes at 2 years in preterm infants undergoing percutaneous transcatheter closure vs. surgical ligation of the PDA.

OBJECTIVE: Review a cohort of preterm infants ≤29 weeks of gestation at birth and compare morbidities and neurodevelopmental outcomes based on PDA status and type of PDA closure. STUDY DESIGN: Single center observational retrospective-prospective case control study of premature infants who had no hsPDA, underwent surgical ligation or percutaneous transcatheter closure of the PDA. Neurodevelopmental testing was done using the Bayley Scales of Infant Development 3rd ed. RESULTS: The percutaneous transcatheter closure group had an older post menstrual age and greater weight at the time of procedure, and started enteral feeds and achieved room air status at an earlier post procedure day. Infants in the surgical ligation group were more likely to experience vocal cord paralysis. There was no difference in neurodevelopmental outcomes between groups. CONCLUSION: Waiting for infants to achieve the appropriate size for percutaneous transcatheter closure of the PDA may lead to reduced short-term complications without increasing the risk of neurodevelopmental impairment.

Interhemispheric inhibition and gait adaptation associations in people with multiple sclerosis.

BACKGROUND: Multiple sclerosis is a neurodegenerative disease that damages the myelin sheath within the central nervous system. Axonal demyelination, particularly in the corpus callosum, impacts communication between the brain's hemispheres in persons with multiple sclerosis (PwMS). Changes in interhemispheric communication may impair gait coordination which is modulated by communication across the corpus callosum to excite and inhibit specific muscle groups. To further evaluate the functional role of interhemispheric communication in gait and mobility, this study assessed the ipsilateral silent period (iSP), an indirect marker of interhemispheric inhibition and how it relates to gait adaptation in PwMS. METHODS: Using transcranial magnetic stimulation (TMS), we assessed interhemispheric inhibition differences between the more affected and less affected hemisphere in the primary motor cortices in 29 PwMS. In addition, these same PwMS underwent a split-belt treadmill walking paradigm, with the faster paced belt moving under their more affected limb. Step length asymmetry (SLA) was the primary outcome measure used to assess gait adaptability during split-belt treadmill walking. We hypothesized that PwMS would exhibit differences in iSP inhibitory metrics between the more affected and less affected hemispheres and that increased interhemispheric inhibition would be associated with greater gait adaptability in PwMS. RESULTS: No statistically significant differences in interhemispheric inhibition or conduction time were found between the more affected and less affected hemisphere. Furthermore, SLA aftereffect was negatively correlated with both average percent depth of silent period (dSP%AVE) (r = -0.40, p = 0.07) and max percent depth of silent period (dSP%MAX) r = -0.40, p = 0.07), indicating that reduced interhemispheric inhibition was associated with greater gait adaptability in PwMS. CONCLUSION: The lack of differences between the more affected and less affected hemisphere indicates that PwMS have similar interhemispheric inhibitory capacity irrespective of the more affected hemisphere. Additionally, we identified a moderate correlation between reduced interhemispheric inhibition and greater gait adaptability. These findings may indicate that interhemispheric inhibition may in part influence responsiveness to motor adaptation paradigms and the need for further research evaluating the neural mechanisms underlying the relationship between interhemispheric inhibition and motor adaptability.

Size matters: Total testicular volume predicts sperm count in Tanner V varicocele patients.

INTRODUCTION: It is known the prevalence of varicoceles in adolescent men is 14-29% but there is debate surrounding implications on fertility. As obtaining a semen analysis (SA) may be challenging, there is need for objective tests as measures of fecundity. Our aim was to investigate the relationship between testicular volume differential (TVD), varicocele grade, and total testicular volume (TTV) on seminal parameters including total motile sperm count (TMSC). MATERIALS AND METHODS: We conducted a retrospective single-center chart review over 14 years of 486 Tanner V adolescent males. Three hundred and four met inclusion of palpable, non-operated left-sided varicocele who underwent at least one SA and ultrasound. Abnormal TMSC was defined by World Health Organization 2010 criteria for minimal reference ranges. Multivariate logistic regression, receiver operating characteristic analysis with Youden J-statistic and descriptive statistics were performed. RESULTS: Three hundred and four Tanner V adolescents with median age of 18.0 years (18.0-19.0), median TTV of 34.5 cc (28.9, 40.2) and median TMSC of 62.5 million/ejaculate (25.4, 123.4) were evaluated. TTV cutoff of 29.5 cc was found to predict TMSC of <9 million/ejaculate with negative predictive value of 96.2% and odds ratio of 6.08 ([2.13-17.42], p < 0.001). TVD greater than 20% did not reach statistical significance with an odds ratio of 1.66 ([0.41-6.62], p = 0.50). DISCUSSION: In clinical practice, each patient will need to have an individualized plan. Based on our data, for older adolescents (17 or 18 years) with varicocele and an abnormal TTV, clinicians may have a lower threshold for advising SA, and if unable to obtain, surgical intervention and/or closer surveillance should be stressed. Patients should be informed of their six-fold increase in abnormal SA. Patients with normal TTV should be advised they are at lower risk of having abnormal SA. Younger patients with varicocele and an initial TVD>20%, should be followed closely but intervention delayed until 17 or 18 to better assess TTV. The importance of trending patient data should be emphasized as a single measurement has low predictive value for developing adolescents. Limitations of our study include a retrospective design and the lack of uniform correlation between adolescent SA and paternity. CONCLUSIONS: Total testicular volume less than 29.5 cc increased odds of abnormal semen analysis by over six times and had a negative predictive value of 96.2%. Ultrasound results may be useful for risk stratification and counselling on appropriateness of surgical intervention.

