Early expression of mature αß TCR in CD4-CD8- T cell progenitors enables MHC to drive development of T-ALL bearing NOTCH mutations.

During normal T cell development in mouse and human, a low-frequency population of immature CD4-CD8- double-negative (DN) thymocytes expresses early, mature αß T cell antigen receptor (TCR). We report that these early αß TCR+ DN (EADN) cells are DN3b-DN4 stage and require CD3δ but not major histocompatibility complex (MHC) for their generation/detection. When MHC - is present, however, EADN cells can respond to it, displaying a degree of coreceptor-independent MHC reactivity not typical of mature, conventional αß T cells. We found these data to be connected with observations that EADN cells were susceptible to T cell acute lymphoblastic leukemia (T-ALL) transformation in both humans and mice. Using the OT-1 TCR transgenic system to model EADN-stage αß TCR expression, we found that EADN leukemogenesis required MHC to induce development of T-ALL bearing NOTCH1 mutations. This leukemia-driving MHC requirement could be lost, however, upon passaging the tumors in vivo, even when matching MHC was continuously present in recipient animals and on the tumor cells themselves. These data demonstrate that MHC:TCR signaling can be required to initiate a cancer phenotype from an understudied developmental state that appears to be represented in the mouse and human disease spectrum.

Disseminating early interventions for disaster mental health response using the ECHO model.

Extension for Community Healthcare Outcomes (ECHO)-based telementoring was evaluated for disseminating early disaster interventions, Psychological First Aid (PFA) and Skills for Psychological Recovery (SPR), to school professionals throughout rural, disaster-affected communities further affected by COVID-19. PFA and SPR complemented their Multitiered System of Support: PFA complemented tier 1 (universal) and SPR tier 2 (targeted) prevention. We evaluated the outcomes of a pretraining webinar (164 participants, January 2021) and four-part PFA training (84 participants, June 2021) and SPR training (59 participants, July 2021) across five levels of Moore's continuing medical education evaluation framework: (1) participation, (2) satisfaction, (3) learning, (4) competence, and (5) performance, using pre-, post-, and 1-month follow-up surveys. Positive training outcomes were observed across all five levels, with high participation and satisfaction throughout, and high use at the 1-month follow-up. ECHO-based telementoring may successfully engage and train community providers in these underused early disaster response models. Recommendations regarding training format and using evaluation to improve training are provided.

Community Health Workers: Bridge to Pediatric Mental Health Equity.

We currently face a national crisis1 in youth mental health and well-being and significant child behavioral health inequities. There is a growing recognition among health care institutions, policymakers, researchers, and communities that major health problems of our time, including this crisis, must be confronted by addressing the underlying "causes of the causes,"2 or social determinants of health. Social determinants of health3 are defined by the US Centers for Disease Control and Prevention as the conditions in which people live, learn, work, play, worship, and age and highlight the role that power and privilege occupy in shaping societal access to these resources. Social determinants of mental health (SDoMH) encompass the same conditions of social determinants of health, with the addition of the stigma often associated with mental health and substance use disorders. SDoMH focus on the social/environmental factors that place certain groups at increased risk for mental health concerns and worsening outcomes for individuals who already have mental health concerns.4 Addressing SDoMH is a key strategy to toward Healthy People 2030 goals and "the attainment of the highest level of health for all people."5.

Slow angled-descent forepaw grasping (SLAG): an innate behavioral task for identification of individual experimental mice possessing functional vision.

BACKGROUND: There is significant interest in the generation of improved assays to clearly identify experimental mice possessing functional vision, a property that could qualify mice for inclusion in behavioral and neuroscience studies. Widely employed current methods rely on mouse responses to visual cues in assays of reflexes, depth perception, or cognitive memory. However, commonly assessed mouse reflexes can sometimes be ambiguous in their expression, while depth perception assays are sometimes confounded by variation in anxiety responses and exploratory conduct. Furthermore, in situations where experimental groups vary in their cognitive memory capacity, memory assays may not be ideal for assessing differences in vision. RESULTS: We have optimized a non-invasive behavioral assay that relies on an untrained, innate response to identify individual experimental mice possessing functional vision: slow angled-descent forepaw grasping (SLAG). First, we verified that SLAG performance depends on vision and not olfaction. Next, all members of an age-ranged cohort of 158 C57BL/6 mice (57 wild-type, 101 knockout, age range 44-241 days) were assessed for functional vision using the SLAG test without training or conditioning. Subjecting the population to a second innate behavioral test, Dark Chamber preference, corroborated that the functional vision assessment of SLAG was valid. CONCLUSIONS: We propose that the SLAG assay is immediately useful to quickly and clearly identify experimental mice possessing functional vision. SLAG is based on a behavioral readout with a significant innate component with no requirement for training. This will facilitate the selection of mice of known sighted status in vision-dependent experiments that focus on other types of behavior, neuroscience, and/or cognitive memory.

