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Mutation of the RB-1 and p53 tumor suppressors is associated with the development of human osteosarcoma. With the goal of generating a mouse model of this disease, we used conditional and transgenic mouse strains to inactivate Rb and/or p53 specifically in osteoblast precursors. The resulting Rb;p53 double mutant (DKO) animals are viable but develop early onset osteosarcomas with complete penetrance. These tumors display many of the characteristics of human osteosarcomas, including being highly metastatic. We established cell lines from the DKO osteosarcomas to further investigate their properties. These immortalized cell lines are highly proliferative and they retain their tumorigenic potential, as judged by their ability to form metastatic tumors in immunocompromised mice. Moreover, they can be induced to differentiate and, depending on the inductive signal, will adopt either the osteogenic or adipogenic fate. Consistent with this multipotency, a significant portion of these tumor cells express Sca-1, a marker that is typically associated with stem cells/uncommitted progenitors. By assaying sorted cells in transplant assays, we demonstrate that the tumorigenicity of the osteosarcoma cell lines correlates with the presence of the Sca-1 marker. Finally, we show that loss of Rb and p53 in Sca-1-positive mesenchymal stem/progenitor cells is sufficient to yield transformed cells that can initiate osteosarcoma formation in vivo.

The life altering nature of major limb amputations may be further complicated by neuroma formation in up to 60% of the estimated 2 million major limb amputees in the United States. This can be a source of pain and functional limitation of the residual limb. Pain associated with neuromas may limit prosthetic limb use, require reoperation, lead to opioid dependence, and dramatically reduce quality of life. A number of management options have been described including excision alone, excision with repair, excision with transposition, and targeted muscle reinnervation. Targeted muscle reinnervation has been shown to reduce phantom limb and neuroma pain for patients with upper and lower extremity amputations. It may be performed at the time of initial amputation to prevent pain development or secondarily for the treatment of established pain. Encouraging outcomes have been reported, and targeted muscle reinnervation is emerging as a leading surgical technique for pain prevention in patients undergoing major limb amputations and pain management in patients with pre-existing amputations.

We report our experience with next-generation incisional negative pressure wound therapy (iNPWT) applied after major limb amputation or amputation revision. In this high-risk patient population, the need for reliable post-operative soft tissue management is imperative. In both cases reported, healing was uncomplicated. Using the next generation iNPWT in this unique way optimizes the post-operative residual limb by improved incision healing, residual limb edema reduction, and reduced risk of surgical site infection (SSI). This is the first case report of its kind reporting a novel use of next-generation iNPWT, and it demonstrates a need to examine this particular use further.

The retinoblastoma tumor-suppressor protein, pRb, is a member of the pocket protein family that includes p107 and p130. These proteins have well-defined roles in regulating entry into and exit from the cell cycle and also have cell cycle-independent roles in facilitating differentiation. Here we investigate the overlap between pocket protein's function during embryonic development by using conditional mutant alleles to generate Rb;p107 double-mutant embryos (DKOs) that develop in the absence of placental defects. These DKOs die between e13.5 and e14.5, much earlier than either the conditional Rb or the germline p107 single mutants, which survive to birth or are largely viable, respectively. Analyses of the e13.5 DKOs shows that p107 mutation exacerbates the phenotypes resulting from pRb loss in the central nervous system and lens, but not in the peripheral nervous system. In addition, these embryos exhibit novel phenotypes, including increased proliferation of blood vessel endothelial cells, and heart defects, including double-outlet right ventricle (DORV). The DORV is caused, at least in part, by a defect in blood vessel endothelial cells and/or heart mesenchymal cells. These findings demonstrate novel, overlapping functions for pRb and p107 in numerous murine tissues.

