Boston University

Network dysfunction is implicated in numerous diseases and psychiatric disorders, and the hippocampus serves as a common origin for these abnormalities. To test the hypothesis that chronic modulation of neurons and astrocytes induces impairments in cognition, we activated the hM3D(Gq) pathway in CaMKII+ neurons or GFAP+ astrocytes within the ventral hippocampus across 3, 6, and 9 months. CaMKII-hM3Dq activation impaired fear extinction at 3 months and acquisition at 9 months. Both CaMKII-hM3Dq manipulation and aging had differential effects on anxiety and social interaction. GFAP-hM3Dq activation impacted fear memory at 6 and 9 months. GFAP-hM3Dq activation impacted anxiety in the open field only at the earliest time point. CaMKII-hM3Dq activation modified the number of microglia, while GFAP-hM3Dq activation impacted microglial morphological characteristics, but neither affected these measures in astrocytes. Overall, our study elucidates how distinct cell types can modify behavior through network dysfunction, while adding a more direct role for glia in modulating behavior.

Place attachment, as an important emotional and functional bond between people and place, has received extensive attention in the early-21st century. This trend is especially evident in China, where rapid market transitions have fundamentally changed urban neighborhoods. Using a survey of residents in Guangzhou, China, remote sensing imagery, geographic information system (GIS) techniques, and hierarchical linear modeling (HLM), this study investigates the role of physical and social environments in place attachment. Results indicate that commodity housing residents generally do not necessarily have strong place attachment. However, higher quality physical and social environments do contribute to stronger place attachment. Specifically, perceived housing conditions, social ties, sense of security, and lower floor area ratio (FAR) are positively associated with place identity, while perceived housing conditions, perceived neighborhood environment, social ties, lower FAR, and built environment quality are positively associated with place dependence. Social ties are the strongest predictor of place identity while housing conditions are the strongest predictor of place dependence. We conclude that social environments still matter as social and physical environments play different roles in place identity and place dependence. Based on the findings, we advocate that urban (re)development and housing policies should shift the focus from large-scale demolitions to micro-scale dwelling improvements; and in addition to objective measures, subjective evaluation by residents should also be used to evaluate urban (re)development projects.

Filamentous fungi drive carbon and nutrient cycling across our global ecosystems, through its interactions with growing and decaying flora and their constituent microbiomes. The remarkable metabolic diversity, secretion ability, and fiber-like mycelial structure that have evolved in filamentous fungi have been increasingly exploited in commercial operations. The industrial potential of mycelial fermentation ranges from the discovery and bioproduction of enzymes and bioactive compounds, the decarbonization of food and material production, to environmental remediation and enhanced agricultural production. Despite its fundamental impact in ecology and biotechnology, molds and mushrooms have not, to-date, significantly intersected with synthetic biology in ways comparable to other industrial cell factories (e.g. Escherichia coli,Saccharomyces cerevisiae, and Komagataella phaffii). In this review, we summarize a suite of synthetic biology and computational tools for the mining, engineering and optimization of filamentous fungi as a bioproduction chassis. A combination of methods across genetic engineering, mutagenesis, experimental evolution, and computational modeling can be used to address strain development bottlenecks in established and emerging industries. These include slow mycelium growth rate, low production yields, non-optimal growth in alternative feedstocks, and difficulties in downstream purification. In the scope of biomanufacturing, we then detail previous efforts in improving key bottlenecks by targeting protein processing and secretion pathways, hyphae morphogenesis, and transcriptional control. Bringing synthetic biology practices into the hidden world of molds and mushrooms will serve to expand the limited panel of host organisms that allow for commercially-feasible and environmentally-sustainable bioproduction of enzymes, chemicals, therapeutics, foods, and materials of the future.

Model-free continuous control for robot navigation tasks using Deep Reinforcement Learning (DRL) that relies on noisy policies for exploration is sensitive to the density of rewards. In practice, robots are usually deployed in cluttered environments, containing many obstacles and narrow passageways. Designing dense effective rewards is challenging, resulting in exploration issues during training. Such a problem becomes even more serious when tasks are described using temporal logic specifications. This work presents a deep policy gradient algorithm for controlling a robot with unknown dynamics operating in a cluttered environment when the task is specified as a Linear Temporal Logic (LTL) formula. To overcome the environmental challenge of exploration during training, we propose a novel path planning-guided reward scheme by integrating sampling-based methods to effectively complete goal-reaching missions. To facilitate LTL satisfaction, our approach decomposes the LTL mission into sub-goal-reaching tasks that are solved in a distributed manner. Our framework is shown to significantly improve performance (effectiveness, efficiency) and exploration of robots tasked with complex missions in large-scale cluttered environments. A video demonstration can be found on YouTube Channel: https://youtu.be/yMh_NUNWxho</uri