Leveraging community health workers in extending pediatric telebehavioral health care in rural communities: Evaluation design and methods.

OBJECTIVE: The pandemic exacerbated and intensified pediatric behavioral health and access needs in rural and underserved areas due to long-standing workforce shortages, lack of resources, and multigenerational poverty and trauma. Kansas is a predominantly rural and frontier state with 94% of counties designated as mental health professional shortage areas. INNOVATION: The Telehealth ROCKS (THR) program is among the first of its kind to increase the behavioral health workforce capacity by integrating trained school-based community health workers (CHWs) directly into rural communities. CHWs facilitate the coordination of behavioral health appointments and access to social determinants of health needs. METHODS AND RESULTS: We plan to assess the implementation, clinical outcomes, quality of care, and access to care through a mixed-methods design to evaluate the process and impact of expanding the rural behavioral health workforce via CHWs. Preliminary program data suggest CHWs have supported over 90 students/families around social determinants of health in the first 6 months. CONCLUSION: The THR program aims to bring childserving systems of care together, cultivate relationships with rural communities, empower and increase workforce capacity in health care and education, and build trust to enhance acceptance and thus program sustainability. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Oncolytic Urabe mumps virus: A promising virotherapy for triple-negative breast cancer.

Historically, the clinical utility of oncolytic virotherapy as a treatment for a wide range of cancer types was first demonstrated by three pilot human clinical trials conducted in Japan in the 1970s and 1980s using a wild-type Urabe mumps virus (MuV) clinical isolate. Using a sample of the actual original oncolytic Urabe MuV clinical trial virus stock (MuV-U-Japan) used in these Japanese clinical trials, we found that MuV-U-Japan consisted of a wide variety of very closely related Urabe MuVs that differed by an average of only three amino acids. Two MuV-U-Japan isolates, MuV-UA and MuV-UC, potently killed a panel of established human breast cancer cell lines in vitro, significantly extended survival of nude mice with human triple-negative breast cancer (TNBC) MDA-MB-231 tumor xenografts in vivo, and demonstrated significant killing activity against breast cancer patient-derived xenograft (PDX) cell lines grown as 3D organoids, including PDXs from patients resistant to anthracycline- and taxane-based chemotherapy. We also report success in developing a large-scale MuV-U production and purification process suitable for supporting Investigational New Drug applications for clinical trials. This study demonstrates the suitability of the MuV-UC virus for translation to modern clinical trials for treating patients with TNBC.

The early proximal αß TCR signalosome specifies thymic selection outcome through a quantitative protein interaction network.

During αß T cell development, T cell antigen receptor (TCR) engagement transduces biochemical signals through a protein-protein interaction (PPI) network that dictates dichotomous cell fate decisions. It remains unclear how signal specificity is communicated, instructing either positive selection to advance cell differentiation or death by negative selection. Early signal discrimination might occur by PPI signatures differing qualitatively (customized, unique PPI combinations for each signal), quantitatively (graded amounts of a single PPI series), or kinetically (speed of PPI pathway progression). Using a novel PPI network analysis, we found that early TCR-proximal signals distinguishing positive from negative selection appeared to be primarily quantitative in nature. Furthermore, the signal intensity of this PPI network was used to find an antigen dose that caused a classic negative selection ligand to induce positive selection of conventional αß T cells, suggesting that the quantity of TCR triggering was sufficient to program selection outcome. Because previous work had suggested that positive selection might involve a qualitatively unique signal through CD3δ, we reexamined the block in positive selection observed in CD3δ0 mice. We found that CD3δ0 thymocytes were inhibited but capable of signaling positive selection, generating low numbers of MHC-dependent αß T cells that expressed diverse TCR repertoires and participated in immune responses against infection. We conclude that the major role for CD3δ in positive selection is to quantitatively boost the signal for maximal generation of αß T cells. Together, these data indicate that a quantitative network signaling mechanism through the early proximal TCR signalosome determines thymic selection outcome.

Characterization of the dust/smoke aerosol that settled east of the World Trade Center (WTC) in lower Manhattan after the collapse of the WTC 11 September 2001.

