A mHealth application for the training of caregivers of children with developmental disorders in South Africa: rationale and initial piloting.

Background: Evidence-based mobile health (mHealth) interventions have been successful for an array of physical and mental health conditions. Children with developmental disorders (DD) often have secondary speech and language disorders. The lack of high-quality medical and educational services in low- and middle-income countries limits the opportunities for children with DD to succeed in life. South Africa currently offers limited access to education, social, and health services. Methods: Twelve caregivers of twelve children with DD between the ages of 3 and 6 years who already received monthly early childhood therapy participated in this study. A mHealth app, called Nna'Le'wena, a Setswana phrase meaning "Me and You", was designed, developed, installed, and tested on tablets. The app provided a systematic framework and guidance to the caregivers in order to use evidence-based communication interaction strategies with the children over a twelve-week period. The app could be used offline and provided audio instructions in English and Setswana, two dominant languages in South Africa. The app automatically generated log files and collected answers to weekly surveys. At the end of the study, caregivers were asked to evaluate the app by using relevant portions of the Mobile App Rating Scale (MARS). Results: Caregivers were able to successfully interact and use the app. The app was well-received and liked by the caregivers. Caregivers listened to the instructional audios in English and Setswana during the 12-week period. They were able to provide communication opportunities to their children during daily living activities, especially during play- and mealtime activities. Conclusions: The Nna'Le'wena app was successfully deployed and used by caregivers of children with DD. mHealth solutions can be effective and are relatively affordable solutions that can enhance health care and educational delivery in different settings, including in low-and middle-income countries with limited Internet capabilities.

How Nurse Faculty in Saudi Arabia View Their Competencies in All Aspects of the Faculty Role: A Descriptive Study.

ABSTRACT: This study used a quantitative descriptive survey with a sample of 92 participants to assess perceived nurse faculty competency in their role at Saudi Arabian universities. Participants' perceptions overall were highly positive in the areas of teaching, scholarship, and service competencies. Participants reported less competence in the areas of scholarship and service when they started in their role. Orientation and a mentor relationship with senior faculty were reported to aid in their transition to the faculty role. The findings of the study identify strategies to support the new nurse educator.

Intensive Glycemic Management Is Associated With Reduced Retinal Structure Abnormalities on Ocular Coherence Tomography in the DCCT/EDIC Study.

OBJECTIVE: To investigate quantitative and qualitative changes in retinal structure using optical coherence tomography (OCT) and their associations with systemic or other risk factors in individuals with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: In the Epidemiology of Diabetes Interventions and Complications (EDIC) study, OCT images were obtained during study years 25-28 (2019-2022) in 937 participants; 54% and 46% were from the original intensive (INT) and conventional (CONV) glycemic management treatment groups, respectively. RESULTS: Average age for participants was 61 years old, diabetes duration 39 years, and HbA1c 7.6%. Participants originally in the CONV group were more likely to have disorganization of retinal inner layers (DRIL) (CONV 27.3% vs. INT 18.7%; P = 0.0003), intraretinal fluid (CONV 24.4% vs. INT 19.2%; P = 0.0222), and intraretinal cysts (CONV 20.8% vs. INT 16.6%; P = 0.0471). In multivariable models, sex, age, smoking, mean updated systolic blood pressure, and history of "clinically significant" macular edema (CSME) and of anti-VEGF treatment were independently associated with changes in central subfield thickness, while HbA1c, BMI, and history of CSME and of ocular surgery were associated with DRIL. Visual acuity (VA) decline was associated with significant thinning of all retinal subfields except for the central and inner nasal subfields. CONCLUSIONS: Early intensive glycemic management in T1D is associated with a decreased risk of DRIL. This important morphological abnormality was associated with a history of macular edema, a history of ocular surgery, and worse VA. This study reveals benefits of intensive glycemic management on the retina beyond features detected by fundus photographs and ophthalmoscopy.

Major adverse events in youth-onset type 1 and type 2 diabetes: The SEARCH and TODAY studies.