Musical abilities, both in the pitch and temporal dimension, have been shown to be positively associated with phonological awareness and reading abilities in both children and adults. There is increasing evidence that the relationship between music and language relies primarily on the temporal dimension, including both meter and rhythm. It remains unclear to what extent skill level in these temporal aspects of music may uniquely contribute to the prediction of reading outcomes. A longitudinal design was used to test a group-administered musical sequence transcription task (MSTT). This task was designed to preferentially engage sequence processing skills while controlling for fine-grained pitch discrimination and rhythm in terms of temporal grouping. Forty-five children, native speakers of Portuguese (Mage = 7.4 years), completed the MSTT and a cognitive-linguistic protocol that included visual and auditory working memory tasks, as well as phonological awareness and reading tasks in second grade. Participants then completed reading assessments in third and fifth grades. Longitudinal regression models showed that MSTT and phonological awareness had comparable power to predict reading. The MSTT showed an overall classification accuracy for identifying low-achievement readers in Grades 2, 3, and 5 that was analogous to a comprehensive model including core predictors of reading disability. In addition, MSTT was the variable with the highest loading and the most discriminatory indicator of a phonological factor. These findings carry implications for the role of temporal sequence processing in contributing to the relationship between music and language and the potential use of MSTT as a language-independent, time- and cost-effective tool for the early identification of children at risk of reading disability.

Despite high rates of traumatic experiences reported among Hispanic/Latino/a immigrants in the U.S., the effect of post-traumatic stress on parenting stress among Hispanic/Latino/a immigrant parents with young children has been overlooked. The present study tested the direct and indirect relationships of self-reported maternal post-traumatic stress symptoms on parenting stress, and the mediating role of protective factors among Hispanic/Latino/a mothers with young children. Baseline data collected from mothers participating in a community-based child-parent dyadic intervention were analyzed. Measures included the post-traumatic stress disorder (PTSD) Checklist, the Protective Factors Survey, and the Parenting Stress Index-Short Form (PSI). The sample included 80 mothers with a child between ages 0-6 years. About 75% of these mothers were migrants from Central America. A multivariate regression analysis showed that maternal post-traumatic stress symptoms predicted higher levels of PSI, and two protective factors (social support and family functioning/resilience) fully mediated the relationship between maternal post-traumatic stress symptoms and PSI. Higher social support and family functioning/resiliency may have protective effects on Hispanic/Latino/a mothers with post-traumatic stress, leading to lower levels of stress related to parenting. Findings underscore the importance of interventions that enhance access to social support and promote family functioning/resilience for Hispanic/Latino/a immigrant mothers with trauma histories to cope better with parenting stress.

Objective: Temporal lobe epilepsy (TLE) is a progressive disorder mediated by pathological changes in molecular cascades and hippocampal neural circuit remodeling that results in spontaneous seizures and cognitive dysfunction. Targeting these cascades may provide disease-modifying treatments for TLE patients. Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) inhibitors have emerged as potential disease-modifying therapies; a more detailed understanding of JAK/STAT participation in epileptogenic responses is required, however, to increase the therapeutic efficacy and reduce adverse effects associated with global inhibition. Methods: We developed a mouse line in which tamoxifen treatment conditionally abolishes STAT3 signaling from forebrain excitatory neurons (nSTAT3KO). Seizure frequency (continuous in vivo electroencephalography) and memory (contextual fear conditioning and motor learning) were analyzed in wild-type and nSTAT3KO mice after intrahippocampal kainate (IHKA) injection as a model of TLE. Hippocampal RNA was obtained 24 h after IHKA and subjected to deep sequencing. Results: Selective STAT3 KO in excitatory neurons reduced seizure progression and hippocampal memory deficits without reducing the extent of cell death or mossy fiber sprouting induced by IHKA injection. Gene expression was rescued in major networks associated with response to brain injury, neuronal plasticity, and learning and memory. We also provide the first evidence that neuronal STAT3 may directly influence brain inflammation. Interpretation: Inhibiting neuronal STAT3 signaling improved outcomes in an animal model of TLE, prevented progression of seizures and cognitive co-morbidities while rescuing pathogenic changes in gene expression of major networks associated with epileptogenesis. Specifically targeting neuronal STAT3 may be an effective disease-modifying strategy for TLE. This article is protected by copyright. All rights reserved.

