Core pathway proteins and the molecular basis of planar polarity in the zebrafish gastrula.

The planar polarization of cells and subcellular structures is critical for embryonic development. Coordination of this polarity can provide cells a sense of direction in relation to the anterior-posterior and dorsal-ventral body axes. Fly epithelia use a core pathway comprised of transmembrane (Van Gogh/Strabismus, Frizzled, and Flamingo/Starry night) and cytoplasmic (Prickle or Spiny-legs, Dishevelled, and Diego) proteins to communicate directional information between cells and thereby promote the uniform orientation of structures such as hairs. In the zebrafish gastrula, planar polarity underlies complex cellular processes, including directed migration and intercalation, that are required to shape the embryo body. Like other vertebrates, the zebrafish genome encodes homologs of each core protein, and it is well-established that polarized gastrula cell behaviors are regulated by some of them. However, it is unknown whether a conserved six-member core protein pathway regulates planar polarity during zebrafish gastrulation. Here, we review our current understanding of core protein function as it relates to two specific examples of planar polarity, the dorsal convergence of lateral gastrula cells and the mediolateral intercalation of midline cells. We consider the hallmarks of fly planar polarity and discuss data regarding asymmetric protein localization and function, and the intercellular communication of polarity information.

The weekend warrior effect: Consistent intermittent exercise induces persistent cognitive benefits.

Exercise provides a range of cognitive benefits, including improved memory performance. Previously, we demonstrated that 14 days of continuous voluntary wheel-running exercise enables learning in a hippocampus-dependent Object Location Memory (OLM) task under insufficient, subthreshold training conditions in adult mice. Whether similar exercise benefits can be obtained from consistent intermittent exercise as continuous exercise is unknown. Here, we examine whether intermittent exercise (the weekend warrior effect: 2 days of exercise a week for 7 weeks) displays similar or distinct cognitive benefits as previously examined with 14 days of continuous exercise. We find that both continuous and intermittent exercise parameters similarly enable hippocampus-dependent OLM compared to the 2-day exercise control group. Mice receiving intermittent exercise maintained cognitive benefits following a 7-day sedentary delay, whereas mice that underwent 14 continuous days of exercise showed diminished cognitive benefits as previously reported. Further, compared to continuous exercise, intermittent exercise mice exhibited persistently elevated levels of the genes Acvr1c and Bdnf which we know to be critically involved in hippocampus-dependent long-term memory in the dorsal hippocampus. Together findings suggest that consistent intermittent exercise persistently enables hippocampal-dependent long-term memory. Understanding the optimal parameters for persistent cognitive function and the mechanisms mediating persistent effects will aid in therapeutic pursuits investigating the mitigation of cognitive ailments.

Catalytic Hydrodeoxygenation of Phenols and Cresols to Gasoline Range Biofuels.

Unlike fossil fuels, biomass has oxygen amounts exceeding 10 wt%. Hydrodeoxygenation (HDO) is a crucial step in upgrading biomass to higher heating value liquid fuels. Oxygen removal has many challenges due to the complex chemistry and the high reactivity leading to irreversible catalyst deactivation. In this study, the focus is on the catalytic HDO of aromatic oxygen-containing model compounds in biomass: phenols and cresols. In the current work, literature on catalytic HDO of phenols using molecular hydrogen is reviewed, with a focus on non-nickel-based mono- and bi-metallic catalysts, as nickel-based catalysts were reviewed elsewhere. In addition, the catalytic HDO of m-cresol using molecular hydrogen is examined. This review also addresses the use of hydrogen donors for the HDO of phenols and cresols. The operating conditions, catalysts, products, and yields are summarized to find the catalyst with promising activity and high selectivity toward aromatics. A critical review of the reactions that successfully led to HDO is presented and research gaps related to the HDO of phenols and cresols are highlighted. The conclusions provide potential successful catalyst combinations that can be used for HDO of phenols, cresols, and liquid aromatic hydrocarbons.

