Fetal liver blood flow distribution: role in human developmental strategy to prioritize fat deposition versus brain development

Among primates, human neonates have the largest brains but also the highest proportion of body fat. If placental nutrient supply is limited, the fetus faces a dilemma: should resources be allocated to brain growth, or to fat deposition for use as a potential postnatal energy reserve? We hypothesised that resolving this dilemma operates at the level of umbilical blood distribution entering the fetal liver. In 381 uncomplicated pregnancies in third trimester, we measured blood flow perfusing the fetal liver, or bypassing it via the ductus venosus to supply the brain and heart using ultrasound techniques. Across the range of fetal growth and independent of the mother's adiposity and parity, greater liver blood flow was associated with greater offspring fat mass measured by dual-energy X-ray absorptiometry, both in the infant at birth (r = 0.43, P<0.001) and at age 4 years (r = 0.16, P = 0.02). In contrast, smaller placentas less able to meet fetal demand for essential nutrients were associated with a brain-sparing flow pattern (r = 0.17, p = 0.02). This flow pattern was also associated with a higher degree of shunting through ductus venosus (P = 0.04). We propose that humans evolved a developmental strategy to prioritize nutrient allocation for prenatal fat deposition when the supply of conditionally essential nutrients requiring hepatic inter-conversion is limited, switching resource allocation to favour the brain if the supply of essential nutrients is limited. Facilitated placental transfer mechanisms for glucose and other nutrients evolved in environments less affluent than those now prevalent in developed populations, and we propose that in circumstances of maternal adiposity and nutrient excess these mechanisms now also lead to prenatal fat deposition. Prenatal developmental influences play important roles in the human propensity to deposit fa

Enhanced Aromatic Sequons Increase Oligosaccharyltransferase Glycosylation Efficiency and Glycan Homogeneity

SummaryN-Glycosylation plays an important role in protein folding and function. Previous studies demonstrate that a phenylalanine residue introduced at the n-2 position relative to an Asn-Xxx-Thr/Ser N-glycosylation sequon increases the glycan occupancy of the sequon in insect cells. Here, we show that any aromatic residue at n-2 increases glycan occupancy in human cells and that this effect is dependent upon oligosaccharyltransferase substrate preferences rather than differences in other cellular processing events such as degradation or trafficking. Moreover, aromatic residues at n-2 alter glycan processing in the Golgi, producing proteins with less complex N-glycan structures. These results demonstrate that manipulating the sequence space surrounding N-glycosylation sequons is useful both for controlling glycosylation efficiency, thus enhancing glycan occupancy, and for influencing the N-glycan structures produced

Impact of COVID-19 Infection During Pregnancy on Neonatal Birth Outcomes

Approximately 116 million births have been reported worldwide in the nine months following the start of the COVID-19 pandemic. Currently, the effects of COVID-19 infection during pregnancy on birth outcomes are not fully understood. An IRB-approved study enrolled 115 mothers since March 2020, 5 of whom had a confirmed history of COVID-19 infection during pregnancy. For each COVID-19-infected mother, two mothers of similar age, gestation period, and race who were not infected with COVID-19 during pregnancy were matched 2-to-1 for a case-control analysis. Descriptive statistics were generated, and the Mann-Whitney U test was used to compare continuous variables between the two groups. Fisher’s Exact test was used to evaluate categorical outcomes between the groups. Phttps://digitalcommons.unmc.edu/surp2021/1007/thumbnail.jp

Common Variants in 40 Genes Assessed for Diabetes Incidence and Response to Metformin and Lifestyle Intervention in the Diabetes Prevention Program

OBJECTIVE: Genome-wide association studies have begun to elucidate the genetic architecture of type 2 diabetes. We examined whether single nucleotide polymorphisms (SNPs) identified through targeted complementary approaches affect diabetes incidence in the at-risk population of the Diabetes Prevention Program (DPP) and whether they influence a response to preventive interventions. RESEARCH DESIGN AND METHODS: We selected SNPs identified by prior genome-wide association studies for type 2 diabetes and related traits, or capturing common variation in 40 candidate genes previously associated with type 2 diabetes, implicated in monogenic diabetes, encoding type 2 diabetes drug targets or drug-metabolizing/transporting enzymes, or involved in relevant physiological processes. We analyzed 1,590 SNPs for association with incident diabetes and their interaction with response to metformin or lifestyle interventions in 2,994 DPP participants. We controlled for multiple hypothesis testing by assessing false discovery rates. RESULTS: We replicated the association of variants in the metformin transporter gene $SLC47A1$ with metformin response and detected nominal interactions in the AMP kinase (AMPK) gene $STK11$, the AMPK subunit genes $PRKAA1$ and $PRKAA2$, and a missense SNP in $SLC22A1$, which encodes another metformin transporter. The most significant association with diabetes incidence occurred in the AMPK subunit gene $PRKAG2$ (hazard ratio 1.24, 95% CI 1.09–1.40, P = 7 × 10$^{−4}$). Overall, there were nominal associations with diabetes incidence at 85 SNPs and nominal interactions with the metformin and lifestyle interventions at 91 and 69 mostly nonoverlapping SNPs, respectively. The lowest $P$ values were consistent with experiment-wide 33% false discovery rates. CONCLUSIONS: We have identified potential genetic determinants of metformin response. These results merit confirmation in independent samples

A model of impaired Langerhans cell maturation associated with HPV induced epithelial hyperplasia.

