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Developmental myelination is a protracted process in the mammalian brain1. One theory for why oligodendrocytes mature so slowly posits that myelination may stabilize neuronal circuits and temper neuronal plasticity as animals age2-4. We tested this theory in the visual cortex, which has a well-defined critical period for experience-dependent neuronal plasticity5. During adolescence, visual experience modulated the rate of oligodendrocyte maturation in visual cortex. To determine whether oligodendrocyte maturation in turn regulates neuronal plasticity, we genetically blocked oligodendrocyte differentiation and myelination in adolescent mice. In adult mice lacking adolescent oligodendrogenesis, a brief period of monocular deprivation led to a significant decrease in visual cortex responses to the deprived eye, reminiscent of the plasticity normally restricted to adolescence. This enhanced functional plasticity was accompanied by a greater turnover of dendritic spines and coordinated reductions in spine size following deprivation. Furthermore, inhibitory synaptic transmission, which gates experience-dependent plasticity at the circuit level, was diminished in the absence of adolescent oligodendrogenesis. These results establish a critical role for oligodendrocytes in shaping the maturation and stabilization of cortical circuits and support the concept of developmental myelination acting as a functional brake on neuronal plasticity.

Multiple sclerosis (MS) is a chronic and debilitating neurological disease that results in inflammatory demyelination. While endogenous remyelination helps to recover function, this restorative process tends to become less efficient over time. Currently, intense efforts aimed at the mechanisms that promote remyelination are being considered promising therapeutic approaches. The M1 muscarinic acetylcholine receptor (M1R) was previously identified as a negative regulator of oligodendrocyte differentiation and myelination. Here, we validate M1R as a target for remyelination by characterizing expression in human and rodent oligodendroglial cells (including those in human MS tissue) using a highly selective M1R probe. As a breakthrough to conventional methodology, we conjugated a fluorophore to a highly M1R selective peptide (MT7) which targets the M1R in the subnanomolar range. This allows for exceptional detection of M1R protein expression in the human CNS. More importantly, we introduce PIPE-307, a brain-penetrant, small-molecule antagonist with favorable drug-like properties that selectively targets M1R. We evaluate PIPE-307 in a series of in vitro and in vivo studies to characterize potency and selectivity for M1R over M2-5R and confirm the sufficiency of blocking this receptor to promote differentiation and remyelination. Further, PIPE-307 displays significant efficacy in the mouse experimental autoimmune encephalomyelitis model of MS as evaluated by quantifying disability, histology, electron microscopy, and visual evoked potentials. Together, these findings support targeting M1R for remyelination and support further development of PIPE-307 for clinical studies.

Background: Asynchronous telepsychiatry (ATP) consultations are a novel form of psychiatric consultation. Studies comparing patient and provider satisfaction for ATP with that for synchronous telepsychiatry (STP) do not exist. Methods: This mixed-methods study is a secondary analysis of patients' and primary care providers' (PCPs) satisfaction from a randomized clinical trial of ATP compared with STP. Patients and their PCPs completed satisfaction surveys, and provided unstructured feedback about their experiences with either ATP or STP. Differences in patient satisfaction were assessed using mixed-effects logistic regression models, and the qualitative data were analyzed using thematic analysis with an inductive coding framework. Results: Patient satisfaction overall was high with 84% and 97% of respondents at 6 months reported being somewhat or completely satisfied with ATP and STP, respectively. Patients in the STP group were more likely to report being completely satisfied, to recommend the program to a friend, and to report being comfortable with their care compared with ATP (all p < 0.05). However, there was no difference between the patients in ATP and STP in perceived change in clinical outcomes (p = 0.51). The PCP quantitative data were small, and thus only summarized descriptively. Conclusions: Patients expressed their overall satisfaction with both STP and ATP. Patients in ATP reported more concerns about the process, likely because feedback after ATP was slower than that after STP consultations. PCPs had no apparent preference for STP or ATP, and reported implementing the psychiatrists' recommendations for both groups when such recommendations were made, which supports our previous findings. Trial Registration: ClinicalTrials.gov NCT02084979; https://clinicaltrials.gov/ct2/show/NCT02084979.

