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The visionary talents of writer Chris Claremont and legendary illustrator Bill Sienkiewicz bring the Demon Bear that has haunted Danielle Moonstar's dreams to horrifying life! It took her parents, and now it has returned for Dani - and only the combined efforts of her fellow New Mutants can stop it from finishing the job! Sink your teeth into a true classic! Then, Dani's nightmare returns years later as San Francisco - and her new team X-Force, come under attack from a similarly unholy ursine!

The DNA-binding protein PfAP2-G is found to be a master regulator of sexual development in the malaria parasite; this protein appears to regulate early gametocytogenesis and is epigenetically silenced in the majority of blood-stage parasites. Malarial virulence factor primed for action For malaria parasites to be transmitted to the mosquito vector they must undergo sexual development and produce gametocytes. The molecular mechanisms underlying the commitment to gametocyte development have been unclear. Two complementary manuscripts now show that AP2-G, a member of the apicomplexan AP2 family of transcription factors, is a master regulator of sexual development in the malaria parasite, acting as a developmental switch by triggering the transcription of early gametocyte genes. Abhinav Sinha et al . worked with the rodent malaria parasite Plasmodium berghei , and Björn Kafsack et al . with the human pathogen P. falciparum . AP2-G activity in human infectious malaria parasites could be a potential target for antimalarials designed to interfere with gametocyte formation. The life cycles of many parasites involve transitions between disparate host species, requiring these parasites to go through multiple developmental stages adapted to each of these specialized niches. Transmission of malaria parasites ( Plasmodium spp.) from humans to the mosquito vector requires differentiation from asexual stages replicating within red blood cells into non-dividing male and female gametocytes. Although gametocytes were first described in 1880, our understanding of the molecular mechanisms involved in commitment to gametocyte formation is extremely limited, and disrupting this critical developmental transition remains a long-standing goal 1 . Here we show that expression levels of the DNA-binding protein PfAP2-G correlate strongly with levels of gametocyte formation. Using independent forward and reverse genetics approaches, we demonstrate that PfAP2-G function is essential for parasite sexual differentiation. By combining genome-wide PfAP2-G cognate motif occurrence with global transcriptional changes resulting from PfAP2-G ablation, we identify early gametocyte genes as probable targets of PfAP2-G and show that their regulation by PfAP2-G is critical for their wild-type level expression. In the asexual blood-stage parasites pfap2-g appears to be among a set of epigenetically silenced loci 2 , 3 prone to spontaneous activation 4 . Stochastic activation presents a simple mechanism for a low baseline of gametocyte production. Overall, these findings identify PfAP2-G as a master regulator of sexual-stage development in malaria parasites and mark the first discovery of a transcriptional switch controlling a differentiation decision in protozoan parasites.

The biology and behavior of adults differ substantially from those of developing animals, and cell-specific information is critical for deciphering the biology of multicellular animals. Thus, adult tissue-specific transcriptomic data are critical for understanding molecular mechanisms that control their phenotypes. We used adult cell-specific isolation to identify the transcriptomes of C. elegans' four major tissues (or \"tissue-ome\"), identifying ubiquitously expressed and tissue-specific \"enriched\" genes. These data newly reveal the hypodermis' metabolic character, suggest potential worm-human tissue orthologies, and identify tissue-specific changes in the Insulin/IGF-1 signaling pathway. Tissue-specific alternative splicing analysis identified a large set of collagen isoforms. Finally, we developed a machine learning-based prediction tool for 76 sub-tissue cell types, which we used to predict cellular expression differences in IIS/FOXO signaling, stage-specific TGF-β activity, and basal vs. memory-induced CREB transcription. Together, these data provide a rich resource for understanding the biology governing multicellular adult animals.

Astrocytes, the most abundant glial cell type in the brain, are underrepresented in traditional cortical organoid models due to the delayed onset of cortical gliogenesis. Here we introduce a new glia-enriched cortical organoid model that exhibits accelerated astrogliogenesis. We demonstrated that induction of a gliogenic switch in a subset of progenitors enabled the rapid derivation of astroglial cells, which account for 25–31% of the cell population within 8–10 weeks of differentiation. Intracerebral transplantation of these organoids reliably generated a diverse repertoire of cortical neurons and anatomical subclasses of human astrocytes. Spatial transcriptome profiling identified layer-specific expression patterns among distinct subclasses of astrocytes within organoid transplants. Using an in vivo acute neuroinflammation model, we identified a subpopulation of astrocytes that rapidly activates pro-inflammatory pathways upon cytokine stimulation. Additionally, we demonstrated that CD38 signaling has a crucial role in mediating metabolic and mitochondrial stress in reactive astrocytes. This model provides a robust platform for investigating human astrocyte function. Transplantation of glia-enriched organoids into the mouse brain enables the study of astrocyte subtypes.

