Prefoldin 6 mediates longevity response from heat shock factor 1 to FOXO in C. elegans.

Heat shock factor 1 (HSF-1) and forkhead box O (FOXO) are key transcription factors that protect cells from various stresses. In Caenorhabditis elegans, HSF-1 and FOXO together promote a long life span when insulin/IGF-1 signaling (IIS) is reduced. However, it remains poorly understood how HSF-1 and FOXO cooperate to confer IIS-mediated longevity. Here, we show that prefoldin 6 (PFD-6), a component of the molecular chaperone prefoldin-like complex, relays longevity response from HSF-1 to FOXO under reduced IIS. We found that PFD-6 was specifically required for reduced IIS-mediated longevity by acting in the intestine and hypodermis. We showed that HSF-1 increased the levels of PFD-6 proteins, which in turn directly bound FOXO and enhanced its transcriptional activity. Our work suggests that the prefoldin-like chaperone complex mediates longevity response from HSF-1 to FOXO to increase the life span in animals with reduced IIS.

Pivotal Role of Slitrk1 in Adult Striatal Cholinergic Neurons in Mice: Implication in Tourette Syndrome.

OBJECTIVE: The SLIT and NTRK-like 1 (SLITRK1) gene mutation and striatal cholinergic interneurons (ChIs) loss are associated with Tourette syndrome (TS). ChIs comprise only 1 to 2% of striatal neurons but project widely throughout the stratum to impact various striatal neurotransmission, including TS-related dopaminergic transmission. Here, we link striatal Slitrk1, ChI function, and dopaminergic transmission and their associations with TS-like tic behaviors. METHODS: Slitrk1-KD mice were induced by bilaterally injecting Slitrk1 siRNA into their dorsal striatum. Control mice received scrambled siRNA injection. Their TS-like tic behaviors, prepulse inhibition, sensory-motor function and dopamine-related behaviors were compared. We also compared dopamine and ACh levels in microdialysates, Slitrk protein and dopamine transporter levels, and numbers of Slitrk-positive ChIs and activated ChIs in the striatum between two mouse groups, and electrophysiological properties between Slitrk-positive and Slitrk-negative striatal ChIs. RESULTS: Slitrk1-KD mice exhibit TS-like haloperidol-sensitive stereotypic tic behaviors, impaired prepulse inhibition, and delayed sensorimotor response compared with the control group. These TS-like characteristics correlate with lower striatal Slitrk1 protein levels, fewer Slitrk1-containing ChIs, and fewer activated ChIs in Slitrk1-KD mice. Based on their electrophysiological properties, Slitrk1-negative ChIs are less excitable than Slitrk1-positive ChIs. Slitrk1-KD mice have lower evoked acetylcholine and dopamine levels, higher tonic dopamine levels, and downregulated dopamine transporters in the striatum, increased apomorphine-induced climbing behaviors, and impaired methamphetamine-induced hyperlocomotion compared with controls. INTERPRETATION: Slitrk1 is pivotal in maintaining striatal ChIs activity and subsequent dopaminergic transmission for normal motor functioning. Furthermore, conditional striatal Slitrk1-KD mice may serve as a translational modality with aspects of TS phenomenology. ANN NEUROL 2023.

C9orf72-associated arginine-rich dipeptide repeats induce RNA-dependent nuclear accumulation of Staufen in neurons.

RNA-binding proteins (RBPs) play essential roles in diverse cellular processes through post-transcriptional regulation of RNAs. The subcellular localization of RBPs is thus under tight control, the breakdown of which is associated with aberrant cytoplasmic accumulation of nuclear RBPs such as TDP-43 and FUS, well-known pathological markers for amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). Here, we report in Drosophila model for ALS/FTD that nuclear accumulation of a cytoplasmic RBP Staufen may be a new pathological feature. We found that in Drosophila C4da neurons expressing PR36, one of the arginine-rich dipeptide repeat proteins (DPRs), Staufen accumulated in the nucleus in Importin- and RNA-dependent manner. Notably, expressing Staufen with exogenous NLS-but not with mutated endogenous NLS-potentiated PR-induced dendritic defect, suggesting that nuclear-accumulated Staufen can enhance PR toxicity. PR36 expression increased Fibrillarin staining in the nucleolus, which was enhanced by heterozygous mutation of stau (stau+/-), a gene that codes Staufen. Furthermore, knockdown of fib, which codes Fibrillarin, exacerbated retinal degeneration mediated by PR toxicity, suggesting that increased amount of Fibrillarin by stau+/- is protective. stau+/- also reduced the amount of PR-induced nuclear-accumulated Staufen and mitigated retinal degeneration and rescued viability of flies expressing PR36. Taken together, our data show that nuclear accumulation of Staufen in neurons may be an important pathological feature contributing to the pathogenesis of ALS/FTD.