Synthesis and Reactivity of Bis-tris(pyrazolyl)borate Lanthanide/Aluminum Heterobimetallic Trihydride Complexes.

Molecular heterobimetallic hydride complexes of lanthanide (Ln) and main-group (MG) metals exhibit chemical properties unique from their monometallic counterparts and are highly reactive species, making their synthesis and isolation challenging. Herein, molecular Ln/Al heterobimetallic trihydrides [Ln(Tp)2(µ-H)2Al(H)(N″)] [2-Ln; Ln = Y, Sm, Dy, Yb; Tp = hydrotris(1-pyrazolyl)borate; N″ = N(SiMe3)2] have been synthesized by facile insertion of aminoalane [Me3N·AlH3] into the Ln-N amide bonds of [Ln(Tp)2(N″)] (1-Ln). Thus, this is a simple synthetic strategy to access a range of Ln/Al hydrides. Reactivity studies demonstrate that 2-Ln is a heterobimetallic hydride, with evidence for the cooperative nature of 2-Ln shown by the catalytic amine-borane dehydrocoupling under ambient conditions in contrast to its monomeric counterparts.

A forward genetic screen identifies Dolk as a regulator of startle magnitude through the potassium channel subunit Kv1.1.

The acoustic startle response is an evolutionarily conserved avoidance behavior. Disruptions in startle behavior, particularly startle magnitude, are a hallmark of several human neurological disorders. While the neural circuitry underlying startle behavior has been studied extensively, the repertoire of genes and genetic pathways that regulate this locomotor behavior has not been explored using an unbiased genetic approach. To identify such genes, we took advantage of the stereotypic startle behavior in zebrafish larvae and performed a forward genetic screen coupled with whole genome analysis. We uncovered mutations in eight genes critical for startle behavior, including two genes encoding proteins associated with human neurological disorders, Dolichol kinase (Dolk), a broadly expressed regulator of the glycoprotein biosynthesis pathway, and the potassium Shaker-like channel subunit Kv1.1. We demonstrate that Kv1.1 and Dolk play critical roles in the spinal cord to regulate movement magnitude during the startle response and spontaneous swim movements. Moreover, we show that Kv1.1 protein is mislocalized in dolk mutants, suggesting they act in a common genetic pathway. Combined, our results identify a diverse set of eight genes, all associated with human disorders, that regulate zebrafish startle behavior and reveal a previously unappreciated role for Dolk and Kv1.1 in regulating movement magnitude via a common genetic pathway.

A Second Glass Transition Observed in Single-Component Homogeneous Liquids Due to Intramolecular Vitrification.

On supercooling a liquid, the viscosity rises rapidly until at the glass transition it vitrifies into an amorphous solid accompanied by a steep drop in the heat capacity. Therefore, a pure homogeneous liquid is not expected to display more than one glass transition. Here we show that a family of single-component homogeneous molecular liquids, titanium tetraalkoxides, exhibit two calorimetric glass transitions of comparable magnitude, one of which is the conventional glass transition associated with dynamic arrest of the bulk liquid properties, while the other is associated with the freezing out of intramolecular degrees of freedom. Such intramolecular vitrification is likely to be found in molecules in which low-frequency terahertz intramolecular motion is coupled to the surrounding liquid. These results imply that intramolecular barrier-crossing processes, typically associated with chemical reactivity, do not necessarily follow the Arrhenius law but may freeze out at a finite temperature.

Outcomes and Adverse Effects of Baricitinib Versus Tocilizumab in the Management of Severe COVID-19.