Prior research has indicated that healthcare personnel (HCP) who work in areas where Mycobacterium tuberculosis poses an occupational hazard are at high risk of tuberculin skin test (TST) positivity and subsequent conversion to active tuberculosis (TB). U.S. medical laboratory microbiologists confront similar hazards but have not been studied outside of the HCP aggregate. The purpose of this study was to fill this gap by examining the relationships between the predictor variables of self-reported history of bacille Calmette-Guérin (BCG) immunization, place of birth, and years of laboratory experience and the outcomes of self-reported lifetime TST positivity, preventive treatment noninitiation, and barriers to treatment adherence for this subgroup. This quantitative, cross-sectional study was guided by the epidemiologic triad model. A researcher-designed self-administered questionnaire including Part A of the Brief Medication Questionnaire was mailed to 4,335 U.S. microbiologist members of the American Society for Clinical Pathology. From the 1,628 eligible respondents, results showed that prevalence of positive TSTs (17.0%) and treatment noninitiation (9.8%) was low. Multivariate analysis identified BCG and foreign birth, as well as age, nonoccupational exposure, history of TB, work in mycobacteriology, and work outside of microbiology as predictors of a positive TST; foreign birth was a predictor of treatment noninitiation. Additional research is needed to identify other laboratorian groups at increased risk for developing TB. These results enhance positive social change by helping to inform recommendations in the global fight to stop the spread of TB, as well as improve allocation of resources among this specific group of HCP.

Understanding mechanisms of pathogenesis and protection in human tuberculosis (TB) remain major global health challenges. While organized granulomas have long been the focus of TB research, growing evidence for asymptomatic transmission highlights the need to study earlier disease stages, particularly TB pneumonia, which remains underexplored. Defining the alveolar immune niche that governs bacillary expansion before granuloma formation is essential for interrupting transmission. Here, we integrate spatial transcriptomics, single cell RNA sequencing, and high resolution imaging of human lung biopsies to map early TB pneumonia and compare with adjacent granulomas within the same tissues. Pneumonic alveolar spaces were dominated by TREM2-associated macrophages, characterized by sparse T cell infiltration, minimal antimicrobial gene expression, and abundant antigens and transcripts. In contrast, granuloma cores were enriched for antimicrobial pathways, were surrounded by multiple cell types that walled off infection, and contained comparatively fewer bacterial markers. Our findings identify TREM2 positive 'foamy' macrophages as a key permissive alveolar niche for survival and growth. These cells represent an attractive target for early intervention to restrict infection and limit transmission. Early TB pneumonia defines an alveolar niche that fosters bacterial persistence and transmission before granuloma formation.

Tuberculosis (TB) remains a major global health challenge. While organized granulomas have long been the focus of TB pathogenesis research, the early development of TB pneumonia typically preceding granuloma formation has been underexplored. Using spatial transcriptomics, high-resolution proteomics, and scRNA-seq on human pulmonary TB lesions, we reveal a striking compartmentalization of immune responses between early pneumonia and mature granulomas. The immunologic composition of granulomas was distinct from the pneumonia; granulomas are enriched for antimicrobial gene expression in both macrophages and T cells and show reduced bacterial antigen burden. In contrast, TREM2-expressing foamy macrophages are the predominant cell type occupying alveolar spaces in TB pneumonia with T cells infrequent. These TREM2⁺ macrophages exhibit a lipid-associated gene program, accumulate lipid droplets, and harbor Mycobacterium tuberculosis antigens and mRNA corresponding to increased bacterial viability in vitro. We further show that the M. tuberculosis virulence lipids, PDIM and mycolic acids, potently induce and activate TREM2 signaling in TREM2-expressing macrophages, promoting an intracellular environment permissive for bacterial growth. These findings establish TREM2⁺ macrophages as an early niche for M. tuberculosis survival and implicate TB pneumonia as a critical stage in disease transmission. Targeting this foamy macrophage population may offer opportunities to interrupt early TB progression and transmission.Tuberculosis (TB) remains a major global health challenge. While organized granulomas have long been the focus of TB pathogenesis research, the early development of TB pneumonia typically preceding granuloma formation has been underexplored. Using spatial transcriptomics, high-resolution proteomics, and scRNA-seq on human pulmonary TB lesions, we reveal a striking compartmentalization of immune responses between early pneumonia and mature granulomas. The immunologic composition of granulomas was distinct from the pneumonia; granulomas are enriched for antimicrobial gene expression in both macrophages and T cells and show reduced bacterial antigen burden. In contrast, TREM2-expressing foamy macrophages are the predominant cell type occupying alveolar spaces in TB pneumonia with T cells infrequent. These TREM2⁺ macrophages exhibit a lipid-associated gene program, accumulate lipid droplets, and harbor Mycobacterium tuberculosis antigens and mRNA corresponding to increased bacterial viability in vitro. We further show that the M. tuberculosis virulence lipids, PDIM and mycolic acids, potently induce and activate TREM2 signaling in TREM2-expressing macrophages, promoting an intracellular environment permissive for bacterial growth. These findings establish TREM2⁺ macrophages as an early niche for M. tuberculosis survival and implicate TB pneumonia as a critical stage in disease transmission. Targeting this foamy macrophage population may offer opportunities to interrupt early TB progression and transmission.