Liraglutide alleviates experimental diabetic cardiomyopathy in a PDH-dependent manner.

Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist used for the treatment of T2D, has been shown to alleviate diabetic cardiomyopathy (DbCM) in experimental T2D, which was associated with increased myocardial glucose oxidation. To determine whether this increase in glucose oxidation is necessary for cardioprotection, we hypothesized that liraglutide's ability to alleviate DbCM would be abolished in mice with cardiomyocyte-specific deletion of pyruvate dehydrogenase (PDH; Pdha1CM-/- mice), the rate-limiting enzyme of glucose oxidation. Male Pdha1CM-/- mice and their α-myosin heavy chain Cre expressing littermates (αMHCCre mice) were subjected to experimental T2D via 10 weeks of high-fat diet supplementation, with a single low-dose injection of streptozotocin (75 mg/kg) provided at week 4. All mice were randomized to treatment with either vehicle control or liraglutide (30 µg/kg) twice daily during the final 2.5 weeks, with cardiac function assessed via ultrasound echocardiography. As expected, liraglutide treatment improved glucose homeostasis in both αMHCCre and Pdha1CM-/- mice with T2D, in the presence of mild weight loss. Parameters of systolic function were unaffected by liraglutide treatment in both αMHCCre and Pdha1CM-/- mice with T2D. However, liraglutide treatment alleviated diastolic dysfunction in αMHCCre mice, as indicated by an increase and decrease in the e'/a' and E/e' ratios, respectively. Conversely, liraglutide failed to rescue these indices of diastolic dysfunction in Pdha1CM-/- mice. Our findings suggest that increases in glucose oxidation are necessary for GLP-1R agonist mediated alleviation of DbCM. As such, strategies aimed at increasing PDH activity may represent a novel approach for the treatment of DbCM.

Can juvenile supply predict future abundance of large-bodied reef fishes?

The extent to which juvenile abundance can predict future populations of lethrinids at Ningaloo Reef was assessed using size frequency data collected over 13 consecutive years. Annual abundance of juvenile lethrinids (<5 cm TL) was highest in northern Ningaloo during La Niña years, when seawater is warmer and oceanic currents stronger. Juvenile lethrinid abundance explained 35% of the variance in 1-2 year-old Lethrinus nebulosus abundance the following year, a steeper relationship in the north suggesting greater survival of juveniles. Juvenile lethrinid abundance was also positively correlated to abundance of 1-2 year-old L. atkinsoni in the southern region of Ningaloo. Abundance of juvenile lethrinids were however poor predictors of L. nebulosus and L. atkinsoni older than 2 years of age. Post settlement processes likely weaken the link between juvenile supply and abundance of lethrinids >2 years old making it difficult to accurately quantify the overall size of future lethrinid populations.

Protocol modifications reduce risk of delayed pericardial effusions after vein of Marshall ethanol infusion: follow-up from the Maine experience.

BACKGROUND: While ethanol infusion into the vein of Marshall (VOM) as an adjunct to atrial fibrillation ablation has shown promise, adoption has been limited by the technical expertise required, unclear antiarrhythmic mechanism, and complication risk. Delayed pericardial effusions have been associated with ethanol infusion into the VOM in prior studies. Very little is known about how the procedural approach itself can impact the risk of delayed effusions. We sought to understand the incidence and influence of procedural technique on complications including delayed pericardial effusions from VOM ethanol infusion at a large single medical center. METHODS: A total of 275 atrial ablation cases wherein VOM ethanol infusion was attempted were identified from the time of the program's inception in 2019 at Maine Medical Center (Portland, ME) until October of 2023. Cases were classified into phase I cases (early experience) and phase II cases (later experience) based upon temporal programmatic changes in the ethanol dose and infusion rate as well as the use of routine VOM venography. Procedural details and complications were adjudicated from the medical record. RESULTS: The overall VOM ethanol infusion success was 91.4%. Nine complications (3.3%) occurred in eight patients (2.9% of patients). These were more frequent in phase I (5.8%) compared to phase II (1.3%, p = 0.047). This difference was driven by a difference in delayed presentations of tamponade, which occurred in four patients in phase I (3.3%) and in no patients in phase II (0%, p = 0.037). Twelve-month estimated atrial arrhythmia freedom did not differ between groups (73.8% phase I vs 70.4% phase II, p = 0.24). CONCLUSION: In our single-center experience, adjustments to the procedural approach with lower ethanol infusion rate and dosage, combined with utilizing selective VOM venography, associated with a lowering of complication rates and in particular, delayed pericardial tamponade.