Emergency department claims among Medicare beneficiaries with HIV, STDs, viral hepatitis or tuberculosis before and during the COVID-19 pandemic.

BACKGROUND: Changes in emergency department (ED) usage among US Medicare beneficiaries (MB) with fee-for-service claims for HIV, viral hepatitis, sexually transmitted diseases (STDs) or tuberculosis (TB) (HHST) services have not been assessed since the COVID-19 pandemic. METHODS: During 2006-20, we assessed the annual number of MB with each HHST per 1000 persons with ED claims for all conditions, and changes in demographic and geographic distribution of ED claimants for each HHST condition. RESULTS: Of all persons who attended an ED for any condition, 10.5 million (27.5%) were MB with ≥1 ED claim in 2006; that number (percentage) increased to 11.0 million (26.7%) in 2019 and decreased to 9.2 million (22.7%) in 2020; < 5 MB per 1000 ED population had HHST ED claims in 2020. The percentage increase in ED claims was higher for MB with STDs than for those with other HHST conditions, including a 10% decrease for MB with TB in 2020. CONCLUSIONS: Trends in ED usage for HHST conditions were associated with changes in demographic and geographic distribution among MB during 2006-20. Updated ED reimbursement policies and primary care practices among MB might improve prevention, diagnosis and treatment of HHST conditions in the future.

Pancreatic Stellate Cells and the Targeted Therapeutic Strategies in Chronic Pancreatitis.

Chronic pancreatitis (CP) is a disease characterized by inflammatory recurrence that accompanies the development of pancreatic fibrosis. As the mystery of CP pathogenesis is gradually revealed, accumulating evidence suggests that the activation of pancreatic stellate cells (PSCs) and the appearance of a myofibroblast-like phenotype are the key gatekeepers in the development of CP. Targeting PSCs to prevent their activation and conversion to a myofibroblast-like phenotype, as well as increasing antioxidant capacity to counteract ongoing oxidative stress, are effective strategies for preventing or treating CP. Therefore, we reviewed the crosstalk between CP and pancreatic fibrosis, summarized the activation mechanisms of PSCs, and investigated potential CP therapeutic strategies targeting PSCs, including, but not limited to, anti-fibrosis therapy, antioxidant therapy, and gene therapy. Meanwhile, the above therapeutic strategies are selected in order to update the available phytopharmaceuticals as novel complementary or alternative approaches for the prevention and treatment of CP to clarify their potential mechanisms of action and their relevant molecular targets, aiming to provide the most comprehensive therapeutic treatment direction for CP and to bring new hope to CP patients.

MDT-15/MED15 permits longevity at low temperature via enhancing lipidostasis and proteostasis.

Low temperatures delay aging and promote longevity in many organisms. However, the metabolic and homeostatic aspects of low-temperature-induced longevity remain poorly understood. Here, we show that lipid homeostasis regulated by Caenorhabditis elegans Mediator 15 (MDT-15 or MED15), a transcriptional coregulator, is essential for low-temperature-induced longevity and proteostasis. We find that inhibition of mdt-15 prevents animals from living long at low temperatures. We show that MDT-15 up-regulates fat-7, a fatty acid desaturase that converts saturated fatty acids (SFAs) to unsaturated fatty acids (UFAs), at low temperatures. We then demonstrate that maintaining a high UFA/SFA ratio is essential for proteostasis at low temperatures. We show that dietary supplementation with a monounsaturated fatty acid, oleic acid (OA), substantially mitigates the short life span and proteotoxicity in mdt-15(-) animals at low temperatures. Thus, lipidostasis regulated by MDT-15 appears to be a limiting factor for proteostasis and longevity at low temperatures. Our findings highlight the crucial roles of lipid regulation in maintaining normal organismal physiology under different environmental conditions.

