Supporting the Academic Research Needs of Incarcerated Students: Building JSTOR's Offline Solution for Prison Education

Incarcerated students often lack access to the resources and conditions, both physical and digital, that make self-directed research and research skill-building possible. Due to technical constraints – most notably the lack of internet access in most prison environments – few incarcerated students have access to research databases commonly used by students to discover scholarly content that is relevant to their coursework, research projects, and broader learning pursuits. Not only does lack of research experience have an impact on students’ ability to engage with academic work, but it also leaves students without the fundamental information and digital literacy skills that are increasingly essential for future work and continued learning. Since 2007, JSTOR, a digital library of scholarly resources, has been making strides to amend this gap in available scholarly resources and research tools by providing JSTOR access to incarcerated learners. This paper describes the work undertaken by JSTOR Labs, an experimental product development team at JSTOR, to develop an offline index of scholarly resources designed to serve the research needs of incarcerated students. Funded by the Mellon Foundation, this project yielded lessons regarding how to scale access to digital scholarly resources given the changing landscape of technology in prison, and continues to shape JSTOR’s work to help improve higher education in prison and reduce barriers for student research

Factor quinolinone inhibitors disrupt spindles and multiple LSF (TFCP2)-protein interactions in mitosis, including with microtubule-associated proteins

Factor quinolinone inhibitors (FQIs), a first-in-class set of small molecule inhibitors targeted to the transcription factor LSF (TFCP2), exhibit promising cancer chemotherapeutic properties. FQI1, the initial lead compound identified, unexpectedly induced a concentration-dependent delay in mitotic progression. Here, we show that FQI1 can rapidly and reversibly lead to mitotic arrest, even when added directly to mitotic cells, implying that FQI1-mediated mitotic defects are not transcriptionally based. Furthermore, treatment with FQIs resulted in a striking, concentration-dependent diminishment of spindle microtubules, accompanied by a concentration-dependent increase in multi-aster formation. Aberrant γ-tubulin localization was also observed. These phenotypes suggest that perturbation of spindle microtubules is the primary event leading to the mitotic delays upon FQI1 treatment. Previously, FQIs were shown to specifically inhibit not only LSF DNA-binding activity, which requires LSF oligomerization to tetramers, but also other specific LSF-protein interactions. Other transcription factors participate in mitosis through non-transcriptional means, and we recently reported that LSF directly binds α-tubulin and is present in purified cellular tubulin preparations. Consistent with a microtubule role for LSF, here we show that LSF enhanced the rate of tubulin polymerization in vitro, and FQI1 inhibited such polymerization. To probe whether the FQI1-mediated spindle abnormalities could result from inhibition of mitotic LSF-protein interactions, mass spectrometry was performed using as bait an inducible, tagged form of LSF that is biotinylated by endogenous enzymes. The global proteomics analysis yielded expected associations for a transcription factor, notably with RNA processing machinery, but also to nontranscriptional components. In particular, and consistent with spindle disruption due to FQI treatment, mitotic, FQI1-sensitive interactions were identified between the biotinylated LSF and microtubule-associated proteins that regulate spindle assembly, positioning, and dynamics, as well as centrosome-associated proteins. Probing the mitotic LSF interactome using small molecule inhibitors therefore supported a non-transcriptional role for LSF in mediating progression through mitosis.UL1 TR001430 - NCATS NIH HHS; R01 GM078240 - NIGMS NIH HHSPublished versio

Degradation of GSPT1 causes TP53-independent cell death in leukemia whilst sparing normal hematopoietic stem cells

Targeted protein degradation is a rapidly advancing and expanding therapeutic approach. Drugs that degrade GSPT1 via the CRL4CRBN ubiquitin ligase are a new class of cancer therapy in active clinical development with evidence of activity against acute myeloid leukemia in early phase trials. However, other than activation of the integrated stress response, the downstream effects of GSPT1 degradation leading to cell death are largely undefined, and no murine models are available to study these agents. We identified the domains of GSPT1 essential for cell survival and show that GSPT1 degradation leads to impaired translation termination, activation of the integrated stress response pathway, and TP53-independent cell death. CRISPR-Cas9 screens implicated decreased translation initiation as protective to GSPT1 degradation, suggesting that cells with higher levels of translation are more susceptible to GSPT1 degradation. We defined two Crbn amino acids that prevent Gspt1 degradation in mice, generated a knock-in mouse with alteration of these residues, and demonstrated the efficacy of GSPT1-degrading drugs in vivo with relative sparing of numbers and function of long-term hematopoietic stem cells. Our results provide a mechanistic basis for the use of GSPT1 degraders for the treatment of cancer, including TP53-mutant AML

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Gender disparities in cardiovascular care access and delivery in India: Insights from the American college of cardiology\u27s PINNACLE India quality improvement program (PIQIP)