Funder: National Health and Medical Research CouncilLangerhans cells (LC) are skin-resident antigen-presenting cells that regulate immune responses to epithelial microorganisms. Human papillomavirus (HPV) infection can promote malignant epithelial transformation. As LCs are considered important for controlling HPV infection, we compared the transcriptome of murine LCs from skin transformed by K14E7 oncoprotein and from healthy skin. We identified transcriptome heterogeneity at the single cell level amongst LCs in normal skin, associated with ontogeny, cell cycle, and maturation. We identified a balanced co-existence of immune-stimulatory and immune-inhibitory LC cell states in normal skin that was significantly disturbed in HPV16 E7-transformed skin. Hyperplastic skin was depleted of immune-stimulatory LCs and enriched for LCs with an immune-inhibitory gene signature, and LC-keratinocyte crosstalk was dysregulated. We identified reduced expression of interleukin (IL)-34, a critical molecule for LC homeostasis. Enrichment of an immune-inhibitory LC gene signature and reduced levels of epithelial IL-34 were also found in human HPV-associated cervical epithelial cancers

Common Variants in 40 Genes Assessed for Diabetes Incidence and Response to Metformin and Lifestyle Intervention in the Diabetes Prevention Program

OBJECTIVE: Genome-wide association studies have begun to elucidate the genetic architecture of type 2 diabetes. We examined whether single nucleotide polymorphisms (SNPs) identified through targeted complementary approaches affect diabetes incidence in the at-risk population of the Diabetes Prevention Program (DPP) and whether they influence a response to preventive interventions. RESEARCH DESIGN AND METHODS: We selected SNPs identified by prior genome-wide association studies for type 2 diabetes and related traits, or capturing common variation in 40 candidate genes previously associated with type 2 diabetes, implicated in monogenic diabetes, encoding type 2 diabetes drug targets or drug-metabolizing/transporting enzymes, or involved in relevant physiological processes. We analyzed 1,590 SNPs for association with incident diabetes and their interaction with response to metformin or lifestyle interventions in 2,994 DPP participants. We controlled for multiple hypothesis testing by assessing false discovery rates. RESULTS: We replicated the association of variants in the metformin transporter gene SLC47A1 with metformin response and detected nominal interactions in the AMP kinase (AMPK) gene STK11, the AMPK subunit genes PRKAA1 and PRKAA2, and a missense SNP in SLC22A1, which encodes another metformin transporter. The most significant association with diabetes incidence occurred in the AMPK subunit gene PRKAG2 (hazard ratio 1.24, 95% CI 1.09-1.40, P = 7 × 10(-4)). Overall, there were nominal associations with diabetes incidence at 85 SNPs and nominal interactions with the metformin and lifestyle interventions at 91 and 69 mostly nonoverlapping SNPs, respectively. The lowest P values were consistent with experiment-wide 33% false discovery rates. CONCLUSIONS: We have identified potential genetic determinants of metformin response. These results merit confirmation in independent samples

Health behaviour change during the UK COVID-19 lockdown: findings from the first wave of the C-19 health behaviour and wellbeing daily tracker study

Objectives: To provide baseline cohort descriptives and assess change in health behaviours since the UK COVID-19 lockdown. Design: A prospective cohort (N=1,044) of people recruited online, purposively targeting vulnerable populations. Methods: After a baseline survey (April 2020), participants completed 3 months of daily ecological momentary assessments (EMA). Dietary, physical activity, alcohol, smoking, vaping and substance use behaviours collected retrospectively for the pre-COVID-19 period were compared with daily EMA surveys over the first 30 days during early lockdown. Predictors of behaviour change were assessed using multivariable regression models. Results: 30% of the cohort had a COVID-19 at risk health condition, 37% were classed as deprived and 6% self-reported a mental health condition. Relative to pre-pandemic levels, participants ate almost one portion of fruit and vegetables less per day (vegetables mean difference -0.33, 95% CI -0.40, -0.25; fruit -0.57, 95% CI -0.64, -0.50), but showed no change in high sugar portions per day (-0.03, 95% CI -0.12, 0.06). Participants spent half a day less per week doing ≥30 minutes of moderate to vigorous physical activity (-0.57, 95% CI -0.73, -0.40) but slightly increased days of strength training (0.21, 95% CI 0.09, 0.34), increased alcohol intake (AUDIT-C score change 0.25, 95% CI 0.13, 0.37), though did not change smoking, vaping or substance use behaviour. Worsening health behaviour change was associated with being younger, female and higher body mass index. Conclusions: The cohort reported worsening health behaviours during early lockdown. Longer term changes will be investigated using further waves of data collection

EN-BIRTH Data Collector Training - Handbook and Manual

The EN-BIRTH study aims to validate selected newborn and maternal indicators for routine facility-based tracking of coverage and quality of care for use at district, national and global levels. The item contains the EN-BIRTH_Trainer's Manual (14 June 2017) and EN-BIRTH_Training Handbook (23 May 2017)

EN-BIRTH Data Collector Training - Supporting Annexes

The EN-BIRTH study aims to validate selected newborn and maternal indicators for routine facility-based tracking of coverage and quality of care for use at district, national and global levels. The item contains consent forms and participant information, in addition to standard operating procedures (SOP) for adverse clinical events, and managing distress in interviews. The full complement of annex files used during the training can be requested via this site if required