Provisional COVID-19 Age-Adjusted Death Rates, by Race and Ethnicity - United States, 2020-2021.

Disparities in COVID-19 death rates by race and ethnicity have been reported in the United States (1,2). In response to these disparities, preventive, medical care, and social service assistance programs were implemented to lessen disparities in COVID-19 outcomes, including grants to support state, tribal, local, and territorial health department responses (3). The potential impact of such efforts on annual changes in racial and ethnic disparities in mortality rates that identify COVID-19 as the underlying cause of death has not been previously reported. This analysis used U.S. provisional mortality data from death certificates collected by CDC's National Vital Statistics System (NVSS) to estimate changes in COVID-19-related age-adjusted death rates (AADRs) by race and ethnicity during 2020-2021. Compared with non-Hispanic multiracial persons (the group with the lowest death rate), significant decreases in AADR ratios occurred during 2020-2021 among non-Hispanic American Indian or Alaska Native (AI/AN) persons (34.0%), non-Hispanic Asian (Asian) persons (37.6%), non-Hispanic Black or African American (Black) persons (40.2%), Hispanic persons (37.1%), and non-Hispanic White (White) persons (14%); a non-statistically significant 7.2% increase in AADR ratio occurred among non-Hispanic Native Hawaiian or other Pacific Islander (NH/OPI) persons. Despite reductions in AADR disparities from 2020 to 2021, large disparities in AADR by race and ethnicity remained in 2021. Providing effective preventive interventions, including vaccination and clinical care, to all communities in proportion to their need for these interventions is necessary to reduce racial and ethnic disparities in COVID-19 deaths.

Racial and ethnic differences in COVID-19 hospitalizations by metropolitan status among Medicare beneficiaries, 1 January-31 December 2020.

BACKGROUND: Risk for COVID-19 hospitalizations increases with increasing age and presence of underlying medical conditions. However, the burden has not been well-assessed in metropolitan and nonmetropolitan areas by race/ethnicity among Medicare population with chronic conditions. METHODS: We used the 2020 Medicare data to estimate COVID-19 hospitalization rates by race/ethnicity among Medicare beneficiaries for COVID-19 by metropolitan status and to assess the association of hospitalizations from COVID-19 with each of selected 29 chronic conditions for patients by metropolitan status and by race/ethnicity. RESULTS: The COVID-19 hospitalization rate was higher among beneficiaries residing in nonmetropolitan counties than those residing in metropolitan counties in 2020. Approximately 1 in 2 AI/AN, 1 in 3 NHB, Hispanic and A/PI, and 1 in 4 NHW beneficiaries with COVID-19 residing in nonmetropolitan counties were hospitalized. Beneficiaries with COVID-19 and chronic conditions were more likely to be hospitalized compared with those without chronic conditions. CONCLUSIONS: Hospitalization rates among beneficiaries with COVID-19 and chronic conditions were not distributed equally by race/ethnicity and by metropolitan status. Researchers, policymakers and practitioners can use these findings to explore more effective ways of reducing racial/ethnic and geographic disparities among minorities disproportionately affected by COVID-19 and are at highest risk of hospitalization.

How early warning with the Oxygen Reserve Index (ORi™) can improve the detection of desaturation during induction of general anesthesia?

The Oxygen Reserve Index (ORi™) is a dimensionless parameter with a value between 0 and 1. It is related to the real-time oxygenation status in the moderate hyperoxic range. The purpose of this study is to investigate the added warning time provided by different ORi alarm triggers and the continuous trends of ORi, SpO2, and PaO2. We enrolled 25 patients who were scheduled for elective surgery under general anesthesia with planned arterial catheterization before induction. The participants received standardized preoxygenation, induction, and intubation. The patients remained apneic and ventilation was resumed when the SpO2 fell below 90%. The ORi and SpO2 were recorded every ten seconds and arterial blood was sampled every minute, from preoxygenation to resumed ventilation. Alarm triggers set to the ORi peak and the ORi 0.55 values provided 300 and 145 s of significant added warning time compared to SpO2 (p < 0.0001). The coefficient of determination was 0.56 between the ORi and the PaO2 ≤ 240 mmHg and showed a positive correlation. The ORi enables the clinicians to monitor the patients' oxygen status during induction of general anesthesia and can improve the detection of impending desaturation. However, further studies are needed to assess its clinical potential in the high hyperoxic range.The protocol was retrospectively registered at ClinicalTrials.gov on July 21, 2021 (NCT04976504).