Practices rooted in social-emotional learning This spring, artistically designed lists of \"rules\" for classroom video meetings emerged and circulated around social media and popular teaching resource sites including rules such as finding a quiet place, free from distraction; staying on task; keeping the webcam on to promote focus; and refraining from chewing gum, eating, or drinking in front of the camera. Though it is easy to copy and share a list of rules constructed for the \"new\" world of teaching/learning online, there is power in teachers building bridges between/across face-to-face and online spaces, highlighting the contextual, relational aspects of learning that have always been central to working with students in schools. In our synchronous video sessions, we cotaught and worked to nurture a space where students could continue building relationships with us and their grade-level peers, as well as fostering relationships across grade levels through multiage book clubs and schoolwide read-alouds.

Research to date on the native versus non-native English speaker teacher (NEST versus non-NEST) debate has primarily focused on teacher self-perception and performance. A neglected, but essential, viewpoint on this issue comes from English as a second language (ESL) students themselves. This study investigated preferences of adults, specifically immigrant and refugee learners, for NESTs or non-NESTs. A 34-item, 5-point Likert attitudinal survey was given to 102 students (52 immigrants, 50 refugees) enrolled in ESL programs in a large metropolitan area in Texas. After responding to the survey, 32 students volunteered for group interviews to further explain their preferences. Results indicated that adult ESL students have a general preference for NESTs over non-NESTs, but have stronger preferences for NESTs in teaching specific skill areas such as pronunciation and writing. There was not a significant difference between immigrants' and refugees' general preferences for NESTs over non-NESTs based on immigration status.

The role of implicit theories in standard-setting judgments was the focus of this study. In the first phase, behavioral descriptors of a minimally competent police recruit were gathered from 31 experts (experienced police) and 25 nonexperts (public sector managers) and used to construct an implicit theory ratings questionnaire. In the second phase, 196 experts and 195 nonexperts were assigned to experimental and control groups and completed the questionnaire in pretest and posttest conditions. Between pretest and posttest administrations, experimental groups also completed a reasoning ability test used in police recruitment and participated in an Angoff standard-setting exercise to determine a cutoff score for the test. Data from both phases revealed shared and unique conceptions of minimal competence held by experts and nonexperts. Exploratory factor analyses and reliability analyses of the implicit theory questionnaire on half-samples of the expert and nonexpert groups (calibration samples) suggested a four-factor structure of the implicit theories held by experts comprising (i) general policing skills; (ii) self-discipline; (iii) civic-mindedness; and (iv) policing values factors and a three-factor structure for nonexperts comprising (i) investigative skills; (ii) personal qualities; and (iii) job requirements. These hypothetical structures were then tested on the remaining half-samples (validation samples) using confirmatory factor analyses. however, the results were inconclusive. A comparison of the factor structures across expert and nonexpert groups using a LISREL hierarchical multi-sample approach revealed that the groups did not share the four-factor structure proposed for experts. Cutoff scores were also compared with experts setting higher standards on the reasoning ability test than nonexperts $(M\\sb{\\rm experts}=50.27$; $M\\sb{\\rm nonexp.}=45.53$; $t(189)=3.53,\\ p<.01).$ Multiple and bivariate regressions of standards on factor scores revealed that, overall, the implicit theory factors accounted for a significant proportion of variance in the standards set $(R=.34,\\ p<.05$ for experts; $R=.33,\\ p<.05$ for nonexperts). Finally, a comparison of pretest and posttest factor structures showed that, contrary to expectations, the implicit theories of both groups were relatively unaffected by participation in the standard-setting exercise. Theoretical and statistical limitations of the study together with recommendations for future research were also presented.