DHEA: a neglected biological signal that may affect fetal and child development.

BACKGROUND: The stress-sensitive maternal hypothalamic-pituitary-adrenal (HPA) axis through the end-product cortisol, represents a primary pathway through which maternal experience shapes fetal development with long-term consequences for child neurodevelopment. However, there is another HPA axis end-product that has been widely ignored in the study of human pregnancy. The synthesis and release of dehydroepiandosterone (DHEA) is similar to cortisol, so it is a plausible, but neglected, biological signal that may influence fetal neurodevelopment. DHEA also may interact with cortisol to determine developmental outcomes. Surprisingly, there is virtually nothing known about human fetal exposure to prenatal maternal DHEA and offspring neurodevelopment. The current study examined, for the first time, the joint impact of fetal exposure to prenatal maternal DHEA and cortisol on infant emotional reactivity. METHODS: Participants were 124 mother-infant dyads. DHEA and cortisol were measured from maternal hair at 15 weeks (early gestation) and 35 weeks (late gestation). Observational assessments of positive and negative emotional reactivity were obtained in the laboratory when the infants were 6 months old. Pearson correlations were used to examine the associations between prenatal maternal cortisol, prenatal maternal DHEA, and infant positive and negative emotional reactivity. Moderation analyses were conducted to investigate whether DHEA might modify the association between cortisol and emotional reactivity. RESULTS: Higher levels of both early and late gestation maternal DHEA were linked to greater infant positive emotional reactivity. Elevated late gestation maternal cortisol was associated with greater negative emotional reactivity. Finally, the association between fetal cortisol exposure and infant emotional reactivity was only observed when DHEA was low. CONCLUSIONS: These new observations indicate that DHEA is a potential maternal biological signal involved in prenatal programming. It appears to act both independently and jointly with cortisol to determine a child's emotional reactivity. Its role as a primary end-product of the HPA axis, coupled with the newly documented associations with prenatal development shown here, strongly calls for the inclusion of DHEA in future investigations of fetal programming.

Temporal relation between pubertal development and peer victimization in a prospective sample of US adolescents.

Peer victimization typically peaks in early adolescence, leading researchers to hypothesize that pubertal timing is a meaningful predictor of peer victimization. However, previous methodological approaches have limited our ability to parse out which puberty cues are associated with peer victimization because gonadal and adrenal puberty, two independent processes, have either been conflated or adrenal puberty timing has been ignored. In addition, previous research has overlooked the possibility of reverse causality-that peer victimization might drive pubertal timing, as it has been shown to do in non-human primates. To fill these gaps, we followed 265 adolescents (47% female) prospectively across three-time points (Mage : T1 = 9.6, T2 = 12.0, T3 = 14.4) and measured self-report peer victimization and self- and maternal-report of gonadal and adrenal pubertal development on the Pubertal Development Scale. Multilevel modeling revealed that females who were further along in adrenal puberty at age 9 were more likely to report peer victimization at age 12 (Cohen's d = 0.25, p = .005). The relation between gonadal puberty status and peer victimization was not significant for either sex. In terms of the reverse direction, the relation between early peer victimization and later pubertal development was not significant in either sex. Overall, our findings suggest that adrenal puberty status, but not gonadal puberty status, predicted peer victimization in females, highlighting the need to separate gonadal and adrenal pubertal processes in future studies.

Infant hedonic/anhedonic processing index (HAPI-Infant): Assessing infant anhedonia and its prospective association with adolescent depressive symptoms.

