Role of Dmrt5 during development of midbrain dopaminergic progenitors

This thesis investigates the previously un-described role of Dmrt5, a zinc-finger transcription factor, in ventral midbrain development. The spatio-temporal expression pattern of Dmrt5, described for the first time in this thesis, suggests that Dmrt5 may have a role in midbrain dopaminergic development. Exogenous expression of Dmrt5, by in ovo electroporation in the chick embryo and over expression during neuronal differentiation of mouse epistem cells, causes ectopic expression of Hes1, a gene involved in the timing of neurogenesis. Dmrt5 ectopic expression also reduces the number of cells undergoing proliferation and inhibits terminal differentiation. These findings are consistent with the previously described phenotype observed upon Hes1 over expression. Studies in neuronal progenitors derived from mouse epistem cells indicate Dmrt5 mediates this effect by binding to the Hes1 promoter region. Genome-wide analysis of Dmrt5 over expression within the developing chick embryo, implicate Dmrt5 in specification of dorsal-ventral patterning. Dmrt5 promotes a floor-plate-like transcriptional profile when it is ectopically expressed in the dorsal ventral lateral midbrain. This observation is confirmed by ectopic expression studies in the developing chick and by over expression studies in neural progenitors differentiated from mouse epistem cells. In conclusion the data presented in this thesis describe the role of Dmrt5 in neurogenesis and dorsal-ventral patterning of the ventral midbrain. This data contributes to our knowledge of the developmental program involved in the creation of midbrain dopaminergic progenitors

A global transcriptional network connecting noncoding mutations to changes in tumor gene expression.

Although cancer genomes are replete with noncoding mutations, the effects of these mutations remain poorly characterized. Here we perform an integrative analysis of 930 tumor whole genomes and matched transcriptomes, identifying a network of 193 noncoding loci in which mutations disrupt target gene expression. These 'somatic eQTLs' (expression quantitative trait loci) are frequently mutated in specific cancer tissues, and the majority can be validated in an independent cohort of 3,382 tumors. Among these, we find that the effects of noncoding mutations on DAAM1, MTG2 and HYI transcription are recapitulated in multiple cancer cell lines and that increasing DAAM1 expression leads to invasive cell migration. Collectively, the noncoding loci converge on a set of core pathways, permitting a classification of tumors into pathway-based subtypes. The somatic eQTL network is disrupted in 88% of tumors, suggesting widespread impact of noncoding mutations in cancer

Conserved enhancers control notochord expression of vertebrate Brachyury.

The cell type-specific expression of key transcription factors is central to development and disease. Brachyury/T/TBXT is a major transcription factor for gastrulation, tailbud patterning, and notochord formation; however, how its expression is controlled in the mammalian notochord has remained elusive. Here, we identify the complement of notochord-specific enhancers in the mammalian Brachyury/T/TBXT gene. Using transgenic assays in zebrafish, axolotl, and mouse, we discover three conserved Brachyury-controlling notochord enhancers, T3, C, and I, in human, mouse, and marsupial genomes. Acting as Brachyury-responsive, auto-regulatory shadow enhancers, in cis deletion of all three enhancers in mouse abolishes Brachyury/T/Tbxt expression selectively in the notochord, causing specific trunk and neural tube defects without gastrulation or tailbud defects. The three Brachyury-driving notochord enhancers are conserved beyond mammals in the brachyury/tbxtb loci of fishes, dating their origin to the last common ancestor of jawed vertebrates. Our data define the vertebrate enhancers for Brachyury/T/TBXTB notochord expression through an auto-regulatory mechanism that conveys robustness and adaptability as ancient basis for axis development

Salve Regina University Act on Climate: Strategic Plan for the University to Reach State Carbon Neutrality Goals