Substantial energy is used to condition the air that enters California homes through leaks in the building envelope and ductwork - typically about a third of all heating and cooling. Reducing this through air sealing is essential to California achieving zero energy homes. However, this outdoor air also dilutes pollutants emitted inside homes and contributes to a healthy indoor environment and acceptable indoor air quality (IAQ). To address this IAQ issue, California’s Title 24 Building Standards have required mechanical ventilation in new homes since 2008. This report presents a comprehensive study of the impacts of these requirements in recently constructed homes with natural gas appliances. The study included a survey about satisfaction and activities that impact IAQ; a field study of homes built to 2008 or later; and simulations assessing how various ventilation rates would impact chronic exposures to an indoor emitted pollutant as air tightness improves in California. The report focuses on the field study; the webbased survey and simulation elements are described in appendices. The field study characterized 70 homes built between 2011 and 2017. Each home was monitored over roughly one week with the dwelling unit mechanical ventilation system operating and windows closed. Pollutant measurements included time-resolved fine particulate matter (PM2.5) indoors and outdoors, and formaldehyde, nitrogen dioxide (NO2), and carbon dioxide (CO2) indoors. Time-integrated measurements were made for formaldehyde, NO2 and nitrogen oxides (NOX) indoors and outdoors at all homes. Activity monitoring devices were installed on the cooktop, range hood and other exhaust fans, and the heating and cooling system. The field study found that most homes met most ventilation requirements and the dwelling unit ventilation fans on average moved 50% more airflow than the minimum specified in Title 24. Air pollutant concentrations were similar or lower than those reported in a study of recent construction California new homes conducted in 2007-08. Notably, the median formaldehyde level was 38% lower than in the prior study. Measured concentrations were below health guidelines for most pollutants, indicating that IAQ is acceptable in new California homes when dwelling unit mechanical ventilation is used. However, the dwelling unit mechanical ventilation fans were only operating in one quarter of the homes when first visited and the control switches in many homes did not have informative labels as required by the standards. Corrective action needs to be taken to improve labeling and controls for ventilation systems.

The elevated level of replication stress is an intrinsic characteristic of cancer cells. Targeting the mechanisms that maintain genome stability to further increase replication stress and thus induce severe genome instability has become a promising approach for cancer treatment. Here, we identify histone deacetylase 8 (HDAC8) as a drug target whose inactivation synergized with the inhibition of checkpoint kinases to elicit substantial replication stress and compromise genome integrity selectively in cancer cells. We showed that simultaneous inhibition of HDAC8 and checkpoint kinases led to extensive replication fork collapse, irreversible cell-cycle arrest, and synergistic vulnerability in various cancer cells. The efficacy of the combination treatment was further validated in patient tumor- derived organoid (PDO) and xenograft mouse (PDX) models, providing important insights into patient-specific drug responses. Our data revealed that HDAC8 activity was essential for reducing the acetylation level of structural maintenance of chromosomes protein 3 (SMC3) ahead of replication forks and preventing R loop formation. HDAC8 inactivation resulted in slowed fork progression and checkpoint kinase activation. Our findings indicate that HDAC8 guards the integrity of the replicating genome, and the cancer-specific synthetic lethality between HDAC8 and checkpoint kinases provides a promising replication stress-targeting strategy for treating a broad range of cancers., Introduction To maintain the integrity of the human genome, the genetic and epigenetic information in proliferating cells must be precisely duplicated during chromatin replication. Replication stress, defined as any impediment [...]

Myelin repair is an unrealized therapeutic goal in the treatment of multiple sclerosis (MS). Uncertainty remains about the optimal techniques for assessing therapeutic efficacy and imaging biomarkers are required to measure and corroborate myelin restoration. We analyzed myelin water fraction imaging from ReBUILD, a double-blind, randomized placebo-controlled (delayed treatment) remyelination trial, that showed a significant reduction in VEP latency in patients with MS. We focused on brain regions rich in myelin. Fifty MS subjects in two arms underwent 3T MRI at baseline and months 3 and 5. Half of the cohort was randomly assigned to receive treatment from baseline through 3 mo, whereas the other half received treatment from 3 mo to 5 mo post-baseline. We computed myelin water fraction changes occurring in normal-appearing white matter of corpus callosum, optic radiations, and corticospinal tracts. An increase in myelin water fraction was documented in the normal-appearing white matter of the corpus callosum, in correspondence with the administration of the remyelinating treatment clemastine. This study provides direct, biologically validated imaging-based evidence of medically induced myelin repair. Moreover, our work strongly suggests that significant myelin repair occurs outside of lesions. We therefore propose myelin water fraction within the normal-appearing white matter of the corpus callosum as a biomarker for clinical trials looking at remyelination.