BACKGROUND: Anhedonia, an impairment in the motivation for or experience of pleasure, is a well-established transdiagnostic harbinger and core symptom of mental illness. Given increasing recognition of early life origins of mental illness, we posit that anhedonia should, and could, be recognized earlier if appropriate tools were available. However, reliable diagnostic instruments prior to childhood do not currently exist. METHODS: We developed an assessment instrument for anhedonia/reward processing in infancy, the Infant Hedonic/Anhedonic Processing Index (HAPI-Infant). Exploratory factor and psychometric analyses were conducted using data from 6- and 12-month-old infants from two cohorts (N = 188, N = 212). Then, associations were assessed between infant anhedonia and adolescent self-report of depressive symptoms. RESULTS: The HAPI-Infant (47-items), exhibited excellent psychometric properties. Higher anhedonia scores at 6 (r = 0.23, p < .01) and 12 months (r = 0.19, p < .05) predicted elevated adolescent depressive symptoms, and these associations were stronger than for established infant risk indicators such as negative affectivity. Subsequent analyses supported the validity of short (27-item) and very short (12-item) versions of this measure. LIMITATIONS: The primary limitations of this study are that the HAPI-Infant awaits additional tests of generalizability and of its ability to predict clinical diagnosis of depression. CONCLUSIONS: The HAPI-Infant is a novel, psychometrically strong diagnostic tool suitable for recognizing anhedonia during the first year of life with strong predictive value for later depressive symptoms. In view of the emerging recognition of increasing prevalence of affective disorders in children and adolescents, the importance of the HAPI-Infant in diagnosing anhedonia is encouraging. Early recognition of anhedonia could target high-risk individuals for intervention and perhaps prevention of mental health disorders.

Contact with caregivers is associated with composition of the infant gastrointestinal microbiome in the first 6 months of life.

OBJECTIVES: Little is known about how physical contact at birth and early caregiving environments influence the colonization of the infant gastrointestinal microbiome. We investigated how infant contact with caregivers at birth and within the first 2 weeks of life relates to the composition of the gastrointestinal microbiome in a sample of U.S. infants (n = 60). METHODS: Skin-to-skin and physical contact with caregivers at birth and early caregiving environments were surveyed at 2 weeks postpartum. Stool samples were collected from infants at 2 weeks, 2, 6, and 12 months of age and underwent 16S rRNA sequencing as a proxy for the gastrointestinal microbiome. Associations between early caregiving environments and alpha and beta diversity, and differential abundance of bacteria at the genus level were assessed using PERMANOVA, and negative binomial mixed models in DEseq2. RESULTS: Time in physical contact with caregivers explained 10% of variation in beta diversity at 2 weeks' age. The number of caregivers in the first few weeks of life explained 9% of variation in beta diversity at 2 weeks and the number of individuals in physical contact at birth explained 11% of variation in beta diversity at 6 months. Skin-to-skin contact on the day of birth was positively associated with the abundance of eight genera. Infants held for by more individuals had greater abundance of eight genera. DISCUSSION: Results reveal a potential mechanism (skin-to-skin and physical contact) by which caregivers influence the infant gastrointestinal microbiome. Our findings contribute to work exploring the social transmission of microbes.

Prenatal Exposure to Maternal Mood Entropy Is Associated With a Weakened and Inflexible Salience Network in Adolescence.

BACKGROUND: Fetal exposure to maternal mood dysregulation influences child cognitive and emotional development, which may have long-lasting implications for mental health. However, the neurobiological alterations associated with this dimension of adversity have yet to be explored. Here, we tested the hypothesis that fetal exposure to entropy, a novel index of dysregulated maternal mood, would predict the integrity of the salience network, which is involved in emotional processing. METHODS: A sample of 138 child-mother pairs (70 females) participated in this prospective longitudinal study. Maternal negative mood level and entropy (an index of variable and unpredictable mood) were assessed 5 times during pregnancy. Adolescents engaged in a functional magnetic resonance imaging task that was acquired between 2 resting-state scans. Changes in network integrity were analyzed using mixed-effect and latent growth curve models. The amplitude of low frequency fluctuations was analyzed to corroborate findings. RESULTS: Prenatal maternal mood entropy, but not mood level, was associated with salience network integrity. Both prenatal negative mood level and entropy were associated with the amplitude of low frequency fluctuations of the salience network. Latent class analysis yielded 2 profiles based on changes in network integrity across all functional magnetic resonance imaging sequences. The profile that exhibited little variation in network connectivity (i.e., inflexibility) consisted of adolescents who were exposed to higher negative maternal mood levels and more entropy. CONCLUSIONS: These findings suggest that fetal exposure to maternal mood dysregulation is associated with a weakened and inflexible salience network. More broadly, they identify maternal mood entropy as a novel marker of early adversity that exhibits long-lasting associations with offspring brain development.

Across ages and places: Unpredictability of maternal sensory signals and child internalizing behaviors.