OBJECTIVES: The National Institutes of Health and Infectious Diseases Society of America guidelines recommend tocilizumab or baricitinib in the management of severe COVID-19. Despite clinical trials on the individual agents, there are no large-scale studies comparing the two agents to guide the selection of one versus the other. The purpose of this study was to compare the outcomes and adverse effects of baricitinib versus tocilizumab in the management of severe COVID-19. DESIGN: Retrospective, observational cohort study. SETTING: Eleven acute care hospitals in a large health system in Georgia. PATIENTS: Adult patients with severe COVID-19 who received at least one dose of either baricitinib or tocilizumab between June 2021 and October 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was in-hospital mortality. The key secondary outcome was occurrence rate of adverse effects. A total of 956 patients were identified. The median age was 57 years, and 53% were of male sex. The median body mass index was 33.5, and more than 94% of the population was unvaccinated. Propensity score matching by baseline characteristics resulted in a total of 582 patients, 291 in each group. There was no difference in mortality between the two groups; however, the occurrence rate of adverse effects was significantly higher in the tocilizumab group compared with baricitinib: secondary infections (32% vs 22%; p < 0.01); thrombotic events (24% vs 16%; p < 0.01); and acute liver injury (8% vs 3%; p < 0.01). CONCLUSIONS: Our propensity score-matched, retrospective, observational study in patients hospitalized with severe COVID-19 showed no difference in mortality but significantly fewer adverse effects with baricitinib compared with tocilizumab. Our data suggest that baricitinib may be a better choice when treating patients with severe COVID-19, but additional prospective, randomized trials are needed to help clinicians choose the most optimal drug.

Design and Synthesis of Novel Fluorescent 2-(aryloxy)-3-(4,5-diaryl)-1H-imidazol-2-yl)quinolines: Solvatochromic, DFT, TD-DFT Studies, COX-1 and COX-2 Inhibition and Antioxidant Properties.

The present work focuses on the synthesis of novel heterocycles 2-(aryloxy)-3-(4,5-diaryl-1H-imidazol-2-yl)quinolines (6k-v) by an effective condensation reaction. These molecules exhibited fluorescent properties and hence for the proper understanding of their optical behavior and quantum yields, solvatochromic studies have been carried out. Further, frontier molecular orbitals, molecular electrostatic potential (MEP), and geometrical structure optimization have been investigated using the B3LYP/6-311G ++ (d, p) method. The energy gap between the HOMO, LUMO of the optical and energy band gap is determined by DFT and UV-visible spectra for TD-DFT studies are done. The screening of these compounds for in vitro COX-1 and COX-2 inhibition and DPPH free radical scavenging ability assays produced promising results. The binding interactions of these molecules against the COX-2 enzyme (PDB: 5IKR) were validated by docking studies.

Using the Practical Robust Implementation and Sustainability Model (PRISM) to Identify and Address Provider-Perceived Barriers to Optimal Statin Prescribing and Use in Community Health Centers.

Statins are an important but underutilized therapy to prevent cardiovascular events, particularly in high-risk patients. To increase use of statin therapy in high-risk patients, the Centers for Disease Control and Prevention funded a project led by the National Association of Community Health Centers to discover reasons for statin underuse in health centers and identify possible leverage points, particularly among vulnerable and underserved patients. The project further sought to develop training and educational materials to improve statin prescribing for and acceptance in eligible high-risk patients. As a first step, investigators implemented a questionnaire to clinical providers (n = 45) at health centers participating in the project to obtain their perspective on barriers to optimal statin use. We used the practical robust implementation and sustainability model (PRISM) domains to frame the overall project and guide the development of our questionnaire. This paper summarizes top perceived barriers to patient and health system/provider statin initiation and sustainment, as well as facilitators to prescribing, using PRISM as an organizing framework. Our questionnaire yielded important suggestions related to public awareness, education materials, health information technology (HIT)/data solutions, and clinical guidelines as key factors in optimizing statin use. It also informed the design of patient education resources and provider training tools. Future directions include using the full application of the PRISM implementation science model to assess how well our educational and training resources help overcome barriers to statin use in high-risk patients, including evaluating how key contextual factors influence successful implementation.

Impact of COVID-19-related care disruptions on blood pressure management and control in community health centers.

