Premature Senescence and Increased TGFβ Signaling in the Absence of Tgif1

Transforming growth factor β (TGFβ) signaling regulates cell cycle progression in several cell types, primarily by inducing a G1 cell cycle arrest. Tgif1 is a transcriptional corepressor that limits TGFβ responsive gene expression. Here we demonstrate that primary mouse embryo fibroblasts (MEFs) lacking Tgif1 proliferate slowly, accumulate increased levels of DNA damage, and senesce prematurely. We also provide evidence that the effects of loss of Tgif1 on proliferation and senescence are not limited to primary cells. The increased DNA damage in Tgif1 null MEFs can be partially reversed by culturing cells at physiological oxygen levels, and growth in normoxic conditions also partially rescues the proliferation defect, suggesting that in the absence of Tgif1 primary MEFs are less able to cope with elevated levels of oxidative stress. Additionally, we show that Tgif1 null MEFs are more sensitive to TGFβ-mediated growth inhibition, and that treatment with a TGFβ receptor kinase inhibitor increases proliferation of Tgif1 null MEFs. Conversely, persistent treatment of wild type cells with low levels of TGFβ slows proliferation and induces senescence, suggesting that TGFβ signaling also contributes to cellular senescence. We suggest that in the absence of Tgif1, a persistent increase in TGFβ responsive transcription and a reduced ability to deal with hyperoxic stress result in premature senescence in primary MEFs

The Sno Oncogene Antagonizes Wingless Signaling during Wing Development in Drosophila

The Sno oncogene (Snoo or dSno in Drosophila) is a highly conserved protein and a well-established antagonist of Transforming Growth Factor-β signaling in overexpression assays. However, analyses of Sno mutants in flies and mice have proven enigmatic in revealing developmental roles for Sno proteins. Thus, to identify developmental roles for dSno we first reconciled conflicting data on the lethality of dSno mutations. Then we conducted analyses of wing development in dSno loss of function genotypes. These studies revealed ectopic margin bristles and ectopic campaniform sensilla in the anterior compartment of the wing blade suggesting that dSno functions to antagonize Wingless (Wg) signaling. A subsequent series of gain of function analyses yielded the opposite phenotype (loss of bristles and sensilla) and further suggested that dSno antagonizes Wg signal transduction in target cells. To date Sno family proteins have not been reported to influence the Wg pathway during development in any species. Overall our data suggest that dSno functions as a tissue-specific component of the Wg signaling pathway with modest antagonistic activity under normal conditions but capable of blocking significant levels of extraneous Wg, a role that may be conserved in vertebrates

Feasibility and Acceptability of Home-Collected Samples for Human Immunodeficiency Virus Preexposure Prophylaxis and Severe Acute Respiratory Syndrome Coronavirus 2 Laboratory Tests in San Francisco Primary Care Clinics

BackgroundDue to the difficulty of conducting laboratory testing during the pandemic shelter-in-place orders, the objective of this study was to examine the feasibility and acceptability of conducting home-collected samples for preexposure prophylaxis (PrEP) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) laboratory tests.MethodsWe conducted a pilot study among patients on PrEP in San Francisco primary care clinics. Individuals on PrEP provided home-collected laboratory samples using dried blood spot for fourth-generation human immunodeficiency virus antigen/antibody test, serum creatinine, syphilis antibody, and hepatitis C antibody, as needed; 3-site (oropharyngeal, rectal, and urine) swabbing for sexually transmitted infections; and nasopharyngeal swabbing for SARS-CoV-2 polymerase chain reaction. We examined feasibility and acceptability of collecting these laboratory samples using predefined benchmarks to determine feasibility or acceptability.ResultsOf 92 individuals who consented to participate, 73 (79.3%) mailed back their home-collected kit. Nearly 87.7% noted being extremely to moderately satisfied with the ability to complete the laboratory tests without having to come into a clinic. Approximately 49.3% of participants chose this home-collection method as their first choice for providing laboratory samples. Mean time from collection of samples by the participant to receipt of test results was reduced from the first quarter of the study (17 days) to the last quarter of the study (5 days).ConclusionsWe report high levels of feasibility and acceptability with the use of home-collected laboratory samples for patients on PrEP. Our results indicate that home-collected laboratory samples for patients on PrEP is a viable option that should be offered as an alternative to clinic-collected laboratory samples

Stimulation in Hippocampal Region CA1 in Behaving Rats Yields Long-Term Potentiation when Delivered to the Peak of Theta and Long-Term Depression when Delivered to the Trough

Experimental evidence suggests that the hippocampal theta rhythm plays a critical role in learning. Previous studies have shown long-term potentiation (LTP) to be preferentially induced with stimulation on the peak of local theta rhythm in region CA1 in anesthetized rats and with stimulation of the perforant path at the peak of theta in both anesthetized and behaving animals. We set out to determine the effects of tetanic burst stimulation in stratum radiatum of region CA1 in awake behaving animals, delivered during either the peak or the trough of the theta rhythm in the EEG. Bursts delivered to the peak resulted in an increase of 17.9 ± 0.94% in potential slope. When identical stimulation bursts were delivered to the trough of local theta waves, the potential slope decreased 12.9 ± 1.03%. This is the first report of LTP being preferentially induced at the peak of local theta rhythm in behaving animals in region CA1 and that LTD was found in response to tetanic stimulation at the trough of the local theta wave. The results are discussed within the framework of a recent theory that proposes that the theta rhythm sets the dynamics for alternating phases of encoding and retrieval (Hasselmo et al., 20021)