BACKGROUND: Patterns of sensory inputs early in life play an integral role in shaping the maturation of neural circuits, including those implicated in emotion and cognition. In both experimental animal models and observational human research, unpredictable sensory signals have been linked to aberrant developmental outcomes, including poor memory and effortful control. These findings suggest that sensitivity to unpredictable sensory signals is conserved across species and sculpts the developing brain. The current study provides a novel investigation of unpredictable maternal sensory signals in early life and child internalizing behaviors. We tested these associations in three independent cohorts to probe the generalizability of associations across continents and cultures. METHOD: The three prospective longitudinal cohorts were based in Orange, USA (n = 163, 47.2 % female, Mage = 1 year); Turku, Finland (n = 239, 44.8 % female, Mage = 5 years); and Irvine, USA (n = 129, 43.4 % female, Mage = 9.6 years). Unpredictability of maternal sensory signals was quantified during free-play interactions. Child internalizing behaviors were measured via parent report (Orange & Turku) and child self-report (Irvine). RESULTS: Early life exposure to unpredictable maternal sensory signals was associated with greater child fearfulness/anxiety in all three cohorts, above and beyond maternal sensitivity and sociodemographic factors. The association between unpredictable maternal sensory signals and child sadness/depression was relatively weaker and did not reach traditional thresholds for statistical significance. LIMITATIONS: The correlational design limits our ability to make causal inferences. CONCLUSIONS: Findings across the three diverse cohorts suggest that unpredictable maternal signals early in life shape the development of internalizing behaviors, particularly fearfulness and anxiety.

Mothers' prenatal distress accelerates adrenal pubertal development in daughters.

Human life history schedules vary, partly, because of adaptive, plastic responses to early-life conditions. Little is known about how prenatal conditions relate to puberty timing. We hypothesized that fetal exposure to adversity may induce an adaptive response in offspring maturational tempo. In a longitudinal study of 253 mother-child dyads followed for 15 years, we investigated if fetal exposure to maternal psychological distress related to children's adrenarche and gonadarche schedules, assessed by maternal and child report and by dehydroepiandrosterone sulfate (DHEA-S), testosterone, and estradiol levels. We found fetal exposure to elevated maternal prenatal psychological distress predicted earlier adrenarche and higher DHEA-S levels in girls, especially first-born girls, and that associations remained after covarying indices of postnatal adversity. No associations were observed for boys or for gonadarche in girls. Adrenarche orchestrates the social-behavioral transition from juvenility to adulthood; therefore, significant findings for adrenarche, but not gonadarche, suggest that prenatal maternal distress instigates an adaptive strategy in which daughters have earlier social-behavioral maturation. The stronger effect in first-borns suggests that, in adverse conditions, it is in the mother's adaptive interest for her daughter to hasten social maturation, but not necessarily sexual maturation, because it would prolong the duration of the daughter allomothering younger siblings. We postulate a novel evolutionary framework that human mothers may calibrate the timing of first-born daughters' maturation in a way that optimizes their own reproductive success.

Automatic Stub Avoidance for a Powered Prosthetic Leg over Stairs and Obstacles.

Passive prosthetic legs require undesirable compensations from amputee users to avoid stubbing obstacles and stairsteps. Powered prostheses can reduce those compensations by restoring normative joint biomechanics, but the absence of user proprioception and volitional control combined with the absence of environmental awareness by the prosthesis increases the risk of collisions. This paper presents a novel stub avoidance controller that automatically adjusts prosthetic knee/ankle kinematics based on suprasensory measurements of environmental distance from a small, lightweight, low-power, low-cost ultrasonic sensor mounted above the prosthetic ankle. In a case study with two transfemoral amputee participants, this control method reduced the stub rate during stair ascent by 89.95% and demonstrated an 87.5% avoidance rate for crossing different obstacles on level ground. No thigh kinematic compensation was required to achieve these results. These findings demonstrate a practical perception solution for powered prostheses to avoid collisions with stairs and obstacles while restoring normative biomechanics during daily activities.

Controlling Powered Prosthesis Kinematics over Continuous Transitions Between Walk and Stair Ascent.