Litigation is costly because information is not free. Given that information is costly and perfect information prohibitively costly, courts will occasionally err. Finally, the fact that information is costly implies an unavoidable degree of informational asymmetry between disputants. This paper presents a model of the civil justice system that incorporates these features and probes its implications for compliance with the law, efficiency of law, accuracy in adjudication, trial outcome statistics, and the evolution of legal standards. The model’s claims are applied to and tested against the relevant empirical and legal literature.

Abstract Globally, air pollution is amongst the most significant causes of premature death. Nevertheless, studies on the relationship between fine particulate matter (PM2.5) exposure and blood lipids have typically not been population-based. In a large, community-based sample of residents in Yixing city, we assessed the relationship between short-term outdoor PM2.5 exposure and blood lipid concentrations. Participants who attended the physical examination were enrolled from Yixing People’s hospital from 2015 to 2020. We collected general characteristics of participants, including gender and age, as well as test results of indicators of blood lipids. Data on daily meteorological factors were collected from the National Meteorological Data Sharing Center ( http://data.cma.cn/ ) and air pollutant concentrations were collected from the China Air Quality Online Monitoring and Analysis Platform ( https://www.aqistudy.cn/ ) during this period. We applied generalized additive models to estimate short-term effects of ambient PM2.5 exposure on each measured blood lipid-related indicators and converted these indicators into dichotomous variables (non- hyperlipidemia and hyperlipidemia) to calculate risks of hyperlipidemia associated with PM2.5 exposure. A total of 197,957 participants were included in the analysis with mean age 47.90 years (± SD, 14.28). The increase in PM2.5 was significantly associated with hyperlipidemia (odds ratio (OR) 1.003, 95% CI 1.001–1.004), and it was still significant in subgroups of males and age

Background: There is a need to improve speaker diversity at gastroenterology conferences, but little public data exist to quantify this. In addition, the perception of diverse speakers by conference audiences is not appreciated. We sought to identify time trends in speaker profiles and audience ratings at a national inflammatory bowel diseases conference. Methods: Faculty profiles and audience feedback forms from 2014 to 2020 were reviewed for an annual inflammatory bowel diseases meeting. Speaker demographics including gender, race, and years of experience post-training were collected. Continuing medical education surveys were examined for audience ratings of speakers' knowledge level and teaching ability. Results: Six years of data were collected, including 560 main program faculty and 13 905 total feedback forms. The percentage of female speakers increased from 25% in 2016 to 39% in 2020. All-male panels decreased from 47% in 2014 to 2017 to 11% in 2018 to 2020. Racial diversity of speakers remained unchanged (13% Asian, 5% Hispanic/Latinx, 1% Black). In audience feedback forms, female speakers from all sessions were perceived as having equal knowledge base and teaching ability compared with male speakers. However, speakers with <10 years of experience post-training were viewed as less knowledgeable and with poorer teaching abilities compared with more senior faculty. Conclusions: Gender diversity at inflammatory bowel disease conferences is improving. However, there remain significant gaps, particularly in racial diversity and improving perceptions of early-career speakers. These data should inform program committees for future gastroenterology conferences.

People with chronic illnesses are vulnerable to stress and psychopathology during population-level disasters, as a subset of individuals with disabilities. We aimed to examine the relationships between chronic illness, cumulative and specific stressors, and probable depression, probable anxiety, and post-traumatic stress in an under-resourced urban population in New York City during the COVID-19 pandemic. Using cross-sectional survey data collected in April 2020, we utilized bivariate chi-square analyses and multivariable logistic regression models to estimate differences in and adjusted odds of stressor endorsement and diagnostic prevalence between people with and without chronic illness. We also assessed effect modification of the relationship between stressor exposure and psychopathology by chronic illness status. Compared to people without chronic illness, those who reported having a chronic illness experienced increased odds of probable depression, probable anxiety, and post-traumatic stress. They were also more likely to report high cumulative COVID-19-related stress exposure, death of someone close to them due to coronavirus or COVID-19, family problems, feeling alone, supply shortages, and financial problems. Chronic illness was found to be an effect modifier in the relationship between the death of someone close due to coronavirus or COVID-19 and probable depression and between household job loss and probable anxiety.

The Centers for Medicare and Medicaid Services (CMS) has recently issued a national coverage determination for US Food and Drug Administration (FDA)-approved anti-amyloid monoclonal antibodies (mAbs) for the treatment of Alzheimer's disease (AD) under coverage with evidence development (CED). CED schemes are complex, costly, and challenging, and often fail to achieve intended objectives because of administrative and implementation issues. AD is a heterogeneous, progressive neurodegenerative disorder with complex care pathway that additionally presents scientific challenges related to the choice of study design and methods used in evaluating CED schemes. These challenges are herein discussed. Clinical findings from the US Veterans Affairs healthcare system help inform our discussion of specific challenges to CED-required effectiveness studies in AD.