AIMS: To determine contemporary incidence rates and risk factors for major adverse events in youth-onset T1D and T2D. METHODS: Participant interviews were conducted once during in-person visits from 2018 to 2019 in SEARCH (T1D: N = 564; T2D: N = 149) and semi-annually from 2014 to 2020 in TODAY (T2D: N = 495). Outcomes were adjudicated using harmonized, predetermined, standardized criteria. RESULTS: Incidence rates (events per 10,000 person-years) among T1D participants were: 10.9 ophthalmologic; 0 kidney; 11.1 nerve, 3.1 cardiac; 3.1 peripheral vascular; 1.6 cerebrovascular; and 15.6 gastrointestinal events. Among T2D participants, rates were: 40.0 ophthalmologic; 6.2 kidney; 21.2 nerve; 21.2 cardiac; 10.0 peripheral vascular; 5.0 cerebrovascular and 42.8 gastrointestinal events. Despite similar mean diabetes duration, complications were higher in youth with T2D than T1D: 2.5-fold higher for microvascular, 4.0-fold higher for macrovascular, and 2.7-fold higher for gastrointestinal disease. Univariate logistic regression analyses in T1D associated age at diagnosis, female sex, HbA1c and mean arterial pressure (MAP) with microvascular events. In youth-onset T2D, composite microvascular events associated positively with MAP and negatively with BMI, however composite macrovascular events associated solely with MAP. CONCLUSIONS: In youth-onset diabetes, end-organ events were infrequent but did occur before 15 years diabetes duration. Rates were higher and had different risk factors in T2D versus T1D.

Unlocking bacterial defense: Exploring the potent inhibition of NorA efflux pump by coumarin derivatives in Staphylococcus aureus.

The occurrence of bacterial resistance has been increasing, compromising the treatment of various infections. The high virulence of Staphylococcus aureus allows for the maintenance of the infectious process, causing many deaths and hospitalizations. The MepA and NorA efflux pumps are transporter proteins responsible for expelling antimicrobial agents such as fluoroquinolones from the bacterial cell. Coumarins are phenolic compounds that have been studied for their diverse biological actions, including against bacteria. A pharmacokinetic in silico characterization of compounds C10, C11, C13, and C14 was carried out according to the principles of Lipinski's Rule of Five, in addition to searching for similarity in ChemBL and subsequent search for publications in CAS SciFinder. All compounds were evaluated for their in vitro antibacterial and modulatory activity against standard and multidrug-resistant Gram-positive and Gram-negative strains. The effect of coumarins C9, C10, C11, C13, and C14 as efflux pump inhibitors in Staphylococcus aureus strains was evaluated using the microdilution method (MepA or NorA) and fluorimetry (NorA). The behavior of coumarins regarding the efflux pump was determined from their interaction properties with the membrane and coumarin-protein using molecular docking and molecular dynamics simulations. Only the isolated coumarin compound C13 showed antibacterial activity against standard strains of Staphylococcus aureus and Escherichia coli. However, the other tested coumarins showed modulatory capacity for fluoroquinolone and aminoglycoside antibacterials. Compounds C10, C13, and C14 were effective in reducing the MIC of both antibiotics for both multidrug-resistant strains, while C11 potentiated the effect of norfloxacin and gentamicin for Gram-positive and Gram-negative bacteria and only norfloxacin for Gram-negative. Only coumarin C14 produced synergistic effects when associated with ciprofloxacin in MepA-carrying strains. All tested coumarins have the ability to inhibit the NorA efflux pump present in Staphylococcus aureus, both in reducing the MIC and inducing increased ethidium bromide fluorescence emission in fluorimetry. The findings of this study offer an atomistic perspective on the potential of coumarins as active inhibitors of the NorA pump, highlighting their specific mode of action mainly targeting protein inhibition. In molecular docking, it was observed that coumarins are capable of interacting with various amino acid residues of the NorA pump. The simulation showed that coumarin C10 can cross the bilayer; however, the other coumarins interacted with the membrane but were unable to cross it. Coumarins demonstrated their potentiating role in the effect of norfloxacin through a dual mechanism: efflux pump inhibition through direct interaction with the protein (C9, C10, C11, and C13) and increased interaction with the membrane (C10 and C13). In the context of pharmacokinetic prediction studies, the studied structures have a suitable chemical profile for possible oral use. We suggest that coumarin derivatives may be an interesting alternative in the future for the treatment of resistant bacterial infections, with the possibility of a synergistic effect with other antibacterials, although further studies are needed to characterize their therapeutic effects and toxicity.