One of the primary benefits of emerging powered prosthetic legs is their ability to facilitate step-over-step stair ascent by providing positive mechanical work. Existing control methods typically have distinct steady-state activity modes for walking and stair ascent, where activity transitions involve discretely switching between controllers and often must be initiated with a particular leg. However, these discrete transitions do not necessarily replicate able-bodied joint biomechanics, which have been shown to continuously adjust over a transition stride. This paper presents a phase-based kinematic controller for a powered knee-ankle prosthesis that enables continuous, biomimetic transitions between walking and stair ascent. The controller tracks joint angles from a data-driven kinematic model that continuously interpolates between the steady-state kinematic models, and it allows both the prosthetic and intact leg to lead the transitions. Results from experiments with two transfemoral amputee participants indicate that knee and ankle kinematics smoothly transition between walking and stair ascent, with comparable or lower root mean square errors compared to variations from able-bodied data.

Improving Amputee Endurance over Activities of Daily Living with a Robotic Knee-Ankle Prosthesis: A Case Study.

Robotic knee-ankle prostheses have often fallen short relative to passive microprocessor prostheses in time-based clinical outcome tests. User ambulation endurance is an alternative clinical outcome metric that may better highlight the benefits of robotic prostheses. However, previous studies were unable to show endurance benefits due to inaccurate high-level classification, discretized mid-level control, and insufficiently difficult ambulation tasks. In this case study, we present a phase-based mid-level prosthesis controller which yields biomimetic joint kinematics and kinetics that adjust to suit a continuum of tasks. We enrolled an individual with an above-knee amputation and challenged him to perform repeated, rapid laps of a circuit comprising activities of daily living with both his passive prosthesis and a robotic prosthesis. The participant demonstrated improved endurance with the robotic prosthesis and our mid-level controller compared to his passive prosthesis, completing over twice as many total laps before fatigue and muscle discomfort required him to stop. We also show that time-based outcome metrics fail to capture this endurance improvement, suggesting that alternative metrics related to endurance and fatigue may better highlight the clinical benefits of robotic prostheses.

Discrimination and adverse birth outcomes among Latina women: The protective role of social support.

OBJECTIVE: Interpersonal discrimination has been associated with adverse birth outcomes among Black populations, but few studies have examined the impact of discrimination among Latinx/Hispanic populations in the United States, especially in conjunction with resources that could be protective. The present study examined (a) if exposure to discrimination is associated with adverse birth outcomes for Latina/Hispanic women and (b) if prenatal social support buffers these links. METHOD: In two independent prospective studies of Latina/Hispanic women in Southern California (N = 84 and N = 102), the relation between maternal experience of discrimination and birth outcomes (length of gestation and birth weight) was examined. Additionally, social support was tested as a moderator of these relations. RESULTS: In both Studies 1 and 2, exposures to discrimination predicted adverse birth outcomes. Specifically, lifetime experiences of major discrimination predicted lower birth weight. Additionally, in Study 2, chronic experiences of everyday discrimination were linked to lower birth weight. In Study 1, major discrimination also predicted shorter gestational length. Importantly, in both studies, the presence of prenatal social support buffered associations between discrimination and poorer birth outcomes. CONCLUSIONS: Findings implicate discrimination as an important risk factor for adverse birth outcomes among women of Latina/Hispanic descent. Further policies, practice, and research on reducing discrimination and enhancing factors that promote resilience such as social support are needed to facilitate healthy births among Latina/Hispanic women, mitigate intergenerational harm of discrimination-related stress, and advance health equity at birth and across the lifespan. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Gait Event Detection with Proprioceptive Force Sensing in a Powered Knee-Ankle Prosthesis: Validation over Walking Speeds and Slopes.

Many powered prosthetic devices use load cells to detect ground interaction forces and gait events. These sensors introduce additional weight and cost in the device. Recent proprioceptive actuators enable an algebraic relationship between actuator torques and ground contact forces. This paper presents a proprioceptive force sensing paradigm which estimates ground reaction forces as a solution to detect gait events without a load cell. A floating body dynamic model is obtained with constraints at the center of pressure representing foot-ground interaction. Constraint forces are derived to estimate ground reaction forces and subsequently timing of gait events. A treadmill experiment is conducted with a powered knee-ankle prosthesis used by an able-bodied subject walking at various speeds and slopes. Results show accurate gait event timing, with pooled data showing heel strike detection lagging by only 6.7 ± 7.2 ms and toe off detection leading by 30.4 ± 11.0 ms compared to values obtained from the load cell. These results establish proof of concept for predicting gait events without a load cell in powered prostheses with proprioceptive actuators.