Fears of immigrants as a threat to public health have a long and sordid history. At the turn of the 20th century, when immigrants made up one-third of the population in crowded American cities, contemporaries blamed high urban mortality rates on the newest arrivals. We evaluate how the implementation of country-specific immigration quotas in the 1920s affected urban health. Cities with larger quota-induced reductions in immigration experienced a persistent decline in mortality rates, driven by a reduction in deaths from infectious diseases. The unfavorable living conditions immigrants endured explains the majority of the effect as quotas reduced residential crowding and mortality declines were largest in cities where immigrants resided in more crowded conditions and where public health resources were stretched thinnest.

Auditory steady-state response (ASSR) has been studied as a potential biomarker for abnormal auditory sensory processing in autism spectrum disorder (ASD), with mixed results. Motivated by prior somatosensory findings of group differences in inter-trial coherence (ITC) between ASD and typically developing (TD) individuals at twice the steady-state stimulation frequency, we examined ASSR at 25 and 50 as well as 43 and 86 Hz in response to 25-Hz and 43-Hz auditory stimuli, respectively, using magnetoencephalography. Data were recorded from 22 ASD and 31 TD children, ages 6–17 years. ITC measures showed prominent ASSRs at the stimulation and double frequencies, without significant group differences. These results do not support ASSR as a robust ASD biomarker of abnormal auditory processing in ASD. Furthermore, the previously observed atypical double-frequency somatosensory response in ASD did not generalize to the auditory modality. Thus, the hypothesis about modality-independent abnormal local connectivity in ASD was not supported.

Background HIV incidence has recently increased among people who inject drugs (PWID) across the United States, with outbreaks occurring in states with long-standing syringe service programs (SSPs) including Massachusetts (MA). Antiretroviral pre-exposure prophylaxis (PrEP) is an evidence-based HIV prevention strategy recommended for PWID, but uptake in this marginalized population is extraordinarily low. Methods We describe the design and procedures for a National Institute on Drug Abuse (NIDA)-funded (R01) randomized controlled trial (RCT) testing the efficacy of “PrEP for Health,” a multicomponent behavioral intervention to increase PrEP uptake, adherence, and persistence among HIV-negative PWID attending SSPs in two areas of the U.S. Northeast that are heavily affected by injection-related HIV transmission. Participants are equally randomized to receive the “PrEP for Health” intervention (involving individually tailored HIV and PrEP education, motivational interviewing, problem-solving skills and planning, and ongoing navigation support) or an enhanced standard of care (eSOC) control condition involving a brief educational video on the utility of PrEP for HIV prevention. Co-primary outcomes are PrEP uptake (using medical/pharmacy records) and adherence (using tenofovir quantification in hair samples); a secondary outcome is PrEP persistence (using medical/pharmacy records) over 12 months. Major assessments occur at baseline, 1-, 3-, 6-, and 12-month follow-up visits. Planned analyses will examine intervention efficacy, specific hypothesized conceptual mediators of the intervention effect (e.g., self-perceived HIV risk; PrEP knowledge, interest in use, motivation, and behavioral skills) and epidemiologically linked moderators (e.g., age; gender; condomless vaginal or anal sex). Discussion Findings from our extensive preliminary research with the study population revealed that a multicomponent, theory-based intervention targeting PrEP knowledge, motivation, self-efficacy, behavioral skills, and structural barriers to PrEP access is urgently needed for PWID who are at risk of HIV acquisition. We also learned that SSPs represent a highly acceptable service setting for delivering such interventions. In this study, we are evaluating the efficacy of the “PrEP for Health” intervention. If efficacious, findings from our implementation evaluation could help guide its dissemination to diverse SSPs and possibly other community-based settings accessed by this population. Trial registration ClinicalTrials.gov number NCT04430257, registered June 12, 2020.