Fire safety study on high-flow nasal oxygen in shared-airway surgeries with diathermy and laser: simulation based on a physical model.

High-flow nasal oxygen (HFNO) has been used in "tubeless" shared-airway surgeries but whether HFNO increased the fire hazard is yet to be examined. We used a physical model for simulation to explore fire safety through a series of ignition trials. An HFNO device was attached to a 3D-printed nose with nostrils connected to a degutted raw chicken. The HFNO device was set at twenty combinations of different oxygen concentration and gas flow rate. An electrocautery and diode laser were applied separately to a fat cube in the cavity of the chicken. Ten 30 s trials of continuous energy source application were conducted. An additional trial of continuous energy application was conducted if no ignition was observed for all the ten trials. A total of eight short flashes were observed in one hundred electrocautery tests; however, no continuous fire was observed among them. There were thirty-six events of ignition in one hundred trials with laser, twelve of which turned into violent self-sustained fires. The factors found to be related to a significantly increased chance of ignition included laser application, lower gas flow, and higher FiO2. The native tissue and smoke can ignite and turn into violent self-sustained fires under HFNO and continuous laser strikes, even in the absence of combustible materials. The results suggest that airway surgeries must be performed safely with HFNO if only a short intermittent laser is used in low FiO2.

Single-Step Fast Tissue Clearing of Thick Mouse Brain Tissue for Multi-Dimensional High-Resolution Imaging.

Recent advances in optical clearing techniques have dramatically improved deep tissue imaging by reducing the obscuring effects of light scattering and absorption. However, these optical clearing methods require specialized equipment or a lengthy undertaking with complex protocols that can lead to sample volume changes and distortion. In addition, the imaging of cleared tissues has limitations, such as fluorescence bleaching, harmful and foul-smelling solutions, and the difficulty of handling samples in high-viscosity refractive index (RI) matching solutions. To address the various limitations of thick tissue imaging, we developed an Aqueous high refractive Index matching and tissue Clearing solution for Imaging (termed AICI) with a one-step tissue clearing protocol that was easily made at a reasonable price in our own laboratory without any equipment. AICI can rapidly clear a 1 mm thick brain slice within 90 min with simultaneous RI matching, low viscosity, and a high refractive index (RI = 1.466), allowing the imaging of the sample without additional processing. We compared AICI with commercially available RI matching solutions, including optical clear agents (OCAs), for tissue clearing. The viscosity of AICI is closer to that of water compared with other RI matching solutions, and there was a less than 2.3% expansion in the tissue linear morphology during 24 h exposure to AICI. Moreover, AICI remained fluid over 30 days of air exposure, and the EGFP fluorescence signal was only reduced to ~65% after 10 days. AICI showed a limited clearing of brain tissue >3 mm thick. However, fine neuronal structures, such as dendritic spines and axonal boutons, could still be imaged in thick brain slices treated with AICI. Therefore, AICI is useful not only for the three-dimensional (3D) high-resolution identification of neuronal structures, but also for the examination of multiple structural imaging by neuronal distribution, projection, and gene expression in deep brain tissue. AICI is applicable beyond the imaging of fluorescent antibodies and dyes, and can clear a variety of tissue types, making it broadly useful to researchers for optical imaging applications.

Distinct Firing Activities of the Hypothalamic Arcuate Nucleus Neurons to Appetite Hormones.

The hypothalamic arcuate nucleus (Arc) is a central unit that controls the appetite through the integration of metabolic, hormonal, and neuronal afferent inputs. Agouti-related protein (AgRP), proopiomelanocortin (POMC), and dopaminergic neurons in the Arc differentially regulate feeding behaviors in response to hunger, satiety, and appetite, respectively. At the time of writing, the anatomical and electrophysiological characterization of these three neurons has not yet been intensively explored. Here, we interrogated the overall characterization of AgRP, POMC, and dopaminergic neurons using genetic mouse models, immunohistochemistry, and whole-cell patch recordings. We identified the distinct geographical location and intrinsic properties of each neuron in the Arc with the transgenic lines labelled with cell-specific reporter proteins. Moreover, AgRP, POMC, and dopaminergic neurons had different firing activities to ghrelin and leptin treatments. Ghrelin led to the increased firing rate of dopaminergic and AgRP neurons, and the decreased firing rate of POMC. In sharp contrast, leptin resulted in the decreased firing rate of AgRP neurons and the increased firing rate of POMC neurons, while it did not change the firing rate of dopaminergic neurons in Arc. These findings demonstrate the anatomical and physiological uniqueness of three hypothalamic Arc neurons to appetite control.