BACKGROUND: Uncontrolled hypertension is a leading risk factor for cardiovascular disease. To ensure continuity of care, community health centers (CHCs) nationwide implemented virtual care (telehealth) during the pandemic. CHCs use the Centers for Medicare & Medicaid Services (CMS) 165v8 Controlling High Blood Pressure measure to report blood pressure (BP) control performance. CMS 165v8 specifications state that if no BP is documented during the measurement period, the patient's BP is assumed uncontrolled. METHODS: To examine trends in BP documentation and control rates in CHCs as telehealth use increased during the pandemic compared with pre-pandemic period, we assessed documentation of BP measurement and BP control rates from December 2019 - October 2021 among persons ages 18-85 with a diagnosis of hypertension who had an in-person or telehealth encounter in 11 CHCs. Rates were compared between CHCs that did and did not implement self-measured BP monitoring (SMBP). RESULTS: The percent of patients with hypertension with no documented BP measurement was 0.5% in December 2019 and increased to 15.2% (overall), 25.6% (non-SMBP CHCs), and 11.2% (SMBP CHCs) by October 2021. BP control using CMS 165v8 was 63.5% in December 2019 and decreased to 54.9% (overall), 49.1% (non-SMBP), and 57.2% (SMBP) by October 2021. When assessing BP control only in patients with documented BP measurements, CHCs largely maintained BP control rates (63.8% in December 2019; 64.8% (overall), 66.0% (non-SMBP), and 64.4% (SMBP) by October 2021). CONCLUSIONS: The transition away from in-person to telehealth visits during the pandemic likely increased the number of patients with hypertension lacking a documented BP measurement, subsequently negatively impacting BP control using CMS 165v8. There is an urgent need to enhance the flexibility of virtual care, improve EHR data capture capabilities for patient-generated data, and implement expanded policy and systems-level changes for SMBP, an evidence-based strategy that can build patient trust, increase healthcare engagement, and improve hypertension outcomes.

Synthesis and Characterization of Silver Nanoparticles from Rhizophora apiculata and Studies on Their Wound Healing, Antioxidant, Anti-Inflammatory, and Cytotoxic Activity.

Silver nanoparticles (AgNPs) have recently gained interest in the medical field because of their biological features. The present study aimed at screening Rhizophora apiculata secondary metabolites, quantifying their flavonoids and total phenolics content, green synthesis and characterization of R. apiculata silver nanoparticles. In addition, an assessment of in vitro cytotoxic, antioxidant, anti-inflammatory and wound healing activity of R. apiculata and its synthesized AgNPs was carried out. The powdered plant material (leaves) was subjected to Soxhlet extraction to obtain R. apiculata aqueous extract. The R. apiculata extract was used as a reducing agent in synthesizing AgNPs from silver nitrate. The synthesized AgNPs were characterized by UV-Vis, SEM-EDX, XRD, FTIR, particle size analyzer and zeta potential. Further aqueous leaf extract of R. apiculata and AgNPs was subjected for in vitro antioxidant, anti-inflammatory, wound healing and cytotoxic activity against A375 (Skin cancer), A549 (Lung cancer), and KB-3-1 (Oral cancer) cell lines. All experiments were repeated three times (n = 3), and the results were given as the mean ± SEM. The flavonoids and total phenolics content in R. apiculata extract were 44.18 ± 0.086 mg/g of quercetin and 53.24 ± 0.028 mg/g of gallic acid, respectively. SEM analysis revealed R. apiculata AgNPs with diameters ranging from 35 to 100 nm. XRD confirmed that the synthesized silver nanoparticles were crystalline in nature. The cytotoxicity cell viability assay revealed that the AgNPs were less toxic (IC50 105.5 µg/mL) compared to the R. apiculata extract (IC50 47.47 µg/mL) against the non-cancerous fibroblast L929 cell line. Antioxidant, anti-inflammatory, and cytotoxicity tests revealed that AgNPs had significantly more activity than the plant extract. The AgNPs inhibited protein denaturation by a mean percentage of 71.65%, which was equivalent to the standard anti-inflammatory medication diclofenac (94.24%). The AgNPs showed considerable cytotoxic effect, and the percentage of cell viability against skin cancer, lung cancer, and oral cancer cell lines was 31.84%, 56.09% and 22.59%, respectively. R. apiculata AgNPs demonstrated stronger cell migration and percentage of wound closure (82.79%) compared to the plant extract (75.23%). The overall results revealed that R. apiculata AgNPs exhibited potential antioxidant, anti-inflammatory, wound healing, and cytotoxic properties. In future, R. apiculata should be further explored to unmask its therapeutic potential and the mechanistic pathways of AgNPs should be studied in detail in in vivo animal models.