Purpose of reviewPatients, providers, and trainees should understand the current types of asynchronous technologies that can be used to enhance the delivery and accessibility of mental health care. Asynchronous telepsychiatry (ATP) removes the need for real time communication between the clinician and patient, which improves efficiency and enables quality specialty care. ATP can be applied as distinct consultative and supervisory models in clinician-to-clinician, clinician-to-patient, and patient-to-mobile health settings.Recent findingsThis review is based on research literature and the authors' clinical and medical training, using experiences with asynchronous telepsychiatry from before, during, and after the COVID-19 pandemic. Our studies demonstrate that ATP provides positive outcomes in the clinician-to-patient model with demonstrated feasibility, outcomes and patient satisfaction. One author's medical education experience in the Philippines during COVID-19 highlights the potential to utilize asynchronous technology in areas with limitations to online learning. We emphasize the need to teach media skills literacy around mental health to students, coaches, therapists, and clinicians when advocating for mental well-being. Several studies have demonstrated the feasibility of incorporating asynchronous e-tools such as self-guided multimedia and artificial intelligence for data collection at the clinician-to-clinician and patient-to-mobile health level. In addition, we offer fresh perspectives on recent trends in asynchronous telehealth in wellness, applying concepts such as "tele-exercise" and "tele-yoga."SummaryAsynchronous technologies continue to be integrated into mental health care services and research. Future research must ensure that the design and the usability of this technology puts the patient and provider first.

Many biomarkers in clinical neuroscience lack pathological certification. This issue is potentially a significant contributor to the limited success of neuroprotective and neurorestorative therapies for human neurological disease-and is evident even in areas with therapeutic promise such as myelin repair. Despite the identification of promising remyelinating candidates, biologically validated methods to demonstrate therapeutic efficacy or provide robust preclinical evidence of remyelination in the CNS are lacking. Therapies with potential to remyelinate the CNS constitute one of the most promising and highly anticipated therapeutic developments in the pipeline to treat multiple sclerosis and other demyelinating diseases. The optic nerve has been proposed as an informative pathway to monitor remyelination in animals and human subjects. Recent clinical trials using visual evoked potential have had promising results, but without unequivocal evidence about the cellular and molecular basis for signal changes on visual evoked potential, the interpretation of these trials is constrained. The visual evoked potential was originally developed and used in the clinic as a diagnostic tool but its use as a quantitative method for assessing therapeutic response requires certification of its biological specificity. Here, using the tools of experimental pathology we demonstrate that quantitative measurements of myelination using both histopathological measures of nodal structure and ultrastructural assessments correspond to visual evoked potential latency in both inflammatory and chemical models of demyelination. Visual evoked potential latency improves after treatment with a tool remyelinating compound (clemastine), mirroring both quantitative and qualitative myelin assessment. Furthermore, clemastine does not improve visual evoked potential latency following demyelinating injury when administered to a transgenic animal incapable of forming new myelin. Therefore, using the capacity for therapeutic enhancement and biological loss of function we demonstrate conclusively that visual evoked potential measures myelin status and is thereby a validated tool for preclinical verification of remyelination.

Learning requires new oligodendrogenesis, but how myelin patterns change during learning is unclear. Bacmeister et al. show that motor learning induces phase-specific changes in myelination on behaviorally activated axons that correlate with motor performance, suggesting myelin remodeling is involved in learning.

Solar-driven bioelectrosynthesis represents a promising approach for converting abundant resources into value-added chemicals with renewable energy. Microorganisms powered by electrochemical reducing equivalents assimilate CO2, H2O, and N2 building blocks. However, products from autotrophic whole-cell biocatalysts are limited. Furthermore, biocatalysts tasked with N2 reduction are constrained by simultaneous energy-intensive autotrophy. To overcome these challenges, we designed a biohybrid coculture for tandem and tunable CO2 and N2 fixation to value-added products, allowing the different species to distribute bioconversion steps and reduce the individual metabolic burden. This consortium involves acetogen Sporomusa ovata, which reduces CO2 to acetate, and diazotrophic Rhodopseudomonas palustris, which uses the acetate both to fuel N2 fixation and for the generation of a biopolyester. We demonstrate that the coculture platform provides a robust ecosystem for continuous CO2 and N2 fixation, and its outputs are directed by substrate gas composition. Moreover, we show the ability to support the coculture on a high-surface area silicon nanowire cathodic platform. The biohybrid coculture achieved peak faradaic efficiencies of 100, 19.1, and 6.3% for acetate, nitrogen in biomass, and ammonia, respectively, while maintaining product tunability. Finally, we established full solar to chemical conversion driven by a photovoltaic device, resulting in solar to chemical efficiencies of 1.78, 0.51, and 0.08% for acetate, nitrogenous biomass, and ammonia, correspondingly. Ultimately, our work demonstrates the ability to employ and electrochemically manipulate bacterial communities on demand to expand the suite of CO2 and N2 bioelectrosynthesis products.