DRG2 Depletion Promotes Endothelial Cell Senescence and Vascular Endothelial Dysfunction.

Endothelial cell senescence is involved in endothelial dysfunction and vascular diseases. However, the detailed mechanisms of endothelial senescence are not fully understood. Here, we demonstrated that deficiency of developmentally regulated GTP-binding protein 2 (DRG2) induces senescence and dysfunction of endothelial cells. DRG2 knockout (KO) mice displayed reduced cerebral blood flow in the brain and lung blood vessel density. We also determined, by Matrigel plug assay, aorta ring assay, and in vitro tubule formation of primary lung endothelial cells, that deficiency in DRG2 reduced the angiogenic capability of endothelial cells. Endothelial cells from DRG2 KO mice showed a senescence phenotype with decreased cell growth and enhanced levels of p21 and phosphorylated p53, γH2AX, senescence-associated ß-galactosidase (SA-ß-gal) activity, and senescence-associated secretory phenotype (SASP) cytokines. DRG2 deficiency in endothelial cells upregulated arginase 2 (Arg2) and generation of reactive oxygen species. Induction of SA-ß-gal activity was prevented by the antioxidant N-acetyl cysteine in endothelial cells from DRG2 KO mice. In conclusion, our results suggest that DRG2 is a key regulator of endothelial senescence, and its downregulation is probably involved in vascular dysfunction and diseases.

Telehealth Availability and Usage Among Medicare Beneficiaries During the COVID-19 Pandemic, October and November 2020.

CONTEXT: During the COVID-19 pandemic, demand for telehealth services increased to reduce disease exposure for patients and providers and to meet preexisting demand for physician services in health resource shortage areas. OBJECTIVE: To estimate self-reported telehealth availability, equipment for accessing telehealth, and telehealth usage among Medicare beneficiaries during the COVID-19 pandemic. DESIGN: We used data from the 2020 Medicare Current Beneficiary Survey (MCBS) COVID-19 Fall Supplement Public Use File to estimate the weighted percentages of beneficiaries who had (a) access to telehealth before or during COVID-19; (b) equipment for accessing telehealth; and (c) telehealth visits during COVID-19. We used logistic regression to examine sociodemographic factors associated with telehealth usage. PARTICIPANTS: Beneficiaries who participated in the MCBS COVID-19 Fall Supplements. RESULTS: During October and November 2020, telehealth appointments offered by providers were available to 63.8% (95% confidence interval [CI], 61.8-65.9) of Medicare beneficiaries who had accessed medical care by telephone or video. Among those, only 18.0% (95% CI, 16.1-19.9) had been offered telehealth before the pandemic. The majority of beneficiaries (92.2%; 95% CI, 91.2-93.1) had 1 or more types of equipment available for accessing telehealth, but only 44.9% (95% CI, 43.0-46.9) had had a telehealth visit since July 1, 2020. Older adults, minorities, those with a lower income, and non-English speakers had less availability of telehealth equipment. Patient characteristics were significantly (P < .05) associated with telehealth use, including age, sex, race/ethnicity, and equipment availability. CONCLUSION: Telehealth availability for Medicare beneficiaries increased substantially during the COVID-19 pandemic. Even with the improvement in telehealth offerings and use hastened by the pandemic, gaps in access and use still exist. Effectiveness and implementation research can find ways to close gaps in telehealth services between vulnerable and underrepresented populations and counterparts.

Mitochondrial chaperone HSP-60 regulates anti-bacterial immunity via p38 MAP kinase signaling.

