The BLUETIDES mock image catalogue: simulated observations of high-redshift galaxies and predictions for JWST imaging surveys

We present a mock image catalogue of ∼100 000 MUV ≃ −22.5 to −19.6 mag galaxies at z = 7–12 from the bluetides cosmological simulation. We create mock images of each galaxy with the James Webb Space Telescope (JWST), Hubble, Roman, and Euclid Space Telescopes, as well as Subaru, and VISTA, with a range of near- and mid-infrared filters. We perform photometry on the mock images to estimate the success of these instruments for detecting high-z galaxies. We predict that JWST will have unprecedented power in detecting high-z galaxies, with a 95 per cent completeness limit at least 2.5 mag fainter than VISTA and Subaru, 1.1 mag fainter than Hubble, and 0.9 mag fainter than Roman, for the same wavelength and exposure time. Focusing on JWST, we consider a range of exposure times and filters, and find that the NIRCam F356W and F277W filters will detect the faintest galaxies, with 95 per cent completeness at m ≃ 27.4 mag in 10-ks exposures. We also predict the number of high-z galaxies that will be discovered by upcoming JWST imaging surveys. We predict that the COSMOS-Web survey will detect ∼1000 M1500 Å < −20.1 mag galaxies at 6.5 < z < 7.5, by virtue of its large survey area. JADES-Medium will detect almost $100{{\ \rm per\ cent}}$ of M1500 Å ≲ −20 mag galaxies at z < 8.5 due to its significant depth, however, with its smaller survey area it will detect only ∼100 of these galaxies at 6.5 < z < 7.5. Cosmic variance results in a large range in the number of predicted galaxies each survey will detect, which is more evident in smaller surveys such as CEERS and the PEARLS NEP and GOODS-S fields

Inhibition of protein tyrosine phosphatase-1B with antisense oligonucleotides improves insulin sensitivity and increases adiponectin concentrations in monkeys.

Protein tyrosine phosphatase (PTP)-1B antagonizes insulin signaling and is a potential therapeutic target for insulin resistance associated with obesity and type 2 diabetes. To date, studies of PTP-1B have been limited by the availability of specific antagonists; however, treatment of rodents with antisense oligonucleotides (ASOs) directed against PTP-1B improves insulin sensitivity, inhibits lipogenic gene expression, and reduces triglyceride accumulation in liver and adipose tissue. Here we investigated ASO-mediated PTP-1B inhibition in primates. First, PTP-1B ASO (ISIS 113715) dose-dependently inhibited PTP-1B mRNA and protein expression in cultured monkey hepatocytes. Subcutaneous administration of ISIS 113715 reduced PTP-1B mRNA expression in liver and adipose tissue of normal-weight monkeys by 40-50% and improved insulin sensitivity during an iv glucose tolerance test (IVGTT). In obese, insulin-resistant rhesus monkeys, treatment with 20 mg/kg ISIS 113715 for 4 wk reduced fasting concentrations of insulin and glucose and reduced insulin responses during an IVGTT. In these animals, adiponectin concentrations were also increased by 70%, most of which was an increase of high-molecular-weight oligomers. These effects were not observed in monkeys on a lower, dose-escalation regimen (1-10 mg/kg over 9 wk). Overall, the increase of adiponectin concentrations during ISIS 113715 treatment was correlated with the lowering of insulin responses during IVGTT (r = -0.47, P = 0.042). These results indicate that inhibition of PTP-1B with ASOs such as ISIS 113715 may be a viable approach for the treatment and prevention of obesity-associated insulin resistance and type 2 diabetes because they potently increase adiponectin concentrations in addition to improving insulin sensitivity

Treating Maternal Mental Health Problems with an App-Based Program: A Randomized Control Trial of BEAM, for Mothers of Young Children