Objective:To compare clinical recommendations given by psychiatrists and the adherence to these recommendations by primary care physicians (PCP) following consultations conducted by asynchronous telepsychiatry (ATP) and synchronous telepsychiatry (STP).Materials and Methods:ATP and STP consultations were compared using intermediate data from a randomized clinical trial with adult participant enrollment between April 2014 and December 2017. In both study arms, PCPs received written recommendations from the psychiatrist after each encounter. Independent clinicians reviewed PCP documentation to measure adherence to those recommendations in the 6 months following the baseline consultation.Results:Medical records were reviewed for 645 psychiatrists' consult recommendations; 344 from 61 ATP consultations and 301 from 62 STP consultations. Of those recommendations, 191 (56%) and 173 (58%) were rated fully adherent by two independent raters for ATP and STP, respectively. In a multilevel ordinal logistic regression model adjusted for recommendation type and recommended implementation timing, there was no statistically significant difference in adherence to recommendations for ATP compared with STP (adjusted odds ratio = 0.91, 95% confidence interval = 0.51-1.62). The profiles of recommendation type were comparable between ATP and STP.Conclusions:This is the first PCP adherence study comparing two forms of telemedicine. Although we did not find evidence of a difference between ATP and STP; this study supports the feasibility and acceptability of ATP and STP for the provision of collaborative psychiatric care. Clinical Trial Identifier NCT02084979.

The evolution of SARS-CoV-2 virus has resulted in variants likely to be more readily transmitted through respiratory aerosols, underscoring the increased potential for indoor environmental controls to mitigate risk. Use of tight-fitting face masks to trap infectious aerosol in exhaled breath and reduce inhalation exposure to contaminated air is of critical importance for disease control. Administrative controls including the regulation of occupancy and interpersonal spacing are also important, while presenting social and economic challenges. Indoor engineering controls including ventilation, exhaust, air flow control, filtration, and disinfection by germicidal ultraviolet irradiation can reduce reliance on stringent occupancy restrictions. However, the effects of controls-individually and in combination-on reducing infectious aerosol transfer indoors remain to be clearly characterized to the extent needed to support widespread implementation by building operators. We review aerobiologic and epidemiologic evidence of indoor environmental controls against transmission and present a quantitative aerosol transfer scenario illustrating relative differences in exposure at close-interactive, room, and building scales. We identify an overarching need for investment to implement building controls and evaluate their effectiveness on infection in well-characterized and real-world settings, supported by specific, methodological advances. Improved understanding of engineering control effectiveness guides implementation at scale while considering occupant comfort, operational challenges, and energy costs.

Substantial energy is used to condition the air that enters California homes through leaks in the building envelope and ductwork - typically about a third of all heating and cooling. Reducing this through air sealing is essential to California achieving zero energy homes. However, this outdoor air also dilutes pollutants emitted inside homes and contributes to a healthy indoor environment and acceptable indoor air quality (IAQ). To address this IAQ issue, California’s Title 24 Building Standards have required mechanical ventilation in new homes since 2008. This report presents a comprehensive study of the impacts of these requirements in recently constructed homes with natural gas appliances. The study included a survey about satisfaction and activities that impact IAQ; a field study of homes built to 2008 or later; and simulations assessing how various ventilation rates would impact chronic exposures to an indoor emitted pollutant as air tightness improves in California. The report focuses on the field study; the webbased survey and simulation elements are described in appendices. The field study characterized 70 homes built between 2011 and 2017. Each home was monitored over roughly one week with the dwelling unit mechanical ventilation system operating and windows closed. Pollutant measurements included time-resolved fine particulate matter (PM2.5) indoors and outdoors, and formaldehyde, nitrogen dioxide (NO2), and carbon dioxide (CO2) indoors. Time-integrated measurements were made for formaldehyde, NO2 and nitrogen oxides (NOX) indoors and outdoors at all homes. Activity monitoring devices were installed on the cooktop, range hood and other exhaust fans, and the heating and cooling system. The field study found that most homes met most ventilation requirements and the dwelling unit ventilation fans on average moved 50% more airflow than the minimum specified in Title 24. Air pollutant concentrations were similar or lower than those reported in a study of recent construction California new homes conducted in 2007-08. Notably, the median formaldehyde level was 38% lower than in the prior study. Measured concentrations were below health guidelines for most pollutants, indicating that IAQ is acceptable in new California homes when dwelling unit mechanical ventilation is used. However, the dwelling unit mechanical ventilation fans were only operating in one quarter of the homes when first visited and the control switches in many homes did not have informative labels as required by the standards. Corrective action needs to be taken to improve labeling and controls for ventilation systems.

