The effects of school reform under NCLB waivers: Evidence from focus schools in Kentucky.

Under waivers to the No Child Left Behind (NCLB) Act, the federal government required states to identify schools where targeted subgroups of students have the lowest achievement and to implement reforms in these “Focus Schools.” In this study, we examine the Focus School reforms in the state of Kentucky. The reforms in this state are uniquely interesting for several reasons. One is that the state developed unusually explicit guidance for Focus Schools centered on a comprehensive school-planning process. Second, the state identified Focus Schools using a “super subgroup” measure that combined traditionally low-performing subgroups into an umbrella group. This design feature may have catalyzed broader whole-school reforms and attenuated the incentives to target reform efforts narrowly. Using regression discontinuity designs, we find that these reforms led to substantial improvements in school performance, raising math achievement by 17 percent and reading achievement by 9 percent

Characterization of Caenorhabditis Elegans F07A5.4, Human Ortholog of Olfactomedin 1

Accurate control of nervous system development is critical for normal brain patterning, and defects in this process can lead to neurological disorders such as schizophrenia and Autism Spectrum Disorder. The transcription factor neurogenin is necessary for the development of neural subtypes and is deeply conserved across species. However, the transcriptional targets of neurogenin are poorly understood, creating an imperative for further study. We have used the nematode Caenorhabditis elegans as a model to better understand ngn-1/neurogenin function. Previous work from our lab revealed that ngn-1 plays a role in nerve ring architecture, and neural cell fate specification. In addition, ngn-1 mutants have an array of neuromuscular defects such as sluggish, uncoordinated movement and precocious egg laying. To help identify downstream targets of ngn-1, we performed a comparative transcriptome on messenger RNA isolated from wild type and ngn-1 mutants. We discovered that F07A5.4 transcript levels are significantly lower in ngn-1 mutants. F07A5.4 is an ortholog of Human olfactomedin (Olfm1), which is a secreted glycoprotein in the conserved olfactomedin family (OLF). In rodents, OLF domain proteins play important roles in neurogenesis, neural crest formation, and cell adhesion. We hypothesize that F07A5.4 is required for establishing normal nervous system architecture in the worm. To investigate this, we have identified alleles from the Million Mutation Project that mutate conserved amino acids in the F07A5.4 protein sequence. This project aims to characterize the phenotype of those alleles and to establish the normal function of F07A5.4 in C. elegans nervous system development

Race and gender-based perceptions of older septuagenarian adults

OBJECTIVES: Older adults face racism, sexism, and ageism. As the U.S. population ages, it is important to understand how the current population views older adults. METHODS: Participants recruited through Amazon\u27s Mechanical Turk provided perceptions of older Black and White models\u27 photographs. Using mixed-effect models, we assessed interactions between race and gender of participants and models. RESULTS: Among Participants of Color and White participants ( DISCUSSION: Participants had few biases toward older Black and White models, while gender biases favored men

Action of transcription factors in the control of transferrin receptor expression in human brain endothelium

Brain endothelium has a distinctive phenotype, including high expression of transferrin receptor, p-glycoprotein, claudin-5 and occludin. Dermal endothelium expresses lower levels of the transferrin receptor and it is absent from lung endothelium. All three endothelia were screened for transcription factors that bind the transferrin receptor promoter and show different patterns of binding between the endothelia. The transcription factor YY1 has distinct DNA-binding activities in brain endothelium and non-brain endothelium. The target-sites on the transferrin receptor promotor for YY1 lie in close proximity to those of the transcription initiation complex containing TFIID, so the two transcription factors potentially compete or interfere. Notably, the DNA-binding activity of TFIID was the converse of YY1, in different endothelia. YY1 knockdown reduced transferrin receptor expression in brain endothelium, but not in dermal endothelium implying that YY1 is involved in tissue-specific regulation of the transferrin receptor. Moreover a distinct YY1 variant is present in brain endothelium and it associates with Sp3. A model is presented, in which expression from the transferrin receptor gene in endothelium requires the activity of both TFIID and Sp3, but whether the gene is transcribed in different endothelia, is related to the balance between activating and suppressive forms of YY1

A unique subset of glycolytic tumour-propagating cells drives squamous cell carcinoma