Genetic mapping of the wheat leaf rust resistance gene Lr2a and its importance in Canadian wheat cultivars.

KEY MESSAGE: Leaf rust resistance gene Lr2a was located to chromosome arm 2DS in three mapping populations, which will facilitate map-based cloning and marker-assisted selection of Lr2a in wheat breeding programs. Incorporating effective leaf rust resistance (Lr) genes into high-yielding wheat cultivars has been an efficient method of disease control. One of the most widely used genes in Canada is the multi-allelic resistance gene Lr2, with alleles Lr2a, Lr2b, Lr2c, and Lr2d. The Lr2a allele confers complete resistance to a large portion of the Puccinia triticina (Pt) population in Canada. In this study, Lr2a was genetically mapped in two doubled haploid populations developed from the crosses Superb/BW278 and Superb/86ISMN 2137, and an F2 population developed from the cross Chinese Spring/RL6016. Seedlings were tested with the Lr2a avirulent Pt races 74-2 MGBJ (Superb/BW278) and 12-3 MBDS (Superb/86ISMN 2137 and Chinese Spring/RL6016) in greenhouse assays and were genotyped with 90K wheat Infinium SNP and kompetitive allele-specific PCR (KASP) markers. Lr2a was mapped to a collinear position on chromosome arm 2DS in all three populations, within a 1.00 cM genetic interval between KASP markers kwm1620 and kwm1623. This corresponded to a 305 kb genomic region of chromosome 2D in Chinese Spring RefSeq v2.1. The KASP marker kwh740 was predictive of Lr2a in all mapping populations. A panel of 260 wheats were tested with three Pt isolates, which revealed that Lr2a is common in Canadian wheats. The KASP markers kwh740 and kwm1584 were highly associated with resistance at the Lr2 locus, while kwm1622 was slightly less correlated. Genetic mapping of the leaf rust resistance gene Lr2a and DNA markers developed here will facilitate its use in wheat breeding programs.

Genome-wide association and targeted transcriptomic analyses reveal loci and candidate genes regulating preharvest sprouting in barley.

KEY MESSAGE: Genome-wide association study of diverse barley genotypes identified loci, single nucleotide polymorphisms and candidate genes that control seed dormancy and therefore enhance resistance to preharvest sprouting. Preharvest sprouting (PHS) causes significant yield and quality loss in barley and it is strongly associated with the level of seed dormancy. This study performed genome-wide association study using a collection of 255 diverse barley genotypes grown over four environments to identify loci controlling dormancy/PHS. Our phenotypic analysis revealed substantial variation in germination index/dormancy levels among the barley genotypes. Marker-trait association and linkage disequilibrium (LD) decay analyses identified 16 single nucleotide polymorphisms (SNPs) and two QTLs associated with dormancy/PHS, respectively, on chromosome 3H and 5H explaining 6.9% to 11.1% of the phenotypic variation. QTL.5H consist of 14 SNPs of which 12 SNPs satisfy the FDR threshold of α = 0.05, and it may represent the SD2 locus. The QTL on 3H consists of one SNP that doesn't satisfy FDR (α = 0.05). Genes harbouring the significant SNPs were analyzed for their expression pattern in the seeds of selected dormant and non-dormant genotypes. Of these genes, HvRCD1, HvPSRP1 and HvF3H exhibited differential expression between the dormant and non-dormant seed samples, suggesting their role in controlling seed dormancy/PHS. Three SNPs located within the differentially expressed genes residing in QTL.5H explained considerable phenotypic variation (≥ 8.6%), suggesting their importance in regulating PHS resistance. Analysis of the SNP marker data in QTL.5H identified a haplotype for PHS resistance. Overall, the study identified loci, SNPs and candidate genes that control dormancy and therefore play important roles in enhancing PHS resistance in barley through marker-assisted breeding.