Background: Limited data are available to assess whether access to and quality of cardiovascular disease (CVD) care are comparable among men and women in India. We analyzed data from the American College of Cardiology\u27s PINNACLE (Practice Innovation and Clinical Excellence) India Quality Improvement Program (PIQIP) to evaluate gender disparities in CVD care delivery.Methods and results: Between 2011 and 2015, we collected data on performance measures for patients with coronary artery disease (CAD) (n=14,010), heart failure (HF) (n=11,965) and atrial fibrillation (AF) (n=496) in PIQIP, among 17 participating practices. The total number of women was 31,796 (32.0%). Women had fewer total encounters compared to men during the study interval (mean number of encounters=2.59 vs. 2.82 for women and men, respectively, p≤0.001). Women were significantly younger (48.9years vs. 51.5years, p≤0.01), but had a higher co-morbidity burden compared to men - hypertension (62.0% vs. 45.6%, p≤0.01), diabetes (39.4% vs. 35%, p≤0.01), and hyperlipidemia (3.7% vs. 3.1%, p=0.19). On the contrary, the guideline-directed medication prescriptions were strikingly lower in women with CAD compared to men - aspirin (38% vs. 50.4%, p≤0.001), aspirin or thienopyridine combination (46.9% vs. 57.2%, p≤0.001), and beta-blockers (36.8% vs. 47.8%, p≤0.001). Similarly, among women with ejection fraction ≤40%, the use of guideline-directed medical therapy was significantly lower compared to men for beta-blockers (30.8% vs. 37.0%, p≤0.001), angiotensin-converting enzyme inhibitors (ACE-i) or angiotensin receptor blockers (ARBs) (29.3% vs. 34.9%, p≤0.001), and beta-blockers/ACE-i or ARBs (24.6% vs. 31.0%, p≤0.001). Among patients with atrial fibrillation and CHADS2 score≥2, more women were on oral anticoagulation (19.6% vs. 14.6%, p=0.34), although this was not significantly different, and the overall number of patients with atrial fibrillation was low.Conclusions: Despite a significantly higher co-morbidity burden in women, we found fewer women receiving guideline-directed medical therapy for CVD compared with men. If such disparities are confirmed in the larger Indian population, it is important to find potential causes for, and seek solutions to narrow this gap

Guideline-directed medication use in patients with heart failure with reduced ejection fraction in India: American college of cardiology\u27s PINNACLE India quality improvement program

Little is known about the use of guideline-directed medical therapy (GDMT) in outpatients with heart failure with reduced left ventricular ejection fraction (HFrEF; ≤40%) in India. Our objective was to understand the use of GDMT in outpatients with HFrEF in India. The Practice Innovation And Clinical Excellence (PINNACLE) India Quality Improvement Program (PIQIP) is a registry for cardiovascular quality improvement in India supported by the American College of Cardiology Foundation. Between January 2008 and September 2014, we evaluated documentation of use of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) and β-blockers, or both, among outpatients with HFrEF seeking care in 10 centers enrolled in the PIQIP registry. Among 75 639 patients in the PIQIP registry, 34 995 had EF reported, and 15 870 had an EF ≤40%. The mean age was 56 years; 23% were female. Hypertension, diabetes, coronary artery disease, and myocardial infarction were present in 37%, 23%, 27%, and 17%, respectively. Use of ACEIs/ARBs, β-blockers, and both were documented in 33.5%, 34.9%, and 29.6% of patients, respectively. The documentation of GDMT was higher in men, in patients age ≥65 years, and in those with presence of hypertension, diabetes, or coronary artery disease. Documentation of GDMT gradually increased over the study period. Among patients enrolled in the PIQIP registry, about two-thirds of patients with EF ≤40% did not have documented receipt of GDMT. This study is an initial step toward improving adherence to GDMT in India and highlights the feasibility of examining quality of care in HFrEF in a resource-limited setting

Cx43 hemichannels contribute to astrocyte-mediated toxicity in sporadic and familial ALS

Connexin 43 (Cx43) gap junctions and hemichannels mediate astrocyte intercellular communication in the central nervous system under normal conditions and contribute to astrocyte-mediated neurotoxicity in amyotrophic lateral sclerosis (ALS). Here, we show that astrocyte-specific knockout of Cx43 in a mouse model of ALS slows disease progression both spatially and temporally, provides motor neuron (MN) protection, and improves survival. In addition, Cx43 expression is up-regulated in human postmortem tissue and cerebrospinal fluid from ALS patients. Using human induced pluripotent stem cell–derived astrocytes (hiPSC-A) from both familial and sporadic ALS, we establish that Cx43 is up-regulated and that Cx43-hemichannels are enriched at the astrocyte membrane. We also demonstrate that the pharmacological blockade of Cx43-hemichannels in ALS astrocytes using GAP 19, a mimetic peptide blocker, and tonabersat, a clinically tested small molecule, provides neuroprotection of hiPSC-MN and reduces ALS astrocyte-mediated neuronal hyperexcitability. Extending the in vitro application of tonabersat with chronic administration to SOD1G93A mice results in MN protection with a reduction in reactive astrocytosis and microgliosis. Taking these data together, our studies identify Cx43 hemichannels as conduits of astrocyte-mediated disease progression and a pharmacological target for disease-modifying ALS therapies