Accelerating Use of Self-measured Blood Pressure Monitoring (SMBP) Through Clinical-Community Care Models.

Self-measured blood pressure monitoring (SMBP), the regular measurement of blood pressure by a patient outside the clinical setting, plus additional support, is a proven, cost-effective but underutilized strategy to improve hypertension outcomes. To accelerate SMBP use, the Centers for Disease Control and Prevention (CDC) funded the National Association of Community Health Centers, the YMCA of the USA, and Association of State and Territorial Health Officials to develop cross-sector care models to offer SMBP to patients with hypertension. The project aimed to increase the use of SMBP through the coordinated action of health department leaders, community organizations and clinical providers. From 1/31/2017 to 6/30/2018, nine health centers in Kentucky, Missouri, and New York partnered with seven local Y associations (local Y) and their local health departments to design and implement care models that adapted existing primary care SMBP practices by leveraging capacities and resources in community and public health organizations. Nine collaborative care models emerged, shaped by available community assets, strategic priorities, and organizational culture. Overall, 1421 patients were recommended for SMBP; of those, 795 completed at least one cycle of SMBP (BP measurements morning and evening for at least three consecutive days). Of those recommended for SMBP, 308 patients were referred to a local Y to receive additional SMBP and healthy lifestyle support. Community and public health organizations can be brought into the health care delivery process and can play valuable roles in supporting patients in SMBP.

Initial elevation bias in subjective reports.

People's reports of their thoughts, feelings, and behaviors are used in many fields of biomedical and social science. When these states have been studied over time, researchers have often observed an unpredicted and puzzling decrease with repeated assessment. When noted, this pattern has been called an "attenuation effect," suggesting that the effect is due to bias in later reports. However, the pattern could also be consistent with an initial elevation bias. We present systematic, experimental investigations of this effect in four field studies (study 1: n = 870; study 2: n = 246; study 3: n = 870; study 4: n = 141). Findings show clear support for an initial elevation bias rather than a later decline. This bias is larger for reports of internal states than for behaviors and for negative mental states and physical symptoms than for positive states. We encourage increased awareness and investigation of this initial elevation bias in all research using subjective reports.

The power of interdependence: Linking health systems, communities, and health professions educational programs to better meet the needs of patients and populations.

Promoting optimal health outcomes for diverse patients and populations requires the acknowledgement and strengthening of interdependent relationships between health professions education programs, health systems, and the communities they serve. Educational programs must recognize their role as integral components of a larger system. Educators must strive to break down silos and synergize efforts to foster a health care workforce positioned for collaborative, equitable, community-oriented practice. Sharing interprofessional and interinstitutional strategies can foster wide propagation of educational innovation while accommodating local contexts. This paper outlines how member schools of the American Medical Association Accelerating Change in Medical Education Consortium leveraged interdependence to accomplish transformative innovations catalyzed by systems thinking and a community of innovation.

Anticancer activity studies of novel metal complexes of ligands derived from polycyclic aromatic compound via greener route.