Infant effortful control predicts BMI trajectories from infancy to adolescence.

BACKGROUND: Effortful control, or the regulation of thoughts and behaviour, is a potential target for preventing childhood obesity. OBJECTIVES: To assess effortful control in infancy through late childhood as a predictor of repeated measures of body mass index (BMI) from infancy through adolescence, and to examine whether sex moderates the associations. METHODS: Maternal report of offspring effortful control and measurements of child BMI were obtained at 7 and 8 time points respectively from 191 gestational parent/child dyads from infancy through adolescence. General linear mixed models were used. RESULTS: Effortful control at 6 months predicted BMI trajectories from infancy through adolescence, F(5,338) = 2.75, p = 0.03. Further, when effortful control at other timepoints were included in the model, they added no additional explanatory value. Sex moderated the association between 6-month effortful control and BMI, F(4, 338) = 2.59, p = 0.03, with poorer infant effortful control predicting higher BMI in early childhood for girls, and more rapid increases in BMI in early adolescence for boys. CONCLUSIONS: Effortful control in infancy was associated with BMI over time. Specifically, poor effortful control during infancy was associated with higher BMI in childhood and adolescence. These findings support the argument that infancy may be a sensitive window for the development of later obesity.

Distinct Contact Scaling Effects in MoS2 Transistors Revealed with Asymmetrical Contact Measurements.

2D semiconducting materials have immense potential for future electronics due to their atomically thin nature, which enables better scalability. While the channel scalability of 2D materials has been extensively studied, the current understanding of contact scaling in 2D devices is inconsistent and oversimplified. Here physically scaled contacts and asymmetrical contact measurements (ACMs) are combined to investigate the contact scaling behavior in 2D field-effect transistors. The ACMs directly compare electron injection at different contact lengths while using the exact same MoS2  channel, eliminating channel-to-channel variations. The results show that scaled source contacts can limit the drain current, whereas scaled drain contacts do not. Compared to devices with long contact lengths, devices with short contact lengths (scaled contacts) exhibit larger variations, 15% lower drain currents at high drain-source voltages, and a higher chance of early saturation and negative differential resistance. Quantum transport simulations reveal that the transfer length of Ni-MoS2  contacts can be as short as 5 nm. Furthermore, it is clearly identified that the actual transfer length depends on the quality of the metal-2D interface. The ACMs demonstrated here will enable further understanding of contact scaling behavior at various interfaces.

Experiences of COVID-19-Related Racism and Impact on Depression Trajectories Among Racially/Ethnically Minoritized Adolescents.

PURPOSE: In 2020, racially/ethnically minoritized (REMD) youth faced the "dual pandemics" of COVID-19 and racism, both significant stressors with potential for adverse mental health effects. The current study tested whether short- and long-term trajectories of depressive symptoms from before to during the COVID-19 pandemic differed between REMD adolescents who did and did not endorse exposure to COVID-19-era-related racism (i.e., racism stemming from conditions created or exacerbated by the COVID-19 pandemic). METHODS: A community sample of 100 REMD adolescents enrolled in an ongoing longitudinal study of mental health was assessed before and during the COVID-19 pandemic. Participants were 51% girls, mean age = 16, standard deviation = 2.7, and identified as Latinx/Hispanic (48%), Multiethnic (34%), Asian American (12%), and Black (6%). RESULTS: REMD adolescents' depressive symptoms were elevated during the COVID-19 pandemic compared to pre-pandemic levels, and increases were more pronounced over time for those who endorsed exposure to COVID-19-era-related racism. In general, Asian American participants endorsed racism experiences at the highest rates compared to others, including being called names (42%), people acting suspicious around them (33%), and being verbally threatened (17%). Additionally, more than half of Black and Asian American participants reported worry about experiencing racism related to the COVID-19 pandemic, even if they had not experienced it to date. DISCUSSION: REMD adolescents are at increased risk for depressive symptoms related to converging stressors stemming from the COVID-19 pandemic and pandemic-related racism, which has the potential to widen racial/ethnic mental health disparities faced by the REMD youth.

Discovery of a Series of Substituted 1H-((1,2,3-Triazol-4-yl)methoxy)pyrimidines as Brain Penetrants and Potent GluN2B-Selective Negative Allosteric Modulators.