A population-based time-series analysis of opioid agonist treatment dispensed during pregnancy.

BACKGROUND AND AIMS: Identifying effective opioid treatment options during pregnancy is a high priority due to the growing prevalence of opioid use disorder across North America. We assessed the temporal impact of three population-level interventions on the use of opioid agonist treatment (OAT) during pregnancy in Ontario, Canada. DESIGN: This was a population-based time-series analysis to identify trends in the monthly prevalence of pregnant people dispensed methadone and buprenorphine. The impact of adding buprenorphine/naloxone to the public drug formulary, the release of pregnancy-specific guidance and the start of the COVID-19 pandemic were assessed. SETTING AND PARTICIPANTS: The study was conducted in Ontario, Canada between 1 July 2013 and 31 March 2022, comprising people who delivered a live or stillbirth in any Ontario hospital during the study period. MEASUREMENTS: We identified any prescription for methadone or buprenorphine dispensed between the estimated conception date and delivery date and calculated the monthly prevalence of OAT-exposed pregnancies among all pregnant people in Ontario. FINDINGS: Overall, rates of OAT during pregnancy have declined since mid-2018. Methadone-exposed pregnancies decreased from 0.46% of all pregnancies in Ontario in 2015 to a low of 0.16% in 2022. In the primary analysis, none of the interventions had a statistically significant impact on overall OAT rates; however, in the stratified analyses, there was a small increase in buprenorphine after the formulary change [0.006%, 95% confidence interval (CI) = 0.0032-0.0081, P < 0.0001] and a decrease in buprenorphine after the release of the 2017 guidelines (-0.005%, 95% CI = -0.0080 to -0.0020, P = 0.001) and the start of the COVID-19 pandemic (-0.003%, 95% CI = -0.0054 to -0.0006, P = 0.015). CONCLUSION: Despite changes in guidance and funding, opioid agonist treatment during pregnancy has been declining in Ontario, Canada since 2018.

Higher order polyploids exhibit enhanced desiccation tolerance in the grass Microchloa caffra.

Desiccation tolerance evolved recurrently across diverse plant lineages to enable survival in water limited conditions. Many resurrection plants are polyploid and several groups have hypothesized that polyploidy contributed to the evolution of desiccation tolerance. However, due to the vast phylogenetic distance between resurrection plant lineages, the rarity of desiccation tolerance, and the prevalence of polyploidy in plants, this hypothesis has been difficult to test. Here, we surveyed natural variation in morphological, reproductive, and desiccation tolerance traits across several cytotypes of a single species to test for links between polyploidy and increased resilience. We sampled multiple natural populations of the resurrection grass Microchloa caffra across an environmental gradient ranging from mesic to xeric in South Africa. We describe two distinct ecotypes of M. caffra that occupy different extremes of the environmental gradient and exhibit consistent differences in ploidy, morphological, reproductive, and desiccation tolerance traits in both field and common growth conditions. Interestingly, plants with more polyploid genomes exhibited consistently higher recovery from desiccation, were less reproductive, and larger than plants with smaller genomes and lower ploidy. These data suggest that selective pressures in increasingly xeric sites may play a role in maintaining and increasing desiccation tolerance that are mediated by changes in ploidy.

Racial differences in hypertensive disorders in pregnancy during the COVID-19 pandemic.