We report that the neurotrophin receptor p75 contributes to sensory neuron survival through the regulation of cholesterol metabolism in Schwann cells. Selective deletion of p75 in mouse Schwann cells of either sex resulted in a 30% loss of dorsal root ganglia (DRG) neurons and diminished thermal sensitivity. P75 regulates Schwann cell cholesterol biosynthesis in response to BDNF, forming a co-receptor complex with ErbB2 and activating ErbB2-mediated stimulation of sterol regulatory element binding protein 2 (SREBP2), a master regulator of cholesterol synthesis. Schwann cells lacking p75 exhibited decreased activation of SREBP2 and a reduction in 7-dehydrocholesterol (7-DHC) reductase (DHCR7) expression, resulting in accumulation of the neurotoxic intermediate, 7-dehyrocholesterol in the sciatic nerve. Restoration of DHCR7 in p75 null Schwann cells in mice significantly attenuated DRG neuron loss. Together, these results reveal a mechanism by which the disruption of lipid metabolism in glial cells negatively influences sensory neuron survival, which has implications for a wide range of peripheral neuropathies.SIGNIFICANCE STATEMENT Although expressed in Schwann cells, the role of p75 in myelination has remained unresolved in part because of its dual expression in sensory neurons that Schwann cells myelinate. When p75 was deleted selectively among Schwann cells, myelination was minimally affected, while sensory neuron survival was reduced by 30%. The phenotype is mainly due to dysregulation of cholesterol biosynthesis in p75-deficient Schwann cells, leading to an accumulation of neurotoxic cholesterol precursor, 7-dehydrocholesterol (7-DHC). Mechanism-wise, we discovered that in response to BDNF, p75 recruits and activates ErbB2 independently of ErbB3, thereby stimulating the master regulator, sterol regulatory element binding protein 2 (SREBP2). These results together highlight a novel role of p75 in Schwann cells in regulating DRG neuron survival by orchestrating proper cholesterol metabolism.

Oligodendrocyte (OL) maturation arrest in human white matter injury contributes significantly to the failure of endogenous remyelination in multiple sclerosis (MS) and newborn brain injuries such as hypoxic ischemic encephalopathy (HIE) that cause cerebral palsy. In this study, we identify an oligodendroglial-intrinsic factor that controls OL maturation specifically in the setting of injury. We find a requirement for the ring finger protein Rnf43 not in normal development but in neonatal hypoxic injury and remyelination in the adult mammalian CNS. Rnf43, but not the related Znrf3, is potently activated by Wnt signaling in OL progenitor cells (OPCs) and marks activated OPCs in human MS and HIE. Rnf43 is required in an injury-specific context, and it promotes OPC differentiation through negative regulation of Wnt signal strength in OPCs at the level of Fzd1 receptor presentation on the cell surface. Inhibition of Fzd1 using UM206 promotes remyelination following ex vivo and in vivo demyelinating injury.

Central nervous system demyelination in multiple sclerosis (MS) and subsequent axonal degeneration represent a major cause of clinical morbidity. Learning, salient experiences, and stimulation of neuronal activity induce new myelin formation in rodents, and in animal models of demyelination, remyelination can be enhanced via experience- and activity-dependent mechanisms. Furthermore, preliminary studies in MS patients support the use of neuromodulation and rehabilitation exercises for symptomatic improvement, suggesting that these interventions may represent nonpharmacological strategies for promoting remyelination. Here, we review the literature on myelin plasticity processes and assess the potential to leverage these mechanisms to develop remyelinating therapies. ANN NEUROL 2021;90:558-567.