Herein, we describe a series of substituted 1H-((1,2,3-triazol-4-yl)methoxy)pyrimidines as potent GluN2B negative allosteric modulators. Exploration of several five- and six-membered heterocycles led to the identification of O-linked pyrimidine analogues that possessed a balance of potency and desirable ADME profiles. Due to initial observations of metabolic saturation, early metabolite identification studies were conducted on compound 18, and the results drove further iterative optimization efforts to avoid the formation of undesired saturating metabolites. The comprehensive investigation of substitution on the pyrimidine moiety of the 1H-1,2,3-triazol-4-yl)methoxy)pyrimidines allowed for the identification of compound 31, which demonstrated high GluN2B receptor affinity, improved solubility, and a clean cardiovascular profile. Compound 31 was profiled in an ex vivo target engagement study in rats at a 10 mg/kg oral dose and achieved an ED50 of 1.7 mg/kg.

Maternal prenatal cortisol trajectories predict accelerated growth in infancy.

Higher maternal cortisol in pregnancy has been linked to childhood obesity. Much of the previous research has been limited in that cortisol in pregnancy is only measured at one time-point, precluding the ability to examine critical timing effects of prenatal maternal cortisol. To fill this gap, this longitudinal study measured maternal plasma cortisol at 15, 19, 25, and 31 weeks of pregnancy, and assessed infant body mass index percentile (BMIP)1 at birth, 3, 6, 12, and 24 months in 189 mother-infant pairs. Three distinct patterns of maternal cortisol in pregnancy (typical, steep, and flat trajectories) were identified using general growth mixture modeling (GGMM)2 and then used to predict child growth patterns using multilevel modeling. Infants of mothers who had flat cortisol trajectories, characterized by relatively high cortisol in early gestation that plateaus by mid-gestation, experienced more rapid increases in BMIP from birth to 6 months, and had higher BMIPs at 3 and 6 months, than infants whose mothers had the typical slow cortisol rise over gestation, or steep (rapidly accelerating) trajectories. These results suggest that it is not just the total amount of maternal cortisol in pregnancy that shapes early infant growth, but instead the timing and trajectory of prenatal cortisol exposure. To better understand the early origins of obesity risk, future research is needed to investigate the factors that shape mothers' prenatal cortisol trajectories.

Fine mapping and marker development for the wheat leaf rust resistance gene Lr32.

Wheat leaf rust is caused by the fungal pathogen Puccinia triticina and is one of the wheat diseases of concern globally. Among the known leaf rust resistance genes (Lr) genes, Lr32 is a broadly effective gene derived from the diploid species Aegilops tauschii coss. accession RL5497-1 and has been genetically mapped to chromosome arm 3DS. However, Lr32 resistance has not been utilized in current cultivars in part due to the lack of modern, predictive DNA markers. The goals of this study were to fine map the Lr32 region and develop SNP-based kompetitive allele-specific polymerase chain reaction markers. The genomic analysis was conducted by using doubled haploid and F2-derived mapping populations. For marker development, a 90K wheat chip array, 35K and 820K Axiom R SNPs, A. tauschii pseudomolecules v4.0 and International Wheat Genome Sequencing Consortium ReqSeq v2.1 reference genomes were used. Total 28 kompetitive allele-specific polymerase chain reaction and 2 simple sequence repeat markers were developed. The Lr32 region was fine mapped between kompetitive allele-specific polymerase chain reaction markers Kwh142 and Kwh355 that flanked 34-35 Mb of the diploid and hexaploid reference genomes. Leaf rust resistance mapped as a Mendelian trait that cosegregated with 20 markers, recombination restriction limited the further resolution of the Lr32 region. A total of 10-11 candidate genes associated with disease resistance were identified between the flanking regions on both reference genomes, with the majority belonging to the nucleotide-binding domain and leucine-rich repeat gene family. The validation analysis selected 2 kompetitive allele-specific polymerase chain reaction markers, Kwh147 and Kwh722, for marker-assisted selection. The presence of Lr32 along with other Lr genes such as Lr67 and Lr34 would increase the resistance in future wheat breeding lines and have a high impact on controlling wheat leaf rust.