Mitochondria play key roles in cellular immunity. How mitochondria contribute to organismal immunity remains poorly understood. Here, we show that HSP-60/HSPD1, a major mitochondrial chaperone, boosts anti-bacterial immunity through the up-regulation of p38 MAP kinase signaling. We first identify 16 evolutionarily conserved mitochondrial components that affect the immunity of Caenorhabditis elegans against pathogenic Pseudomonas aeruginosa (PA14). Among them, the mitochondrial chaperone HSP-60 is necessary and sufficient to increase resistance to PA14. We show that HSP-60 in the intestine and neurons is crucial for the resistance to PA14. We then find that p38 MAP kinase signaling, an evolutionarily conserved anti-bacterial immune pathway, is down-regulated by genetic inhibition of hsp-60, and up-regulated by increased expression of hsp-60 Overexpression of HSPD1, the mammalian ortholog of hsp-60, increases p38 MAP kinase activity in human cells, suggesting an evolutionarily conserved mechanism. Further, cytosol-localized HSP-60 physically binds and stabilizes SEK-1/MAP kinase kinase 3, which in turn up-regulates p38 MAP kinase and increases immunity. Our study suggests that mitochondrial chaperones protect host eukaryotes from pathogenic bacteria by up-regulating cytosolic p38 MAPK signaling.

Rhesus Blood Typing within a Few Seconds by Packing-Enhanced Nanoscattering on Individual Erythrocytes.

A method for the ABO and Rhesus (Rh) blood group typing from individual erythrocytes is proposed in this study. Blood-group-specific antibodies immobilized to gold nanoparticles (BG-AuNP) were utilized for the identification of blood groups from individual erythrocytes by objective-type dark-field microscopy (OTDFM). The scattering of free BG-AuNP and their Brownian motion as well as BG-AuNP attached on erythrocytes is easily observed by OTDFM. The strong scattering intensity caused by BG-AuNP packing-enhanced nanoscattering (PENS) on erythrocytes is first demonstrated. PENS combined with OTDFM allows us to identify blood groups within 5 s for all blood group antigens including A, B, D, C, c, E, and e. This was immediately identified by mixing with BG-AuNP without any washing step or waiting for hemoagglutination. Therefore, PENS combined with OTDFM demonstrates feasibility and advantages for use in emergency transfusions where the blood group of patients is unknown. Moreover, matching RhD+ in the case of emergency transfusions may also be beneficial in reducing the shortage of RhD- red blood cell concentrate in the case of a population with a high frequency in RhD-.

Factors Associated With Latent Tuberculosis Infection Treatment Failure Among Patients With Commercial Health Insurance-United States, 2005-2016.

CONTEXT: Approximately 80% of US tuberculosis (TB) cases verified during 2015-2016 were attributed to untreated latent TB infection (LTBI). Identifying factors associated with LTBI treatment failure might improve treatment effectiveness. OBJECTIVE: To identify patients with indicators of isoniazid (INH) LTBI treatment initiation, completion, and failure. METHODS: We searched inpatient and outpatient claims for International Classification of Diseases (Ninth and Tenth Revisions), National Drug, and Current Procedural Terminology codes. We defined treatment completion as 180 days or more of INH therapy during a 9-month period. We defined LTBI treatment failure as an active TB disease diagnosis more than 1 year after starting LTBI treatment among completers and used exact logistic regression to model possible differences between groups. Among treatment completers, we matched 1 patient who failed treatment with 2 control subjects and fit regression models with covariates documented on medical claims paid 6 months or less before INH treatment initiation. PARTICIPANTS: Commercially insured US patients in a large commercial database with insurance claims paid during 2005-2016. MAIN OUTCOME MEASURES: (1) Trends in treatment completion; (2) odds ratios (ORs) for factors associated with treatment completion and treatment failure. RESULTS: Of 21 510 persons who began LTBI therapy during 2005-2016, 10 725 (49.9%) completed therapy. Treatment noncompletion is associated with those younger than 45 years, living in the Northeast or South Census regions, and women. Among persons who completed treatment, 30 (0.3%) progressed to TB disease. Diagnoses of rheumatoid arthritis during the 6 months before treatment initiation and being aged 65 years or older (reference: ages 0-24 years) were significantly associated with INH LTBI treatment failure (adjusted exact OR = 5.1; 95% CI, 1.2-28.2; and adjusted exact OR = 5.1; 95% CI, 1.2-25.3, respectively). CONCLUSION: Approximately 50% of persons completed INH LTBI therapy, and of those, treatment failure was associated with rheumatoid arthritis and persons 65 years or older among a cohort of US LTBI patients with commercial health insurance.

The overexpression of TDP-43 in astrocytes causes neurodegeneration via a PTP1B-mediated inflammatory response.