OBJECTIVE: To compare rates of pregnancy induced hypertensive disorders during the period of the COVID-19 pandemic to prior, baseline years. METHODS: We conducted a retrospective study of 17,742 patients on rates for pregnancy induced hypertensive disorders delivering at 2 local hospitals before (Cohort 1; January 2018 to December 2019; n = 8245) and after (Cohort 2; February 2020 to February 2022; n = 9497) the onset of the COVID-19 pandemic. The primary outcomes were rates of gestational hypertension, pre-eclampsia, and chronic hypertension in patients.Wecompared by year (2018-2022), by patient COVID infection status, and by racial demographics. RESULTS: During the pandemic (Cohort 2), there were lower rates of chronic hypertension (7.4 % vs 6.5 %, p =.02), higher rates of gestational hypertension (26.3 % vs 27.8 %, p =.03), and higher rates of preeclampsia (11.3 % vs 13.1 %, p <.001) compared to years prior to the pandemic (Cohort 1). When evaluating by year, rates of chronic hypertension did not statistically change while rates for preeclampsia increased in the first year of the pandemic and remained high, and rates for gestational hypertension did not increase until the second year of the pandemic. When evaluating by COVID infection status, rates for gestational hypertension were significantly higher for individuals with a positive COVID infection status (COVID negative = 27.4 % vs. COVID positive = 32.8 %; p <.004). Rates of preeclampsia did not differ according to COVID infection status (p = 0.15). CONCLUSION: In this study, rates of pregnancy induced hypertensive disorders increased during the COVID pandemic regardless of COVID infection status.

Vaginal Calculus Formation on Exposed Midurethral Sling Mesh.

The presence of a vaginal calculus is a rare clinical entity which may develop in the setting of vaginal urinary stagnation. Numerous factors contribute to stone formation, and management can be complicated by variations in size, location of the stone, and location of adjacent structures. Generally, once diagnosed, vaginal calculi should be removed and surrounding anatomy should be evaluated thoroughly for secondary fistula, erosion, or presence of an instituting foreign body. This report presents a case of vaginal calculus formation on exposed midurethral sling mesh in an elderly patient with hemorrhagic cystitis. This report emphasizes contributing pathophysiology, diagnostic factors, and treatment.

Still having his say: David Yoder's legacy in AAC.

On February 2 2023, one of the guiding lights in the field of augmentative and alternative communication (AAC) for more than four decades, David E. Yoder, passed away at the age of 90. A voracious reader and gifted storyteller, David was particularly fond of a quote from George Bernard Shaw's Back to Methuselah, "You see things; and you say 'Why?' but I dream things that never were; and I say 'Why not?'" That vision led him to take on multiple leadership roles and influence the field of AAC in multiple ways. He played a pivotal role in establishing both the International Society for Augmentative and Alternative Communication (ISAAC) and the United States Society for Augmentative and Alternative Communication (USSAAC). Additionally, he chaired the panel for the National Institute on Disability and Rehabilitation Research (NIDRR)'s inaugural Consensus Validation Conference on AAC, advocated for the American Speech-Language-Hearing Association to recognize AAC within the profession's scope of practice, and served as the first editor for the Augmentative and Alternative Communication journal. In this tribute, we describe David's diverse and unique contributions to improving the lives of people with communication challenges with a focus on some of his central insights and actions.

Variability in drought gene expression datasets highlight the need for community standardization.

Physiologically relevant drought stress is difficult to apply consistently, and the heterogeneity in experimental design, growth conditions, and sampling schemes make it challenging to compare water deficit studies in plants. Here, we re-analyzed hundreds of drought gene expression experiments across diverse model and crop species and quantified the variability across studies. We found that drought studies are surprisingly uncomparable, even when accounting for differences in genotype, environment, drought severity, and method of drying. Many studies, including most Arabidopsis work, lack high-quality phenotypic and physiological datasets to accompany gene expression, making it impossible to assess the severity or in some cases the occurrence of water deficit stress events. From these datasets, we developed supervised learning classifiers that can accurately predict if RNA-seq samples have experienced a physiologically relevant drought stress, and suggest this can be used as a quality control for future studies. Together, our analyses highlight the need for more community standardization, and the importance of paired physiology data to quantify stress severity for reproducibility and future data analyses.

Neuropathic Pain With and Without Diabetic Peripheral Neuropathy in Type 1 Diabetes.