Importance: Exposure to maternal mental illness in the first 3 years of life is associated with poor child outcomes. Maternal mental health problems increased dramatically during the COVID-19 pandemic with many parents not having access to evidence-based treatments. Mobile health (mHealth) treatments show promise for adult mood and anxiety disorders but rarely include parenting strategies and have high dropout rates. Objective: This study aimed to evaluate the efficacy of the Building Emotion Awareness and Mental Health (BEAM) app-based program, which responds to maternal mental health and parenting needs while building social connection between participants. Design: A two-arm, phase III randomized controlled trial (RCT) was conducted to evaluate the BEAM intervention compared to unrestricted services-as-usual (US). Participants completed self-report measures at eligibility screening (baseline assessment, T0), prior to randomization (pre-intervention, T1) and immediately following the intervention (post-intervention, T2). Setting: Individuals were recruited and completed surveys online. Participants: A final sample of 119 mothers with children aged 18 to 36 months, who self-reported moderate-to-severe symptoms of depression and/or anxiety. Intervention: Individuals randomized to treatment participated in the 10-week BEAM program. It was hypothesized that the treatment group would report decreases in mental health symptoms (anxiety, depression, anger, alcohol use, sleep problems) and harsh parenting (overreactive parenting, conflictual parent-child interactions) compared to the US group. Results: BEAM out-performed the US condition in reducing anxiety symptoms. Participants in both groups experienced significant decreases in depression. Participants with higher levels of anxiety and depression symptoms at screening, experienced significant decreases in mental health symptoms and harsh parenting composite scores, if they received the BEAM program, compared to US. This included specific declines in anxiety, anger, and dysfunctional parenting interactions. There were no significant effects for sleep problems, alcohol misuse, or overactive discipline. Conclusion and Relevance: BEAM is a highly scalable intervention that has the potential to rapidly reach underserved groups in need of mental health and parenting support. Next steps include improving the user interface and exploring engagement and implementation of the program within existing health and social service systems for long-term improvements in family health and well-being

Inhibition of Protein Tyrosine Phosphatase-1B with Antisense Oligonucleotides Improves Insulin Sensitivity and Increases Adiponectin Concentrations in Monkeys

Protein tyrosine phosphatase (PTP)-1B antagonizes insulin signaling and is a potential therapeutic target for insulin resistance associated with obesity and type 2 diabetes. To date, studies of PTP-1B have been limited by the availability of specific antagonists; however, treatment of rodents with antisense oligonucleotides (ASOs) directed against PTP-1B improves insulin sensitivity, inhibits lipogenic gene expression, and reduces triglyceride accumulation in liver and adipose tissue. Here we investigated ASO-mediated PTP-1B inhibition in primates. First, PTP-1B ASO (ISIS 113715) dose-dependently inhibited PTP-1B mRNA and protein expression in cultured monkey hepatocytes. Subcutaneous administration of ISIS 113715 reduced PTP-1B mRNA expression in liver and adipose tissue of normal-weight monkeys by 40–50% and improved insulin sensitivity during an iv glucose tolerance test (IVGTT). In obese, insulin-resistant rhesus monkeys, treatment with 20 mg/kg ISIS 113715 for 4 wk reduced fasting concentrations of insulin and glucose and reduced insulin responses during an IVGTT. In these animals, adiponectin concentrations were also increased by 70%, most of which was an increase of high-molecular-weight oligomers. These effects were not observed in monkeys on a lower, dose-escalation regimen (1–10 mg/kg over 9 wk). Overall, the increase of adiponectin concentrations during ISIS 113715 treatment was correlated with the lowering of insulin responses during IVGTT (r = −0.47, P = 0.042). These results indicate that inhibition of PTP-1B with ASOs such as ISIS 113715 may be a viable approach for the treatment and prevention of obesity-associated insulin resistance and type 2 diabetes because they potently increase adiponectin concentrations in addition to improving insulin sensitivity

Genome-wide sequencing and the clinical diagnosis of genetic disease: The CAUSES study

Genome-wide sequencing (GWS) is a standard of care for diagnosis of suspected genetic disorders, but the proportion of patients found to have pathogenic or likely pathogenic variants ranges from less than 30% to more than 60% in reported studies. It has been suggested that the diagnostic rate can be improved by interpreting genomic variants in the context of each affected individual's full clinical picture and by regular follow-up and reinterpretation of GWS laboratory results. Trio exome sequencing was performed in 415 families and trio genome sequencing in 85 families in the CAUSES study. The variants observed were interpreted by a multidisciplinary team including laboratory geneticists, bioinformaticians, clinical geneticists, genetic counselors, pediatric subspecialists, and the referring physician, and independently by a clinical laboratory using standard American College of Medical Genetics and Genomics (ACMG) criteria. Individuals were followed for an average of 5.1 years after testing, with clinical reassessment and reinterpretation of the GWS results as necessary. The multidisciplinary team established a diagnosis of genetic disease in 43.0% of the families at the time of initial GWS interpretation, and longitudinal follow-up and reinterpretation of GWS results produced new diagnoses in 17.2% of families whose initial GWS interpretation was uninformative or uncertain. Reinterpretation also resulted in rescinding a diagnosis in four families (1.9%). Of the families studied, 33.6% had ACMG pathogenic or likely pathogenic variants related to the clinical indication. Close collaboration among clinical geneticists, genetic counselors, laboratory geneticists, bioinformaticians, and individuals’ primary physicians, with ongoing follow-up, reanalysis, and reinterpretation over time, can improve the clinical value of GWS