Methoxy and tert-butyl substituted carboxamide, carboxylic acid and hydrazone Schiff base groups have been assembled into our newly designed fluorenone based ligands and prepared coordination compounds of some first row transition metals and characterized thoroughly with spectroscopic (1H and 13C NMR, IR, GC-MS, UV-Vis), analytical, TGA and molar conductance measurements. The stoichiometry of all the metal complexes is found to be 1: 2 (M: L2) with the general formula, [M(L)2], where L is a singly deprotonated ligand and the geometry of all the metal complexes is found to be octahedral. Ligands and their metal complexes successfully cleaved the pBR322 plasmid DNA and in case of anticancer activity against MCF-7 (human breast adenocarcinoma) cell line, the synthesized compounds found to exhibit excellent activity with prominent apoptotic effect which is characterized by cell shrinkage, cell breakage and turgidity and results were compared with the standard drug cisplatin. Very significant anticancer activity was observed for compounds L1H, Cu(L1)2, Cu(L2)2, Ni(L1)2 and Ni(L2)2 with IC50 value of <10 µgmL-1. Molecular docking studies were performed to assess the bonding mode of synthesized compounds. In case of antioxidant activity study, the compounds L1H, Ni(L1)2, Ni(L2)2, Cu(L1)2 and Cu(L2)2 exhibited significant scavenging activity with good percentage when compared with remaining tested compounds.

Who Are the Undiagnosed? Disparities in Hypertension Diagnoses in Vulnerable Populations.

This study builds upon a project that developed clinical criteria to identify undiagnosed hypertension patients "hiding in plain sight" (HIPS) by examining patient characteristics to understand whether there are disparities in hypertension diagnosis. We examined electronic health record demographic data for patients identified by the HIPS criteria and subgroups at 3 Missouri health centers. Identified patients who returned for a follow-up visit and were subsequently diagnosed with hypertension tended to be older, black/African American, uninsured, and classified as having obesity. Younger, white, healthy weight females were less likely to be diagnosed. These findings point to exploring possible biases/other nonclinical factors in hypertension diagnosis.

Vaccination Capability Inventory of Community, Migrant, and Homeless Health Centers: A Survey Report.

CONTEXT: Federally funded Community, Migrant, and Homeless Health Centers provide health services to the most vulnerable communities in the United States. However, little is known about their capabilities and processes for providing vaccinations to adults. PROGRAM: We conducted the first national survey of health centers assessing their inventory, workflow, capacity for, and barriers to provision of routinely recommended adult vaccines. In addition, we asked health center leaders' perceptions regarding best practices and policy recommendations for adult vaccinations. IMPLEMENTATION: A survey was developed on the basis of domains elicited from advisory panels and focus groups and was sent electronically to leaders of 762 health centers throughout the United States and its territories; data were collected and analyzed in 2018. EVALUATION: A total of 319 survey responses (42%) were obtained. Health centers reported stocking most routinely recommended vaccines for adults; zoster vaccines were not stocked regularly due to supply and storage issues. Respondents most commonly reported adequate reimbursement for vaccination services from private insurance and Medicaid. Most vaccinations were provided during primary care encounters; less than half of health centers reported providing vaccines during specialist visits. Vaccines administered at the health center were most commonly documented in an open field of the electronic health record (96%) or in an immunization information system (72%). Recommendations for best practices related to better documentation of vaccinations and communication with immunization information systems were provided. DISCUSSION: Health centers provide most adult vaccines to their patients despite financial and technological barriers to optimal provisioning. Further studies at point of care could help identify mechanisms for system improvements.

Injectable RANKL sustained release formulations to accelerate orthodontic tooth movement.

BACKGROUND: Accelerating orthodontic tooth movement (OTM) through biologically effective methods, such as increasing osteoclast-mediated alveolar resorption, could effectively shorten treatment time. OBJECTIVE: To evaluate an injectable formulation containing receptor activator of nuclear factor kappa-B ligand (RANKL) on the OTM. MATERIALS AND METHODS: We fabricated a RANKL formulation from 100 µl of 100 µg/ml RANKL adsorbed on 10 mg of poly(lactic acid-co-glycolic acid) microspheres embedded in a 10 wt% aqueous hydroxyethyl cellulose carrier gel. We characterized these formulations for the rate of RANKL release, and then tested for bioactivity using in vitro cell culture. In vivo OTM studies were conducted using 15 week old male Wistar rats for 14 days. We injected the RANKL formulations palatal to the left maxillary first molar and accomplished OTM with a nickel-titanium (NiTi) coil spring applying 5-8 g force. Control groups involved the application of NiTi coil spring with and without placebo formulation. The outcome measure included the distance of tooth movement, bone volume fraction, tissue density, and root volume determined with micro-computed tomography. We determined the amount of osteoclast activity using tartrate-resistant acid phosphatase (TRAP) staining. RESULTS: These formulations were able to sustain the release of RANKL for more than 30 days, and the released RANKL showed a positive effect on mice osteoclast precursor cells (RAW 264.7). Reported injectable RANKL formulations were effective in accelerating OTM compared with other control groups, with 129.2 per cent more tooth movement than no formulation and 71.8 per cent more than placebo formulation, corresponding with a significant increase in the amount of TRAP activity. We did not observe any significant differences in root resorption between the groups. CONCLUSION: Our study shows a significant increase in OTM with injectable formulations containing RANKL.