BACKGROUND: Cytoplasmic inclusions of transactive response DNA binding protein of 43 kDa (TDP-43) in neurons and astrocytes are a feature of some neurodegenerative diseases, such as frontotemporal lobar degeneration with TDP-43 (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). However, the role of TDP-43 in astrocyte pathology remains largely unknown. METHODS: To investigate whether TDP-43 overexpression in primary astrocytes could induce inflammation, we transfected primary astrocytes with plasmids encoding Gfp or TDP-43-Gfp. The inflammatory response and upregulation of PTP1B in transfected cells were examined using quantitative RT-PCR and immunoblot analysis. Neurotoxicity was analysed in a transwell coculture system of primary cortical neurons with astrocytes and cultured neurons treated with astrocyte-conditioned medium (ACM). We also examined the lifespan, performed climbing assays and analysed immunohistochemical data in pan-glial TDP-43-expressing flies in the presence or absence of a Ptp61f RNAi transgene. RESULTS: PTP1B inhibition suppressed TDP-43-induced secretion of inflammatory cytokines (interleukin 1 beta (IL-1ß), interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α)) in primary astrocytes. Using a neuron-astrocyte coculture system and astrocyte-conditioned media treatment, we demonstrated that PTP1B inhibition attenuated neuronal death and mitochondrial dysfunction caused by overexpression of TDP-43 in astrocytes. In addition, neuromuscular junction (NMJ) defects, a shortened lifespan, inflammation and climbing defects caused by pan-glial overexpression of TDP-43 were significantly rescued by downregulation of ptp61f (the Drosophila homologue of PTP1B) in flies. CONCLUSIONS: These results indicate that PTP1B inhibition mitigates the neuronal toxicity caused by TDP-43-induced inflammation in mammalian astrocytes and Drosophila glial cells.

The Effects of Ankle Position on Torque and Muscle Activity of the Knee Extensor During Maximal Isometric Contraction.

CONTEXT: It is very important to empirically determine the optimal ankle position for the quadriceps femoris (QF) strengthening during isometric exercises. OBJECTIVE: To examine the effect of different ankle positions on torque and electromyography (EMG) activity of QF during maximal isometric contraction. STUDY DESIGN: Within-subject repeated measures. SETTING: University laboratory. PARTICIPANTS: Thirty-six healthy volunteers (15 males and 21 females). MAIN OUTCOME MEASURES: The isometric strength of the QF was measured at 3 different ankle positions: active dorsiflexion (AD), active plantar flexion (AP), and neutral position (NP). Simultaneously, 3 different ankle positions were assessed for EMG activity of the vastus medialis, vastus lateralis, and rectus femoris muscles during maximal voluntary isometric contraction. RESULTS: The peak torque per body weight and average peak torque were significantly higher in AD than in AP and NP (P < .01). The vastus medialis and rectus femoris maximal voluntary isometric contraction EMG activity were significantly higher in AD than in AP and NP (P < .01). The vastus lateralis maximal voluntary isometric contraction EMG activity was significantly higher in AD than in AP and NP (P < .01), and was significantly higher in AP than in NP (P < .05). CONCLUSIONS: These results indicate that the 3 different ankle positions affect the QF torque and EMG activity. In particular, AD position may be more efficient for improving QF strength than AP and NP position. Future studies should prove whether long-term duration QF isometric exercise effects muscle strength and functional performance in different ankle positions.

Vaccinia-related kinase 2 plays a critical role in microglia-mediated synapse elimination during neurodevelopment.

During postnatal neurodevelopment, excessive synapses must be eliminated by microglia to complete the establishment of neural circuits in the brain. The lack of synaptic regulation by microglia has been implicated in neurodevelopmental disorders such as autism, schizophrenia, and intellectual disability. Here we suggest that vaccinia-related kinase 2 (VRK2), which is expressed in microglia, may stimulate synaptic elimination by microglia. In VRK2-deficient mice (VRK2KO ), reduced numbers of presynaptic puncta within microglia were observed. Moreover, the numbers of presynaptic puncta and synapses were abnormally increased in VRK2KO mice by the second postnatal week. These differences did not persist into adulthood. Even though an increase in the number of synapses was normalized, adult VRK2KO mice showed behavioral defects in social behaviors, contextual fear memory, and spatial memory.