Malaria parasites must produce gametocytes for transmission to the mosquito vector, although the molecular mechanisms underlying commitment to gametocyte production remain unclear; here this process is found to be controlled by PbAP2-G, a member of the ApiAP2 family of DNA-binding proteins, in the rodent-infecting Plasmodium berghei parasite. Malarial virulence factor primed for action For malaria parasites to be transmitted to the mosquito vector they must undergo sexual development and produce gametocytes. The molecular mechanisms underlying the commitment to gametocyte development have been unclear. Two complementary manuscripts now show that AP2-G, a member of the apicomplexan AP2 family of transcription factors, is a master regulator of sexual development in the malaria parasite, acting as a developmental switch by triggering the transcription of early gametocyte genes. Abhinav Sinha et al . worked with the rodent malaria parasite Plasmodium berghei , and Björn Kafsack et al . with the human pathogen P. falciparum . AP2-G activity in human infectious malaria parasites could be a potential target for antimalarials designed to interfere with gametocyte formation. Commitment to and completion of sexual development are essential for malaria parasites (protists of the genus Plasmodium ) to be transmitted through mosquitoes 1 . The molecular mechanism(s) responsible for commitment have been hitherto unknown. Here we show that PbAP2-G, a conserved member of the apicomplexan AP2 (ApiAP2) family of DNA-binding proteins, is essential for the commitment of asexually replicating forms to sexual development in Plasmodium berghei , a malaria parasite of rodents. PbAP2-G was identified from mutations in its encoding gene, PBANKA_143750, which account for the loss of sexual development frequently observed in parasites transmitted artificially by blood passage. Systematic gene deletion of conserved ApiAP2 genes in Plasmodium confirmed the role of PbAP2-G and revealed a second ApiAP2 member (PBANKA_103430, here termed PbAP2-G2) that significantly modulates but does not abolish gametocytogenesis, indicating that a cascade of ApiAP2 proteins are involved in commitment to the production and maturation of gametocytes. The data suggest a mechanism of commitment to gametocytogenesis in Plasmodium consistent with a positive feedback loop involving PbAP2-G that could be exploited to prevent the transmission of this pernicious parasite.

Beside image vision, light plays a pivotal role in regulating diverse non-visual functions, including affective behaviors. Recently, bright light stimulation (BLS) was revealed to be beneficial for treating non-seasonal depression, although its mechanism of action is not fully understood. We developed a novel mouse model of refractory depression, induced through social isolation and chronic despair during the active (dark) phase of the animal, and we have tested if antidepressant treatments, including BLS, could protect against anxio-depressive-like behavior. We report that anxiety- and depressive-like behaviors are resistant to BLS as well as to both conventional and new antidepressants, including ketamine. Remarkably, we unveil that BLS potentiates the effect of antidepressants, and this beneficial effect is mediated via rod retinal photoreceptors. Furthermore, we demonstrate that both chemogenetic activation of lateral habenula (LHb) astroglia and serotonin (5-HT) depletion prevent the potentiating effect of BLS on chronic despair. These results reveal, for the first time, that BLS enhances the efficacy of antidepressants through an unexpectedly circuit involving rods, LHb astroglia and 5-HT.

Background Clinical events suggestive of nutrition care found in electronic health records (EHRs) are rarely explored for their associations with hypertension outcomes. Methods Longitudinal analysis using structured EHR data from primary care visits at a health system in the US from December 2017—December 2020 of adult patients with hypertension ( n  = 4,237) tested for associations between last visit blood pressure (BP) control (≤ 140 Systolic BP and ≤ 90 Diastolic BP) and ≥ 1 nutrition care clinical event operationalized as (overweight or obesity (BMI > 25 or 30, respectively) diagnoses, preventive care visits, or provision of patient education materials (PEM)). Descriptive statistics and longitudinal targeted maximum likelihood estimation (LTMLE) models were conducted to explore average treatment effects (ATE) of timing and dose response from these clinical events on blood pressure control overall and by race. Results The median age was 62 years, 29% were male, 52% were Black, 25% were from rural areas and 50% had controlled BP at baseline. Annual documentation of overweight/obesity diagnoses ranged 3.0–7.8%, preventive care visits ranged 6.2–15.7%, and PEM with dietary and hypertension content were distributed to 8.5–28.8% patients. LTMLE models stratified by race showed differences in timing, dose, and type of nutrition care. Black patients who had nutrition care in Year 3 only compared to none had lower odds for BP control (ATE -0.23, 95% CI: -0.38,-0.08, p  = 0.003), preventive visits in the last 2 years high higher odds for BP control (ATE 0.31, 95% CI: 0.07,0.54, p  = 0.01), and early or late PEMs had lower odds for BP control (ATE -0.08, 95% CI: -0.15,-0.01, p  = 0.03 and ATE -0.23, 95% CI: -0.41,-0.05, p  = 0.01, respectively). Conclusions In this study, clinical events suggestive of nutrition care are significantly associated with BP control, but are infrequent and effects differ by type, timing, and patient race. Preventive visits appear to have the most effect; additional research should include examining clinical notes for evidence of nutrition care among different populations, which may uncover areas for improving nutrition care for patients with chronic disease.