The explosion and collapse of the World Trade Center (WTC) was a catastrophic event that produced an aerosol plume impacting many workers, residents, and commuters during the first few days after 11 September 2001. Three bulk samples of the total settled dust and smoke were collected at weather-protected locations east of the WTC on 16 and 17 September 2001; these samples are representative of the generated material that settled immediately after the explosion and fire and the concurrent collapse of the two structures. We analyzed each sample, not differentiated by particle size, for inorganic and organic composition. In the inorganic analyses, we identified metals, radionuclides, ionic species, asbestos, and inorganic species. In the organic analyses, we identified polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls, polychlorinated dibenzodioxins, polychlorinated dibenzofurans, pesticides, phthalate esters, brominated diphenyl ethers, and other hydrocarbons. Each sample had a basic pH. Asbestos levels ranged from 0.8% to 3.0% of the mass, the PAHs were > 0.1% of the mass, and lead ranged from 101 to 625 microg/g. The content and distribution of material was indicative of a complex mixture of building debris and combustion products in the resulting plume. These three samples were composed primarily of construction materials, soot, paint (leaded and unleaded), and glass fibers (mineral wool and fiberglass). Levels of hydrocarbons indicated unburned or partially burned jet fuel, plastic, cellulose, and other materials that were ignited by the fire. In morphologic analyses we found that a majority of the mass was fibrous and composed of many types of fibers (e.g., mineral wool, fiberglass, asbestos, wood, paper, and cotton). The particles were separated into size classifications by gravimetric and aerodynamic methods. Material < 2.5 microm in aerodynamic diameter was 0.88-1.98% of the total mass. The largest mass concentrations were > 53 microm in diameter. The results obtained from these samples can be used to understand the contact and types of exposures to this unprecedented complex mixture experienced by the surviving residents, commuters, and rescue workers directly affected by the plume from 11 to 12 September and the evaluations of any acute or long-term health effects from resuspendable dust and smoke to the residents, commuters, and local workers, as well as from the materials released after 11 September until the fires were extinguished. Further, these results support the need to have the interior of residences, buildings, and their respective HVAC systems professionally cleaned to reduce long-term residential risks before rehabitation.

A co-housing strategy to improve fecundity of mice in timed matings.

Timed matings of mice are often carried out to obtain offspring of a precise age when required for a study. Timed matings involve housing male and female mice together for a limited time period, typically overnight. A limitation of this practice is that many mouse pairs fail to mate during the brief co-housing period. The authors co-housed each breeding pair in the same cage but separated by a transparent partition for 3 d before carrying out timed matings. This co-housing strategy resulted in increased copulation during the timed mating period and also significantly increased the average number of pups produced per breeding pair. The authors suggest that co-housing likely permits male urine-borne pheromones to induce female estrus and also enables the expression of male and female mating behaviors.

Measurement of drinking water contaminants by solid phase microextraction initially quantified in source water samples by the USGS.

Two adsorbent solid phase microextraction (SPME) fibers, 70 microm Carbowax divinylbenzene (CW/DVB) and 65 microm polydimethylsiloxane divinylbenzene (PDMS/DVB), were selected for the analysis of several target analytes (phenols, phosphates, phthalates, polycyclic aromatic hydrocarbons, and chlorinated pesticides) identified by the USGS in surface waters. Detection limits for standards ranged from 0.1 to 1 ng/mL for the CW/ DVB fiber and 0.1 to 2 ng/mL for the PDMS/DVB fiber for 20 of the analytes. The remaining analytes were not extracted because their polarity precluded their partition to the solid phase of the SPMEfiber. Groundwater and treated water samples collected from wells in northern New Jersey were then sampled for the USGS analytes by the SPME method as well as a modified version of EPA 525.5 using C-18 bonded solid phase extraction columns. Nine of the USGS analytes-bisphenol A, bis(2-ethylhexyl) phthalate, butylated hydroxytoluene, butlyated hydroxyanisole, diethyltoulamide, diethyl phthalate, bis(2-ethylhexyl) adipate, 1,4-dichlorobenzene, and triphenyl phosphate-were detected in groundwater samples using the CW/ DVB fiber.

Potential sources of background contaminants in solid phase extraction and microextraction.

A study to identify the sources of background contamination from SPE, using a C-18 sorbent, and solid-phase microextraction (SPME), using a 70 microm carbowax/divinylbenzene (CW/DVB) fiber, was carried out. To determine the source of contamination, each material used in the procedure was isolated and examined for their contribution. The solid-phase column components examined were: sorbent material and frits, column housings and each solvent used to elute analytes off the column. The components examined in the SPME procedure were: SPME fiber, SPME vials, water (HPLC grade), and salt (sodium chloride) used to increase the ionic strength. The majority of the background contaminants from SPE were found to be from the SPE sorbent material and frits. The class of contaminants extracted during a blank extraction were phthalates and other plasticizers used during the manufacturing process. All had blank levels corresponding to measured concentrations below 2 ng/ mL, except for undecane, which had a concentration of 5.4 ng/mL. The most prevalent contaminants in the SPME blank procedure are 1,9-nonanediol, a mixture of phthalates and highly bis-substituted phenols. All the concentrations were below 2 ng/mL, with the exception of bis (2-ethylhexyl) phthalate, which had concentrations ranging from 5 to 20 ng/mL.