Background: In order to improve quality and efficiency of surgical trials, we assessed protocols complexity and examined whether it influenced the conduct, as measured by the number and types of deviations that occurred during the execution phase. Knowledge of these facts and performance of research team would allow to effectively mitigate the occurrence of deviations. Methods: Thirty-five research protocols were rated according to a previously established complexity scoring model. Statistical analyses were performed to examine associations between protocol complexity, number of protocol/informed consent amendments vs. number/types of protocol deviations; as well as correlations with phase of the study, type of investigational product, personnel changes/experience level were assessed. Results: Assessment of complexity score in Pearson's correlation test with the number of protocol deviations showed weak correlation, suggesting that other factors can influence protocol adherence. There was no correlation observed between number of deviations and type of study by investigational product category. In examining association between protocol deviations and number of subjects enrolled a trend was observed towards increased number of deviations once more subjects have entered the study. The higher number of protocol deviations was associated with increased number of protocol amendments (p = 0.0396), and there was no statistical significance observed between number of deviations and informed consent amendments (p = 0.5083). There was a moderate correlation detected between increased number of protocol deviations and total number of investigators on the study. Conclusion: Protocol adherence can be improved with effective training and retention of research coordinators, investigators and frequent internal auditing to address discrepancies and effectively implement corrective actions. Upfront training of research personnel, with subsequent monitoring of performance metrics throughout the execution phase can reduce the total number of protocol deviations, ensure data integrity and improve quality of research conducted. Engagement of all stakeholders upfront, including clinical site personnel, can help develop well-designed clinical trial protocol, avoid time consuming and costly protocol and informed consent amendments at execution phase and ensure higher quality of research conducted, while allowing to meet objectives of the trial in a more efficient manner.

The COVID-19 pandemic remains a major health concern worldwide, and SARS-CoV-2 is continuously evolving. There is an urgent need to identify new antiviral drugs and develop novel therapeutic strategies. Combined use of newly authorized COVID-19 medicines including molnupiravir, nirmatrelvir and remdesivir, has been actively pursued. Mechanistically, nirmatrelvir inhibits SARS-CoV-2 replication by targeting the viral main protease (Mpro ), a critical enzyme in the processing of the immediately translated coronavirus polyproteins for viral replication. Molnupiravir and remdesivir, on the other hand, inhibit SARS-CoV-2 replication by targeting RNA-dependent RNA-polymerase (RdRp), which is directly responsible for genome replication and production of subgenomic RNAs. Molnupiravir targets RdRp and induces severe viral RNA mutations (genome), commonly referred to as error catastrophe. Remdesivir, in contrast, targets RdRp and causes chain termination and arrests RNA synthesis of the viral genome. In addition, all three medicines undergo extensive metabolism with strong therapeutic significance. Molnupiravir is hydrolytically activated by carboxylesterase-2 (CES2); nirmatrelvir is inactivated by cytochrome P450-based oxidation (e.g., CYP3A4); and remdesivir is hydrolytically activated by CES1 but covalently inhibits CES2. Additionally, remdesivir and nirmatrelvir are oxidized by the same CYP enzymes. The distinct mechanisms of action provide strong rationale for their combined use. On the other hand, these drugs undergo extensive metabolism that determines their therapeutic potential. This review discusses how metabolism pathways and enzymes involved should be carefully considered during their combined use for therapeutic synergy.

Background In this proof-of-concept study we evaluated if monogenic diabetes due to mutations of the HNF-1α gene (HNF1A-MODY) has a distinctive continuous glucose monitoring (CGM) glucotype, in comparison to type 1 diabetes (T1D). Methods Using CGM data from 5 HNF1A-MODY and 115 T1D subjects we calculated multiple glucose metrics, including measures of within- and between-day variability (such as coefficient variation for each hour (CVb_1h). Results The MODY and T1D cohorts had minimum CVb_1h of 11.3 ± 4.4 and 18.0 ± 4.9, respectively (p = 0.02), and maximum CVb_1h of 33.9 ± 5.0 and 50.3 ± 10, respectively (p < 0.001). All HNF1A-MODY subjects had minimum %CVb_1h ≤ 17.3% and maximum %CVb_1h ≤ 37.1%. In contrast, only 12 of 115 T1D subjects had both a minimum and maximum %CVb_1h below these thresholds (p < 0.001). Conclusion HNF1A- MODY is characterized by a low-hourly between-day glucose variability. CGM-derived glucose metrics may have potential applicability for screening for atypical diabetes phenotypes in the T1D population.

We analyze a crossover between ergodic and nonergodic regimes in an interacting spin chain with a dilute density of impurities, defined as spins with a strong local field. The dilute limit allows us to unravel some finite size effects and propose a mechanism for the delocalization of these impurities in the thermodynamic limit. In particular, we show that impurities always relax by exchanging energy with the rest of the chain. The relaxation rate only weakly depends on the impurity density and decays exponentially, up to logarithmic corrections, with the field strength. We connect the relaxation to fast operator spreading and show that the same mechanism destabilizes the recursive construction of local integrals of motion at any impurity density. In the high field limit, impurities appear to be localized, and the system is nonergodic, over a wide range of system sizes. However, this is a transient effect, and the eventual delocalization can be understood in terms of a flowing localization length.