This paper reports genetic manipulation of the malaria parasite Plasmodium falciparum with zinc-finger nucleases. It demonstrates gene disruption as well as replacement and site-specific editing of both an integrated reporter and an endogenous gene. Malaria afflicts over 200 million people worldwide, and its most lethal etiologic agent, Plasmodium falciparum , is evolving to resist even the latest-generation therapeutics. Efficient tools for genome-directed investigations of P. falciparum -induced pathogenesis, including drug-resistance mechanisms, are clearly required. Here we report rapid and targeted genetic engineering of this parasite using zinc-finger nucleases (ZFNs) that produce a double-strand break in a user-defined locus and trigger homology-directed repair. Targeting an integrated egfp locus, we obtained gene-deletion parasites with unprecedented speed (2 weeks), both with and without direct selection. ZFNs engineered against the parasite gene pfcrt , responsible for escape under chloroquine treatment, rapidly produced parasites that carried either an allelic replacement or a panel of specified point mutations. This method will enable a diverse array of genome-editing approaches to interrogate this human pathogen.

Sexual commitment in Plasmodium parasites is essential for malaria transmission, yet the signaling events initiating sexual conversion in only a subpopulation of parasites remain unclear. We discovered a single valine(V ) to leucine(L ) mutation in a transcription factor required for P. falciparum gametocytogenesis (AP2-G) that abrogates sexual differentiation. AP2-G.L does not bind the ap2-g consensus motif, GnGTAC, or stimulate gene transcription, including autoregulation. The GDV1-dependent expression of AP2-G.L demonstrates GDV1's critical role in the initial activation of the silent ap2-g locus in the absence of functional AP2-G. While AP2-G.V is required for MSRP1 expression, providing a marker that discriminates early from late sexually committed schizonts. Together this work demonstrates that V in AP2-G plays a critical role in DNA binding, highlighting the functional importance of this specific region for malaria transmission as well as the key role of GDV1 in the initial activation of ap2-g expression and induction of sexual differentiation.

•Under highly controlled conditions, time-restricting eating reduces fasting glucose and glycated hemoglobin and tended to improve 24-h glucose in men with obesity but impaired glucose response to a dinner meal.•Time-restricted eating alters the adipose tissue transcriptome, down-regulating genes involved in mitoribosome regulation and proteasome functioning, which may be an adaptive response to lowered energy availability and reduced mitochondrial oxidative stress.•Time-restricted eating could be a preventative or therapeutic strategy to assist glycemic management for people with prediabetes or type 2 diabetes. We sought to examine the effects of 8 wk of time-restricted eating (TRE) on glucose metabolism and the adipose tissue transcriptome during a metabolic ward stay in men with obesity. In a single-arm, pre-post trial, 15 men (ages 63 ± 4 y, body mass index = 30.5 ± 2.4 kg/m2, waist circumference = 113 ± 4 cm) with obesity but no history of diabetes were enrolled and underwent 2 wk of baseline monitoring before they were instructed to eat their regular diets within a contiguous 10-h time frame each day for 8 wk. Metabolic testing was performed at baseline and week 8 during a 35-h metabolic ward stay, during which all food intake was strictly timed and controlled. Identical meal-tolerance tests were performed at breakfast and dinner. Blood glucose, glucoregulatory hormones, and subjective appetite score were measured. Subcutaneous adipose tissue biopsies were performed and the transcriptome was assessed. The primary outcome, plasma glucose area under the curve, was altered by TRE, being unchanged at breakfast but increased at dinner. However, TRE reduced fasting glucose, glycated hemoglobin, body weight, and body fat, and increased glucose-dependent insulinotropic peptide area under the curve at dinner. In subcutaneous adipose tissue, 117 genes were up-regulated and 202 genes down-regulated by TRE. Pathway analysis revealed down-regulation of genes involved in proteasome function and mitochondrial regulation. TRE had a net effect of reducing glycemia and dampening energy-consuming pathways in adipose tissue.