Poor air quality affects the health and wellbeing of large populations around the globe. Although source controls are the most effective approaches for improving air quality and reducing health risks, individuals can also take actions to reduce their personal exposure by staying indoors, reducing physical activity, altering modes of transportation, filtering indoor air, and using respirators and other types of face masks. A synthesis of available evidence on the efficacy, effectiveness, and potential adverse effects or unintended consequences of personal interventions for air pollution is needed by clinicians to assist patients and the public in making informed decisions about use of these interventions. To address this need, the American Thoracic Society convened a workshop in May of 2018 to bring together a multidisciplinary group of international experts to review the current state of knowledge about personal interventions for air pollution and important considerations when helping patients and the general public to make decisions about how best to protect themselves. From these discussions, recommendations were made regarding when, where, how, and for whom to consider personal interventions. In addition to the efficacy and safety of the various interventions, the committee considered evidence regarding the identification of patients at greatest risk, the reliability of air quality indices, the communication challenges, and the ethical and equity considerations that arise when discussing personal interventions to reduce exposure and risk from outdoor air pollution.

Severe cognitive decline is a hallmark of Alzheimer's disease (AD). In addition to gray matter loss, significant white matter pathology has been identified in AD patients. Here, we characterized the dynamics of myelin generation and loss in the APP/PS1 mouse model of AD. Unexpectedly, we observed a dramatic increase in the rate of new myelin formation in APP/PS1 mice, reminiscent of the robust oligodendroglial response to demyelination. Despite this increase, overall levels of myelination are decreased in the cortex and hippocampus of APP/PS1 mice and postmortem AD tissue. Genetically or pharmacologically enhancing myelin renewal, by oligodendroglial deletion of the muscarinic M1 receptor or systemic administration of the pro-myelinating drug clemastine, improved the performance of APP/PS1 mice in memory-related tasks and increased hippocampal sharp wave ripples. Taken together, these results demonstrate the potential of enhancing myelination as a therapeutic strategy to alleviate AD-related cognitive impairment.

This paper presents pollutant concentrations and performance data for code-required mechanical ventilation equipment in 23 low-income apartments at 4 properties constructed or renovated 2013-2017. All apartments had natural gas cooking burners. Occupants pledged to not use windows for ventilation during the study but several did. Measured airflows of range hoods and bathroom exhaust fans were lower than product specifications. Only eight apartments operationally met all ventilation code requirements. Pollutants measured over one week in each apartment included time-resolved fine particulate matter (PM2.5 ), nitrogen dioxide (NO2 ), formaldehyde and carbon dioxide (CO2 ) and time-integrated formaldehyde, NO2 and nitrogen oxides (NOX ). Compared to a recent study of California houses with code-compliant ventilation, apartments were smaller, had fewer occupants, higher densities, and higher mechanical ventilation rates. Mean PM2.5 , formaldehyde, NO2 , and CO2 were 7.7 µg/m3 , 14.1, 18.8, and 741 ppm in apartments; these are 4% lower, 25% lower, 165% higher, and 18% higher compared to houses with similar cooking frequency. Four apartments had weekly PM2.5 above the California annual outdoor standard of 12 µg/m3 and also discrete days above the World Health Organization 24-hour guideline of 25 µg/m3 . Two apartments had weekly NO2 above the California annual outdoor standard of 30 ppb.

Myelin, multilayered lipid-rich membrane extensions formed by oligodendrocytes around neuronal axons, is essential for fast and efficient action potential propagation in the central nervous system. Initially thought to be a static and immutable process, myelination is now appreciated to be a dynamic process capable of responding to and modulating neuronal function throughout life. While the importance of this type of plasticity, called adaptive myelination, is now well accepted, we are only beginning to understand the underlying cellular and molecular mechanisms by which neurons communicate experience-driven circuit activation to oligodendroglia and precisely how changes in oligodendrocytes and their myelin refine neuronal function. Here, we review recent findings addressing this reciprocal relationship in which neurons alter oligodendroglial form and oligodendrocytes conversely modulate neuronal function.