Comparison of short-term outcomes following robotic ventral hernia repair in patients with obesity: a review of 9742 patients from the Abdominal Core Health Quality Collaborative database.

Despite the paucity of evidence on robotic ventral hernia repair (RVHR) in patients with obesity, the robotic platform is being used more frequently in hernia surgery. The impact of obesity on RVHR outcomes has not been thoroughly studied. Obesity is considered a major risk factor for the development of recurrent ventral hernias and postoperative complications; however, we hypothesize that patients undergoing robotic repairs will have similar complication profiles despite their body mass index (BMI). We performed a retrospective analysis of patients aged 18-90 years who underwent RVHR between 2013 and 2023 using data from the Abdominal Core Health Quality Collaborative registry. Preoperative, intraoperative, and postoperative characteristics were compared in non-obese and obese groups, determined using a univariate and logistic regression analysis to compare short-term outcomes. The registry identified 9742 patients; 3666 were non-obese; 6076 were classified as obese (BMI > 30 kg/m2). There was an increased odds of surgical site occurrence in patients with obesity, mostly seroma formation; however, obesity was not a significant factor for a complication requiring a procedural intervention after RVHR. In contrast, the hernia-specific quality-of-life scores significantly improved following surgery for all patients, with those with obesity having more substantial improvement from baseline. Obesity does increase the risk of certain complications following RVHR in a BMI-dependent fashion; however, the odds of requiring a procedural intervention are not significantly increased by BMI. Patients with obesity have a significant improvement in their quality of life, and RVHR should be carefully considered in this population.

Play Well Triple P: Developing and Evaluating a Program to Promote Positive Parental Involvement in Junior Sport.

Parents play a central role in children's ongoing participation and enjoyment of sport. Despite compelling evidence that parental behaviour can undermine the quality of children's experiences in sport, little research has examined whether strategies to support parents to engage in positive sports parenting behaviour are effective. In this paper, we report two studies that had the overall aim of developing, implementing and evaluating a program designed to promote positive parental involvement and improve spectator behaviour in junior rugby league in Australia. Study 1 involved the development of a prototype version of the program, named Play Well Triple P, which was qualitatively evaluated through interviews with 19 parents about their satisfaction with the program. In Study 2, we used feedback from Study 1 to refine the program and develop a pilot version, which was then evaluated in a quasi-experimental feasibility study with 101 parents (mean age = 38.42 years; 72% mothers) of junior rugby league players. The pilot version involved one interactive online module and text messages to reinforce content and prompt strategy implementation across the season. Participation in Play Well Triple P was associated with increased positive sports parenting behaviour and reduced controlling and intrusive sports parenting behaviour, with a trend towards reducing over-reactive parenting practices at home. These findings are discussed in relation to the feasibility of implementing a brief and engaging sports parenting intervention in the context of a broader integrated system designed to facilitate ongoing participation of children in sport.

Cross-Sectional Melt Pool Geometry of Laser Scanned Tracks and Pads on Nickel Alloy 718 for the 2022 Additive Manufacturing Benchmark Challenges.

The Additive Manufacturing Benchmark Series (AM Bench) is a NIST-led organization that provides a continuing series of additive manufacturing benchmark measurements, challenge problems, and conferences with the primary goal of enabling modelers to test their simulations against rigorous, highly controlled additive manufacturing benchmark measurement data. To this end, single-track (1D) and pad (2D) scans on bare plate nickel alloy 718 were completed with thermography, cross-sectional grain orientation and local chemical composition maps, and cross-sectional melt pool size measurements. The laser power, scan speed, and laser spot size were varied for single tracks, and the scan direction was varied for pads. This article focuses on the cross-sectional melt pool size measurements and presents the predictions from challenge problems. Single-track depth correlated with volumetric energy density while width did not (within the studied parameters). The melt pool size for pad scans was greater than single tracks due to heat buildup. Pad scan melt pool depth was reduced when the laser scan direction and gas flow direction were parallel. The melt pool size in pad scans showed little to no trend against position within the pads. Uncertainty budgets for cross-sectional melt pool size from optical micrographs are provided for the purpose of model validation.

Monitoring carbohydrate 3D structure quality with the Privateer database.