OBJECTIVE: Diabetic peripheral neuropathy (DPN) is common; however, the features and burden of neuropathic pain (NP) in type 1 diabetes (T1D) are poorly understood. We evaluated the incidence of first occurrence, annual prevalence, remission, and risk factors for NP during long-term follow-up of participants with T1D. RESEARCH DESIGN AND METHODS: The Michigan Neuropathy Screening Instrument (MNSI) was administered annually (1994-2020) for 1,324 participants in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. NP with clinical signs of DPN (NP DPN+) was defined according to self-reported NP plus an examination score >2, while NP without clinical signs of DPN (NP DPN-) was defined according to self-reported NP and an examination score ≤2. RESULTS: At EDIC year 1, median age for participants was 36 years (interquartile range 30, 41), diabetes duration 13 years (10, 18), and HbA1c 7.9% (7.2, 8.9). At year 26 (median diabetes duration 39 years), cumulative incidence of NP was 57%, regardless of concomitant clinical signs of DPN (36% NP DPN+ vs. 46% NP DPN-). NP prevalence was 20% at 26 years (11% NP DPN+ and 9% NP DPN-), suggesting frequent remission. Annualized remission rates were similar regardless of pain medication use. In addition to HbA1c, female sex was associated with NP DPN-. CONCLUSIONS: NP incidence in T1D was high and frequently occurred in the absence of clinical signs of neuropathy, as assessed with the MNSI. Pain remission was not explained by pain medication use. Effective clinical strategies for identification and management are needed.

SCB-2019 protein vaccine as heterologous booster of neutralizing activity against SARS-CoV-2 Omicron variants after immunization with other COVID-19 vaccines.

We assessed the non-inferiority of homologous boosting compared with heterologous boosting with the recombinant protein vaccine, SCB-2019, in adults previously immunized with different COVID-19 vaccines. Three equal cohorts (N ~ 420) of Philippino adults (18-80 years) previously immunized with Comirnaty, CoronaVac or Vaxzevria COVID-19 vaccines were randomized 1:1 to receive homologous or heterologous (SCB-2019) boosters. Neutralizing antibodies against prototype SARS-CoV-2 (Wuhan-Hu-1) were measured in all participants and against Delta variant and Omicron sub-lineages in subsets (30‒50 per arm) 15 days after boosting. Participants recorded solicited adverse events for 7 days and unsolicited and serious adverse events until Day 60. Prototype SARS-CoV-2 neutralizing responses on Day 15 after SCB-2019 were statistically non-inferior to homologous Vaxzevria boosters, superior to CoronaVac, but lower than homologous Comirnaty. Neutralizing responses against Delta and Omicron BA.1, BA.2, BA.4 and BA.5 variants after heterologous SCB-2019 were higher than homologous CoronaVac or Vaxzevria, but lower than homologous Comirnaty. Responses against Omicron BF.7, BQ.1.1.3, and XBB1.5 following heterologous SCB-2019 were lower than after homologous Comirnaty booster but significantly higher than after Vaxzevria booster. SCB-2019 reactogenicity was similar to CoronaVac or Vaxzevria, but lower than Comirnaty; most frequent events were mild/moderate injection site pain, headache and fatigue. No vaccine-related serious adverse events were reported. Heterologous SCB-2019 boosting was well tolerated and elicited neutralizing responses against all tested SARS-COV-2 viruses including Omicron BA.1, BA.2, BA.4, BA.5, BF.7, BQ.1.1.3, and XBB1.5 sub-lineages that were non-inferior to homologous boosting with CoronaVac or Vaxzevria, but not homologous Comirnaty booster.

A chromosome-level genome for the nudibranch gastropod Berghia stephanieae helps parse clade-specific gene expression in novel and conserved phenotypes.

