Impeding DNA Break Repair Enables Oocyte Quality Control.

Oocyte quality control culls eggs with defects in meiosis. In mouse, oocyte death can be triggered by defects in chromosome synapsis and recombination, which involve repair of DNA double-strand breaks (DSBs) between homologous chromosomes. We show that RNF212, a SUMO ligase required for crossing over, also mediates oocyte quality control. Both physiological apoptosis and wholesale oocyte elimination in meiotic mutants require RNF212. RNF212 sensitizes oocytes to DSB-induced apoptosis within a narrow window as chromosomes desynapse and cells transition into quiescence. Analysis of DNA damage during this transition implies that RNF212 impedes DSB repair. Consistently, RNF212 is required for HORMAD1, a negative regulator of inter-sister recombination, to associate with desynapsing chromosomes. We infer that oocytes impede repair of residual DSBs to retain a "memory" of meiotic defects that enables quality-control processes. These results define the logic of oocyte quality control and suggest RNF212 variants may influence transmission of defective genomes.

The Development of a Text Messaging Platform to Enhance a Youth Diabetes Prevention Program: Observational Process Study.

BACKGROUND: Approximately 1 in 5 adolescents in the United States has prediabetes, and racially and ethnically minoritized youths are disproportionately impacted. Unfortunately, there are few effective youth diabetes prevention programs, and in-person interventions are challenging because of barriers to access and engagement. OBJECTIVE: We aimed to develop and assess the preliminary feasibility and acceptability of a youth-informed SMS text messaging platform to provide additional support and motivation to adolescents with prediabetes participating in a diabetes prevention workshop in East Harlem, New York City, New York, United States. We collaborated with our youth action board and a technology partner (mPulse Mobile) to develop and pilot-test the novel interactive platform. METHODS: The technology subcommittee of our community action board (comprising youths and young adults) used the results from focus groups that we had previously conducted with youths from our community to develop 5 message types focused on healthy eating and active living: goal setting, behavior tracking, individually tailored guidance, motivational messages, and photo diary. We used an iterative process to develop and pilot the program with our internal study team, including youths from our community action board and mPulse Mobile developers. We then conducted a pilot of the 12-week SMS text messaging program with 13 youths with prediabetes. RESULTS: Participants (aged 15-21 years; 10/13, 77% female; 3/10, 23% Black and 10/13, 77% Hispanic or Latinx) received an average of 2 automated messages per day. The system correctly sent 84% (2231/2656) of the messages at the time intended; the remaining 16% (425/2656) of the messages were either sent at the incorrect time, or the system did not recognize a participant response to provide the appropriate reply. The level of engagement with the program ranged from 1 (little to no response) to 5 (highly responsive) based on how frequently participants responded to the interactive (2-way) messages. Highly responsive participants (6/13, 46%) responded >75% (1154/1538) of the time to interactive messages sent over 12 weeks, and 69% (9/13) of the participants were still engaged with the program at week 12. During a focus group conducted after program completion, the participants remarked that the message frequency was appropriate, and those who had participated in our in-person workshops reflected that the messages were reminiscent of the workshop content. Participants rated goal setting, behavior tracking, and tailored messages most highly and informed planned adaptations to the platform. Participants described the program as: "interactive, informative, enjoyable, very convenient, reliable, motivational, productive, and reflective." CONCLUSIONS: We partnered with youths in the initial content development and pilot testing of a novel SMS text messaging platform to support diabetes prevention. This study is unique in the triple partnership we formed among researchers, technology experts, and diverse youths to develop a mobile health platform to address diabetes-related disparities.

Metabolic Effects of JAK1/2 Inhibition in Patients with Myeloproliferative Neoplasms.

Ruxolitinib is an FDA approved janus kinase (JAK)1/2 inhibitor used to treat myeloproliferative neoplasms (MPNs), including myelofibrosis and polycythemia vera. We aimed to determine the metabolic consequences of ruxolitinib treatment in patients with MPNs. We performed a retrospective single-center cohort study utilizing an electronic medical record based database of patients who began treatment with ruxolitinib for MPNs from January 2010 to March 2017. We also examined the effects of ruxolitinib on adipose tissue JAK/STAT signaling in a mouse model. 127 patients were identified, of which 69 had data available for weight, and at least one other parameter of interest before, and 72 weeks after starting ruxolitinib. Mean baseline weight was 73.9 ± 17.0 kg, and 78.54 ± 19.1 kg at 72 weeks (p < 0.001). 50% of patients gained >5% body weight. Baseline body mass index (BMI) was 25.8 ± 4.8 kg/m2, and 27.5 ± 5.5 kg/m2 at 72 weeks (p < 0.001). Patients treated with ruxolitinib had a higher systolic blood pressure, serum AST, and ALT at 72 weeks, compared with baseline (p = 0.03, p = 0.01, p = 0.04, respectively). In mice, ruxolitinib decreased basal and GH-stimulated STAT5 phosphorylation in adipose tissue. As pharmacological JAK1/2 inhibitors are being developed and used in clinical practice, it is important to understand their long-term metabolic consequences.