Fate mapping during regeneration: Cells that undergo compensatory proliferation in damaged Drosophila eye imaginal discs differentiate into multiple retinal accessory cell types.

Regeneration of tissues that have been damaged by cell loss requires new growth, often via proliferation of precursor cells followed by differentiation to replace loss of specific cell types. When regeneration occurs after normal differentiation of the tissue is complete, developmental pathways driving differentiation must be re-activated. How proliferation and differentiation are induced and balanced during regeneration is not well understood. To investigate these processes, we utilized a paradigm for tissue damage and regeneration in the developing Drosophila melanogaster eye. Previous studies have demonstrated that tissue damage resulting from extensive cell death stimulates quiescent, undifferentiated cells in the developing larval eye to re-enter the cell cycle and proliferate. Whether these cells are restricted to certain fates or can contribute to all retinal cell types and thus potentially be fully regenerative is not known. Here we found by fate mapping experiments that these cells are competent to differentiate into all accessory cell types in the retina but do not differentiate into photoreceptors, likely because cell cycle re-entry in response to damage occurs after photoreceptor differentiation has completed. We conclude that the ability to re-enter the cell cycle in response to tissue damage in the developing Drosophila eye is not restricted to precursors of a specific cell type and that cell cycle re-entry following damage does not disrupt developmental programs that control differentiation.

Ketogenic and anaplerotic dietary modifications ameliorate seizure activity in Drosophila models of mitochondrial encephalomyopathy and glycolytic enzymopathy.

Seizures are a feature not only of the many forms of epilepsy, but also of global metabolic diseases such as mitochondrial encephalomyopathy (ME) and glycolytic enzymopathy (GE). Modern anti-epileptic drugs (AEDs) are successful in many cases, but some patients are refractory to existing AEDs, which has led to a surge in interest in clinically managed dietary therapy such as the ketogenic diet (KD). This high-fat, low-carbohydrate diet causes a cellular switch from glycolysis to fatty acid oxidation and ketone body generation, with a wide array of downstream effects at the genetic, protein, and metabolite level that may mediate seizure protection. We have recently shown that a Drosophila model of human ME (ATP61) responds robustly to the KD; here, we have investigated the mechanistic importance of the major metabolic consequences of the KD in the context of this bioenergetics disease: ketogenesis, reduction of glycolysis, and anaplerosis. We have found that reduction of glycolysis does not confer seizure protection, but that dietary supplementation with ketone bodies or the anaplerotic lipid triheptanoin, which directly replenishes the citric acid cycle, can mimic the success of the ketogenic diet even in the presence of standard carbohydrate levels. We have also shown that the proper functioning of the citric acid cycle is crucial to the success of the KD in the context of ME. Furthermore, our data reveal that multiple seizure models, in addition to ATP61, are treatable with the ketogenic diet. Importantly, one of these mutants is TPIsugarkill, which models human glycolytic enzymopathy, an incurable metabolic disorder with severe neurological consequences. Overall, these studies reveal widespread success of the KD in Drosophila, further cementing its status as an excellent model for studies of KD treatment and mechanism, and reveal key insights into the therapeutic potential of dietary therapy against neuronal hyperexcitability in epilepsy and metabolic disease.