BACKGROUND: How novel phenotypes originate from conserved genes, processes, and tissues remains a major question in biology. Research that sets out to answer this question often focuses on the conserved genes and processes involved, an approach that explicitly excludes the impact of genetic elements that may be classified as clade-specific, even though many of these genes are known to be important for many novel, or clade-restricted, phenotypes. This is especially true for understudied phyla such as mollusks, where limited genomic and functional biology resources for members of this phylum have long hindered assessments of genetic homology and function. To address this gap, we constructed a chromosome-level genome for the gastropod Berghia stephanieae (Valdés, 2005) to investigate the expression of clade-specific genes across both novel and conserved tissue types in this species. RESULTS: The final assembled and filtered Berghia genome is comparable to other high-quality mollusk genomes in terms of size (1.05 Gb) and number of predicted genes (24,960 genes) and is highly contiguous. The proportion of upregulated, clade-specific genes varied across tissues, but with no clear trend between the proportion of clade-specific genes and the novelty of the tissue. However, more complex tissue like the brain had the highest total number of upregulated, clade-specific genes, though the ratio of upregulated clade-specific genes to the total number of upregulated genes was low. CONCLUSIONS: Our results, when combined with previous research on the impact of novel genes on phenotypic evolution, highlight the fact that the complexity of the novel tissue or behavior, the type of novelty, and the developmental timing of evolutionary modifications will all influence how novel and conserved genes interact to generate diversity.

Cellular and molecular alterations in a human hepatocellular in vitro model of nonalcoholic fatty liver disease development and stratification.

The rapidly increasing incidence of nonalcoholic fatty liver disease (NAFLD) is a growing health crisis worldwide. If not detected early, NAFLD progression can lead to irreversible pathological states, including liver fibrosis and cirrhosis. Using in vitro models to understand the molecular pathogenesis has been extremely beneficial; however, most studies have utilized only short-term exposures, highlighting a limitation in current research to model extended fat-induced liver injury. We treated Hep3B cells continuously with a low dose of oleic and palmitic free fatty acids (FFAs) for 7 or 28 days. Transcriptomic analysis identified dysregulated molecular pathways and differential expression of 984 and 917 genes after FFA treatment for 7 and 28 days respectively. DNA methylation analysis of altered DNA methylated regions (DMRs) found 7 DMRs in common. Pathway analysis of differentially expressed genes (DEGs) revealed transcriptomic changes primarily involved in lipid metabolism, small molecule biochemistry, and molecular transport. Western blot analysis revealed changes in PDK4 and CPT1A protein levels, indicative of mitochondrial stress. In line with this, there was mitochondrial morphological change demonstrating breakdown of the mitochondrial network. This in vitro model of human NAFL mimics results observed in human patients and may be used as a pre-clinical model for drug intervention.

Learning Pelvic Anatomy and Pathology Through Drawing: An Interactive Session in the Obstetrics and Gynecology Clerkship.

Introduction: Within undergraduate medical education, there is a gap between students' understanding of anatomy and application of that knowledge within surgical specialties. The integration of drawing, in conjunction with traditional learning, has been shown to increase retention and understanding of information. Currently, no educational curriculum integrates drawing to aid in medical students' understanding of surgical pelvic anatomy. We anticipated that the utilization of drawing anatomy in an OB/GYN clerkship would enhance students' ability to explain surgical pelvic anatomy and pelvic pathology. Methods: At the beginning of the OB/GYN clerkship, third-year medical students participated in an interactive, 1.5-hour session requiring them to draw pelvic anatomy, present their work, and explain topics related to pelvic surgery and pathology to the other clerkship students. At the end of their clinical rotation, the students were invited to complete a five-item survey to assess long-term retention and understanding of concepts presented in the session. Frequencies and percentages were calculated for all categorical/ordinal variables to describe survey participants and question responses. Results: Thirty-seven of 44 respondents (84%) reported that the anatomy interactive session prepared them for the surgical portion of the OB/GYN clinical rotation. Thirty-five respondents (80%) reported that drawing the pelvic structures helped their understanding of pelvic pathology; 33 respondents (75%) reported they had a thorough understanding of pelvic anatomy after taking the OB/GYN anatomy interactive educational session (p < .001). Discussion: Our session shows that integrating drawing and anatomy increases students' ability to discuss pelvic pathology and surgical anatomy.