In order to become more sustainable and meet the mandate set by the 2021 Rhode Island Act on Climate law (RI General Law §42-6.2), Salve Regina University must work to reach net-zero greenhouse gas emissions by the year 2050. Action to meet these standards begins now and must be continually built upon to ensure that Salve Regina University, as leader in Rhode Island, is always working for a more sustainable future. Throughout the Spring 2022 semester, students of the BIO-140: Humans and Their Environment course instructed by Dr. Jameson Chace have researched ways in which Salve Regina can begin on the path to zero greenhouse gas emissions today. By focusing on change in the areas of energy, transportation, food, financial investments, and sequestration, Salve Regina can reduce the greenhouse gas emissions of today for a more sustainable tomorrow. Recommendations are broken into three time periods. Action for today to achieve by 2030 include improving energy efficiency, installing the first electric vehicle (EV) parking/charging stations, increasing carbon sequestration, reducing beef in the campus diet, and assessing the carbon impact of university financial holdings. Actions to be initiated soon and to be achieved by 2040 include shifting away from natural gas heating when system renewals take place, increasing EV parking to meet rising demand, during turnover replace current university vehicles with electric or hybrid, continuing with sequestration efforts on campus, begin phasing out high carbon diet items, and by 2040 the university investment portfolio should be carbon neutral. If carbon neutrality can be reached by 2050 the most challenging aspects of campus life that need to change will require planning now and thoughtful implementation. The class in 2022 envisions a campus in 2050 where solar lights illuminate campus and buildings through the night, all university vehicles and most faculty and staff vehicles are electric and are found charging during the day at solar powered charging stations, dining services in Miley supports community agriculture and includes incentives for meatless and low carbon meal plans, the university has become a leader in low carbon/green market investing demonstrating how careful planning can reap high returns, and carbon sequestration on campus grounds has maximized such that off campus carbon offsets are established with local land trusts to complete the carbon neutrality goals. In doing so no only will the university be recognized as a state-wide leader in climate action, but will also be a global leader in working towards a world that is more harmonious, just, and merciful.https://digitalcommons.salve.edu/bio140_arboretum/1033/thumbnail.jp

Vaccine Effectiveness Estimates, 2004–2005 Mumps Outbreak, England

As vaccinated children approach adolescence, immunity wanes, which may contribute to outbreaks

Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors

Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-beta-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential beta-lactamase stable beta-lactam mimics. Subsequent structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL-carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.Peer reviewe

3D genomics across the tree of life reveals condensin II as a determinant of architecture type

We investigated genome folding across the eukaryotic tree of life. We find two types of three-dimensional(3D) genome architectures at the chromosome scale. Each type appears and disappears repeatedlyduring eukaryotic evolution. The type of genome architecture that an organism exhibits correlates with theabsence of condensin II subunits. Moreover, condensin II depletion converts the architecture of thehuman genome to a state resembling that seen in organisms such as fungi or mosquitoes. In this state,centromeres cluster together at nucleoli, and heterochromatin domains merge. We propose a physicalmodel in which lengthwise compaction of chromosomes by condensin II during mitosis determineschromosome-scale genome architecture, with effects that are retained during the subsequent interphase.This mechanism likely has been conserved since the last common ancestor of all eukaryotes.C.H. is supported by the Boehringer Ingelheim Fonds; C.H., Á.S.C., and B.D.R. are supported by an ERC CoG (772471, “CohesinLooping”); A.M.O.E. and B.D.R. are supported by the Dutch Research Council (NWO-Echo); and J.A.R. and R.H.M. are supported by the Dutch Cancer Society (KWF). T.v.S. and B.v.S. are supported by NIH Common Fund “4D Nucleome” Program grant U54DK107965. H.T. and E.d.W. are supported by an ERC StG (637597, “HAP-PHEN”). J.A.R., T.v.S., H.T., R.H.M., B.v.S., and E.d.W. are part of the Oncode Institute, which is partly financed by the Dutch Cancer Society. Work at the Center for Theoretical Biological Physics is sponsored by the NSF (grants PHY-2019745 and CHE-1614101) and by the Welch Foundation (grant C-1792). V.G.C. is funded by FAPESP (São Paulo State Research Foundation and Higher Education Personnel) grants 2016/13998-8 and 2017/09662-7. J.N.O. is a CPRIT Scholar in Cancer Research. E.L.A. was supported by an NSF Physics Frontiers Center Award (PHY-2019745), the Welch Foundation (Q-1866), a USDA Agriculture and Food Research Initiative grant (2017-05741), the Behavioral Plasticity Research Institute (NSF DBI-2021795), and an NIH Encyclopedia of DNA Elements Mapping Center Award (UM1HG009375). Hi-C data for the 24 species were created by the DNA Zoo Consortium (www.dnazoo.org). DNA Zoo is supported by Illumina, Inc.; IBM; and the Pawsey Supercomputing Center. P.K. is supported by the University of Western Australia. L.L.M. was supported by NIH (1R01NS114491) and NSF awards (1557923, 1548121, and 1645219) and the Human Frontiers Science Program (RGP0060/2017). The draft A. californica project was supported by NHGRI. J.L.G.-S. received funding from the ERC (grant agreement no. 740041), the Spanish Ministerio de Economía y Competitividad (grant no. BFU2016-74961-P), and the institutional grant Unidad de Excelencia María de Maeztu (MDM-2016-0687). R.D.K. is supported by NIH grant RO1DK121366. V.H. is supported by NIH grant NIH1P41HD071837. K.M. is supported by a MEXT grant (20H05936). M.C.W. is supported by the NIH grants R01AG045183, R01AT009050, R01AG062257, and DP1DK113644 and by the Welch Foundation. E.F. was supported by NHGR