The inflammatory environment of demyelinated lesions in multiple sclerosis (MS) patients contributes to remyelination failure. Inflammation activates a cytoprotective pathway, the integrated stress response (ISR), but it remains unclear whether enhancing the ISR can improve remyelination in an inflammatory environment. To examine this possibility, the remyelination stage of experimental autoimmune encephalomyelitis (EAE), as well as a mouse model that incorporates cuprizone-induced demyelination along with CNS delivery of the proinflammatory cytokine IFN-γ were used here. We demonstrate that either genetic or pharmacological ISR enhancement significantly increased the number of remyelinating oligodendrocytes and remyelinated axons in the inflammatory lesions. Moreover, the combined treatment of the ISR modulator Sephin1 with the oligodendrocyte differentiation enhancing reagent bazedoxifene increased myelin thickness of remyelinated axons to pre-lesion levels. Taken together, our findings indicate that prolonging the ISR protects remyelinating oligodendrocytes and promotes remyelination in the presence of inflammation, suggesting that ISR enhancement may provide reparative benefit to MS patients.

TDP-43 is extensively studied in neurons in physiological and pathological contexts. However, emerging evidence indicates that glial cells are also reliant on TDP-43 function. We demonstrate that deletion of TDP-43 in Schwann cells results in a dramatic delay in peripheral nerve conduction causing significant motor deficits in mice, which is directly attributed to the absence of paranodal axoglial junctions. By contrast, paranodes in the central nervous system are unaltered in oligodendrocytes lacking TDP-43. Mechanistically, TDP-43 binds directly to Neurofascin mRNA, encoding the cell adhesion molecule essential for paranode assembly and maintenance. Loss of TDP-43 triggers the retention of a previously unidentified cryptic exon, which targets Neurofascin mRNA for nonsense-mediated decay. Thus, TDP-43 is required for neurofascin expression, proper assembly and maintenance of paranodes, and rapid saltatory conduction. Our findings provide a framework and mechanism for how Schwann cell-autonomous dysfunction in nerve conduction is directly caused by TDP-43 loss-of-function.

Throughout our lifespan, new sensory experiences and learning continually shape our neuronal circuits to form new memories. Plasticity at the level of synapses has been recognized and studied for decades, but recent work has revealed an additional form of plasticity - affecting oligodendrocytes and the myelin sheaths they produce - that plays a crucial role in learning and memory. In this Review, we summarize recent work characterizing plasticity in the oligodendrocyte lineage following sensory experience and learning, the physiological and behavioural consequences of manipulating that plasticity, and the evidence for oligodendrocyte and myelin dysfunction in neurodevelopmental disorders with cognitive symptoms. We also discuss the limitations of existing approaches and the conceptual and technical advances that are needed to move forward this rapidly developing field.

Venting range hoods can control indoor air pollutants emitted during residential cooktop and oven cooking. To quantify their potential benefits, it is important to know how frequently and under what conditions range hoods are operated during cooking. We analyzed data from 54 single family houses and 17 low-income apartments in California in which cooking activities, range hood use, and fine particulate matter (PM2.5) were monitored for one week per home. Range hoods were used for 36% of cooking events in houses and 28% in apartments. The frequency of hood use increased with cooking frequency across homes. In both houses and apartments, the likelihood of hood use during a cooking event increased with the duration of cooktop burner use, but not with the duration of oven use. Actual hood use rates were higher in the homes of participants who self-reported more frequent use in a pre-study survey, but actual use was far lower than self-reported frequency. Residents in single family houses used range hoods more often when cooking caused a discernible increase in PM2.5. In apartments, residents used their range hood more often only when high concentrations of PM2.5 were generated during cooking.

Data were collected in 70 detached houses built in 2011-2017 in compliance with the mechanical ventilation requirements of California's building energy efficiency standards. Each home was monitored for a 1-week period with windows closed and the central mechanical ventilation system operating. Pollutant measurements included time-resolved fine particulate matter (PM2.5 ) indoors and outdoors and formaldehyde and carbon dioxide (CO2 ) indoors. Time-integrated measurements were made for formaldehyde, NO2 , and nitrogen oxides (NOX ) indoors and outdoors. Operation of the cooktop, range hood, and other exhaust fans was continuously recorded during the monitoring period. Onetime diagnostic measurements included mechanical airflows and envelope and duct system air leakage. All homes met or were very close to meeting the ventilation requirements. On average, the dwelling unit ventilation fan moved 50% more airflow than the minimum requirement. Pollutant concentrations were similar to or lower than those reported in a 2006-2007 study of California new homes built in 2002-2005. Mean and median indoor concentrations were lower by 44% and 38% for formaldehyde and 44% and 54% for PM2.5 . Ventilation fans were operating in only 26% of homes when first visited, and the control switches in many homes did not have informative labels as required by building standards.