Diabetes Modulates Iodothyronine Deiodinase 2 Expression in the Mouse Retina: A Role for Thyroid Hormone in the Pathogenesis of Diabetic Retinopathy.

Purpose: Clinical investigations associate hypothyroidism with an increased risk for microvascular complications, yet the mechanism by which thyroid hormone regulates the development of diabetic retinopathy is not clearly understood. We investigated the role of iodothyronine deiodinase 2 (DIO2) in the pathogenesis of diabetic retinopathy. Methods: Retinas from streptozotocin-induced diabetic and nondiabetic mice were evaluated by RNA sequencing, RT-PCR, and immunostaining. Media and cell lysates from mouse retinal microvascular endothelial cells and retinal astrocytes exposed to physiologic (5 mM) and high glucose (25 mM) containing media were assessed by liquid chromatography-tandem mass spectrometry to measure tetraiodothyronine (T4) and tri-iodothyronine (T3) concentrations and by Western blot analysis to determine the relationship of T4/T3 to oxidative stress and inflammatory mediators. Cell death was determined by Trypan Blue exclusion assay. Results: At 12 weeks of diabetes duration, retinas from diabetic mice compared with nondiabetic mice demonstrated a significant decrease in Dio2 transcripts and Dio2 gene and protein (P < 0.05) expression. When cultured in the presence of high glucose, both mouse retinal astrocytes and microvascular endothelial cells demonstrated a significant reduction of DIO2 protein compared with cells cultured in physiologic glucose. High glucose inhibited generation of T3, leading to a significantly increased T4/T3 (P < 0.0079). Supplementation of cells with T3, but not T4, prevented the high glucose-induced rise in endothelial nitric oxide synthase, intercellular cell adhesion molecule 1, and endothelial cell death (P < 0.0079). Conclusions: Decreased intraretinal T3 owing to diabetes-induced loss of DIO2 may lead to dysfunction and death of cells in the retina, thereby contributing to the pathogenesis of early diabetic retinopathy.

A chromosome-level genome for the nudibranch gastropod Berghia stephanieae helps parse clade-specific gene expression in novel and conserved phenotypes.

How novel phenotypes originate from conserved genes, processes, and tissues remains a major question in biology. Research that sets out to answer this question often focuses on the conserved genes and processes involved, an approach that explicitly excludes the impact of genetic elements that may be classified as clade-specific, even though many of these genes are known to be important for many novel, or clade-restricted, phenotypes. This is especially true for understudied phyla such as mollusks, where limited genomic and functional biology resources for members of this phylum has long hindered assessments of genetic homology and function. To address this gap, we constructed a chromosome-level genome for the gastropod Berghia stephanieae (Valdés, 2005) to investigate the expression of clade-specific genes across both novel and conserved tissue types in this species. The final assembled and filtered Berghia genome is comparable to other high quality mollusk genomes in terms of size (1.05 Gb) and number of predicted genes (24,960 genes), and is highly contiguous. The proportion of upregulated, clade-specific genes varied across tissues, but with no clear trend between the proportion of clade-specific genes and the novelty of the tissue. However, more complex tissue like the brain had the highest total number of upregulated, clade-specific genes, though the ratio of upregulated clade-specific genes to the total number of upregulated genes was low. Our results, when combined with previous research on the impact of novel genes on phenotypic evolution, highlight the fact that the complexity of the novel tissue or behavior, the type of novelty, and the developmental timing of evolutionary modifications will all influence how novel and conserved genes interact to generate diversity.

Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of TH17 cell immunity.

Regulatory T cells (Treg cells) are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, in the present study we show that interleukin (IL)-27 is specifically produced by intestinal Treg cells to regulate helper T17 cell (TH17 cell) immunity. Selectively increased intestinal TH17 cell responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83+CD62Llo Treg cell subset that is distinct from previously characterized intestinal Treg cell populations as the main IL-27 producers. Collectively, our study uncovers a new Treg cell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue and provides further mechanistic insights into tissue-specific Treg cell-mediated immune regulation.