Head and neck squamous cell carcinoma (SCC) remains among the most aggressive human cancers. Tumour progression and aggressiveness in SCC are largely driven by tumour-propagating cells (TPCs). Aerobic glycolysis, also known as the Warburg effect, is a characteristic of many cancers; however, whether this adaptation is functionally important in SCC, and at which stage, remains poorly understood. Here, we show that the NAD+-dependent histone deacetylase sirtuin 6 is a robust tumour suppressor in SCC, acting as a modulator of glycolysis in these tumours. Remarkably, rather than a late adaptation, we find enhanced glycolysis specifically in TPCs. More importantly, using single-cell RNA sequencing of TPCs, we identify a subset of TPCs with higher glycolysis and enhanced pentose phosphate pathway and glutathione metabolism, characteristics that are strongly associated with a better antioxidant response. Together, our studies uncover enhanced glycolysis as a main driver in SCC, and, more importantly, identify a subset of TPCs as the cell of origin for the Warburg effect, defining metabolism as a key feature of intra-tumour heterogeneity

Repression of tumor suppressor miR-451 is essential for NOTCH1-induced oncogenesis in T-ALL

miR-451 represses expression of Myc and acts as a tumor suppressor in murine and human T cell acute lymphoblastic leukemia

Hypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function and shuttling of drugs and antibodies

The high selectivity of the human blood-brain barrier (BBB) restricts delivery of many pharmaceuticals and therapeutic antibodies to the central nervous system. Here, we describe an in vitro microfluidic organ-on-a-chip BBB model lined by induced pluripotent stem cell-derived human brain microvascular endothelium interfaced with primary human brain astrocytes and pericytes that recapitulates the high level of barrier function of the in vivo human BBB for at least one week in culture. The endothelium expresses high levels of tight junction proteins and functional efflux pumps, and it displays selective transcytosis of peptides and antibodies previously observed in vivo. Increased barrier functionality was accomplished using a developmentally-inspired induction protocol that includes a period of differentiation under hypoxic conditions. This enhanced BBB Chip may therefore represent a new in vitro tool for development and validation of delivery systems that transport drugs and therapeutic antibodies across the human BBB

Management of patients with advanced prostate cancer—metastatic and/or castration-resistant prostate cancer: report of the Advanced Prostate Cancer Consensus Conference (APCCC) 2022

Background: Innovations in imaging and molecular characterisation together with novel treatment options have improved outcomes in advanced prostate cancer. However, we still lack high-level evidence in many areas relevant to making management decisions in daily clinical practise. The 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) addressed some questions in these areas to supplement guidelines that mostly are based on level 1 evidence. Objective: To present the voting results of the APCCC 2022. Design, setting, and participants: The experts voted on controversial questions where high- level evidence is mostly lacking: locally advanced prostate cancer; biochemical recurrence after local treatment; metastatic hormone-sensitive, non-metastatic, and metastatic castration- resistant prostate cancer; oligometastatic prostate cancer; and managing side effects of hormonal therapy. A panel of 105 international prostate cancer experts voted on the consensus questions. Outcome measurements and statistical analysis: The panel voted on 198 pre-defined questions, which were developed by 117 voting and non-voting panel members prior to the conference following a modified Delphi process. A total of 116 questions on metastatic and/or castration- resistant prostate cancer are discussed in this manuscript. In 2022, the voting was done by a web-based survey because of COVID-19 restrictions. Results and limitations: The voting reflects the expert opinion of these panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results are reported in the supplementary material. We report here on topics in metastatic, hormone-sensitive prostate cancer (mHSPC), non-metastatic, castration-resistant prostate cancer (nmCRPC), metastatic castration-resistant prostate cancer (mCRPC), and oligometastatic and oligoprogressive prostate cancer. Conclusions: These voting results in four specific areas from a panel of experts in advanced prostate cancer can help clinicians and patients navigate controversial areas of management for which high-level evidence is scant or conflicting and can help research funders and policy makers identify information gaps and consider what areas to explore further. However, diagnostic and treatment decisions always have to be individualised based on patient characteristics, including the extent and location of disease, prior treatment(s), co-morbidities, patient preferences, and treatment recommendations and should also incorporate current and emerging clinical evidence and logistic and economic factors. Enrolment in clinical trials is strongly encouraged. Importantly, APCCC 2022 once again identified important gaps where there is non-consensus and that merit evaluation in specifically designed trials. Patient summary: The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with healthcare providers worldwide. At each APCCC, an expert panel votes on pre-defined questions that target the most clinically relevant areas of advanced prostate cancer treatment for which there are gaps in knowledge. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients and their relatives as part of shared and multidisciplinary decision-making. This report focuses on the advanced setting, covering metastatic hormone-sensitive prostate cancer and both non-metastatic and metastatic castration-resistant prostate cancer. Twitter summary: Report of the results of APCCC 2022 for the following topics: mHSPC, nmCRPC, mCRPC, and oligometastatic prostate cancer. Take-home message: At APCCC 2022, clinically important questions in the management of advanced prostate cancer management were identified and discussed, and experts voted on pre-defined consensus questions. The report of the results for metastatic and/or castration- resistant prostate cancer is summarised here