This paper reviews empirical data from evaluations of the influence of residential energy efficiency retrofits on indoor environmental quality conditions and self-reported thermal comfort and health. Data were extracted from 36 studies described in 44 papers plus two reports. Nearly all reviewed studies were performed in Europe or United States. Most studies evaluated retrofits of homes with low-income occupants. Indoor radon and formaldehyde concentrations tended to increase after retrofits that did not add whole-house mechanical ventilation. Study-average indoor concentrations of nitrogen dioxide and volatile organic compounds other than formaldehyde increased and decreased with approximately equal frequency. Average indoor temperatures during winter typically increased after retrofits, usually by less than 1.5 °C. Dampness and mold, usually based on occupant's reports, almost always decreased after retrofits. Subjectively reported thermal comfort, thermal discomfort, non-asthma respiratory symptoms, general health, and mental health nearly always improved after retrofits. For asthma symptoms, the evidence of improvement slightly outweighed the evidence of worsening. There was insufficient evidence to determine whether changes in thermal comfort and health outcomes varied depending on the type of energy efficiency retrofit. The published research has numerous limitations including a lack of data from retrofits in warm-humid climates and minimal data on changes in objective health outcomes. Suggestions for future research are provided.

Cognitive decline remains an unaddressed problem for the elderly. We show that myelination is highly active in young mice and greatly inhibited in aged mice, coinciding with spatial memory deficits. Inhibiting myelination by deletion of Olig2 in oligodendrocyte precursor cells impairs spatial memory in young mice, while enhancing myelination by deleting the muscarinic acetylcholine receptor 1 in oligodendrocyte precursor cells, or promoting oligodendroglial differentiation and myelination via clemastine treatment, rescues spatial memory decline during aging.

Multiple sclerosis is a chronic inflammatory disease characterized by demyelination in the central nervous system. In this issue of Immunity, Werneberg et al. report a striking loss of synapses driven by excessive microglial pruning early in demyelinating disease, which can be rescued by inhibiting the complement component C3.

Previous research has shown that under-ventilation of classrooms is common and negatively impacts student health and learning. To advance understanding of contributing factors, this study visited 104 classrooms from 11 schools that had recently been retrofitted with new heating, ventilation, and air-conditioning (HVAC) units. CO2 concentration, room and supply air temperature and relative humidity, and door opening were measured for four weeks in each classroom. Field inspections identified HVAC equipment, fan control, and/or filter maintenance problems in 51% of the studied classrooms. Across 94 classrooms with valid data, average CO2 concentrations measured during school hours had a mean of 895 ppm and a standard deviation (SD) of 263 ppm. Ventilation rates (VRs), estimated using the daily maximum 15-min CO2 in each classroom, had a mean of 5.2 L/s-person and a SD of 2.0 L/s-person across 94 classrooms. Classrooms with economizers, with or without demand control ventilation (DCV), tended to have lower mean CO2. Improperly selected equipment, lack of commissioning, incorrect fan control settings and maintenance issues (heavily loaded filters) were all associated with under-ventilation in classrooms. Many classrooms in this sample were frequently too warm to support learning. There were 23 out of 103 classrooms that had indoor air temperature above 25.6 °C for more than 20% of the school hours. Better oversight on HVAC system installation and commissioning are needed to ensure adequate classroom ventilation. Periodic testing of ventilation systems and/or continuous real-time CO2 monitoring (either as stand-alone monitors or incorporated into thermostats) is recommended to detect and correct ventilation problems.

In the central nervous system (CNS), oligodendrocytes myelinate multiple axons; in the peripheral nervous system (PNS), Schwann cells (SCs) myelinate a single axon. Why are the myelinating potentials of these glia so fundamentally different? Here, we find that loss of Fbxw7, an E3 ubiquitin ligase component, enhances the myelinating potential of SCs. Fbxw7 mutant SCs make thicker myelin sheaths and sometimes appear to myelinate multiple axons in a fashion reminiscent of oligodendrocytes. Several Fbxw7 mutant phenotypes are due to dysregulation of mTOR; however, the remarkable ability of mutant SCs to ensheathe multiple axons is independent of mTOR signaling. This indicates distinct roles for Fbxw7 in SC biology including modes of axon interactions previously thought to fundamentally distinguish myelinating SCs from oligodendrocytes. Our data reveal unexpected plasticity in the myelinating potential of SCs, which may have important implications for our understanding of both PNS and CNS myelination and myelin repair.