The remediation of the carbohydrate data of the Protein Data Bank (PDB) has brought numerous enhancements to the findability and interpretability of deposited glycan structures, yet crucial quality indicators are either missing or hard to find on the PDB pages. Without a way to access wider glycochemical context, problematic structures may be taken as fact by keen but inexperienced scientists. The Privateer software is a validation and analysis tool that provides access to a number of metrics and links to external experimental resources, allowing users to evaluate structures using carbohydrate-specific methods. Here, we present the Privateer database, a free resource that aims to complement the growing glycan content of the PDB.

Characterization and Engineering of the Type 3 Secretion System Needle Monomer from Salmonella Through the Construction and Screening of a Comprehensive Mutagenesis Library.

Protein production strategies in bacteria are often limited due to the need for cell lysis and complicated purification schemes. To avoid these challenges, researchers have developed bacterial strains capable of secreting heterologous protein products outside the cell, but secretion titers often remain too low for commercial applicability. Improved understanding of the link between secretion system structure and its secretory abilities can help overcome the barrier to engineering higher secretion titers. Here we investigated this link with the PrgI protein, the monomer of the secretory channel of the Type 3 Secretion System (T3SS) of Salmonella enterica . Despite detailed knowledge of the PrgI needle's assembly and structure, little is known about how its structure influences its secretory capabilities. To study this, we recently constructed a comprehensive codon mutagenesis library of the PrgI protein utilizing a novel one pot recombineering approach. We then screened this library for functional T3SS assembly and secretion titer by measuring the secretion of alkaline phosphatase using a high-throughput activity assay. This allowed us to construct a first-of-its-kind secretion fitness landscape (SFL) to characterize the PrgI needle's mutability at each position as well as the mutations which lead to enhanced T3SS secretion. We discovered new design rules for building a functional T3SS as well as identified hypersecreting mutants. This work can be used to increase understanding of the T3SS's assembly and identify further targets for engineering. This work also provides a blueprint for future efforts to engineer other complex protein assemblies through the construction of fitness landscapes. Importance: Protein secretion offers a simplified alternative method for protein purification from bacterial hosts. However, the current state-of-the-art methods for protein secretion in bacteria are still hindered by low yields relative to traditional protein purification strategies. Engineers are now seeking strategies to enhance protein secretion titers from bacterial hosts, often through genetic manipulations. In this study, we demonstrate that protein engineering strategies focused on altering the secretion apparatus can be a fruitful avenue toward this goal. Specifically, this study focuses on how changes to the PrgI needle protein from the type 3 secretion system from Salmonella enterica can impact secretion titer. We demonstrate that this complex is amenable to comprehensive mutagenesis studies and that this can yield both PrgI variants with increased secretory capabilities and insight into the normal functioning of the type 3 secretion system.

Enhancing in vivo cell and tissue targeting by modulation of polymer nanoparticles and macrophage decoys.

The in vivo efficacy of polymeric nanoparticles (NPs) is dependent on their pharmacokinetics, including time in circulation and tissue tropism. Here we explore the structure-function relationships guiding physiological fate of a library of poly(amine-co-ester) (PACE) NPs with different compositions and surface properties. We find that circulation half-life as well as tissue and cell-type tropism is dependent on polymer chemistry, vehicle characteristics, dosing, and strategic co-administration of distribution modifiers, suggesting that physiological fate can be optimized by adjusting these parameters. Our high-throughput quantitative microscopy-based platform to measure the concentration of nanomedicines in the blood combined with detailed biodistribution assessments and pharmacokinetic modeling provides valuable insight into the dynamic in vivo behavior of these polymer NPs. Our results suggest that PACE NPs-and perhaps other NPs-can be designed with tunable properties to achieve desired tissue tropism for the in vivo delivery of nucleic acid therapeutics. These findings can guide the rational design of more effective nucleic acid delivery vehicles for in vivo applications.

Directed conservation of the world's reef sharks and rays.

Many shark populations are in decline around the world, with severe ecological and economic consequences. Fisheries management and marine protected areas (MPAs) have both been heralded as solutions. However, the effectiveness of MPAs alone is questionable, particularly for globally threatened sharks and rays ('elasmobranchs'), with little known about how fisheries management and MPAs interact to conserve these species. Here we use a dedicated global survey of coral reef elasmobranchs to assess 66 fully protected areas embedded within a range of fisheries management regimes across 36 countries. We show that conservation benefits were primarily for reef-associated sharks, which were twice as abundant in fully protected areas compared with areas open to fishing. Conservation benefits were greatest in large protected areas that incorporate distinct reefs. However, the same benefits were not evident for rays or wide-ranging sharks that are both economically and ecologically important while also threatened with extinction. We show that conservation benefits from fully protected areas are close to doubled when embedded within areas of effective fisheries management, highlighting the importance of a mixed management approach of both effective fisheries management and well-designed fully protected areas to conserve tropical elasmobranch assemblages globally.