Comparative growth studies of the lactose and non-lactose fermenting strains of Shigella sonnei.

Thesis (M.A.)--Boston UniversityDuval and Schorer (Bact. and Clin. studies from the Rockefeller Inst. for Med. Res., 1904) first isolated the organism now known as Shigella sonnei from cases of infantile diarrhea. Other investigators reported the isolation of organisms closely resembling Duval's bacillus in outbreaks of dysentery. However, it was Sonne (Cent. Bakt. labt. org., 75: 408, 1915) who identified the organism as specific and distinct from the pseudodysentery organisms previously described by Kruse. Thjotta emphasized the variable fermentation of lactose by this organism. Sears and Schoolnik (J. Bact., 31: 309, 1936), Reynolds, etal. (J. Infect. Dis., 55: 207, 1934) and later Cook, Knox and Tomlinson (Brit. J. Exper. Path., 32: 203, 1951) isolated lactose-fermenting (Lac+) mutants from cultures of normal organisms. Kacoyanis (Diserations, Boston University Graduate School, 1955, 1957) found as few as from one to ten Lac+ mutants grew in the presence of large numbers of normal organisms and produced prompt fermentation of lactose and concluded that delayed fermentation of lactose was due to the absence of lactose rather than to the inhibitory action of the normal cells. He stated further that aeration in the presence of lactose favored the appearance of Lac+ mutants. Although Lac+ mutants and normal Sh. sonnei are known to exist, only normal organisms are found in nature. The purpose of the present investigation is to determine the factors that result in the more successful competition or the normal organism in mixed cultures. The comparative growths or the Lac+ mutant and the normal organism were studied by growing them in various liquid media in both pure and mixed culture under aerated and non-aerated (still) conditions. [TRUNCATED

A study of factors related to primary grade spelling: correlations of factors studied.

Thesis (Ed.M.)--Boston Universit

Collective Home Office

Thesis: M. Arch., Massachusetts Institute of Technology, Department of Architecture, 2018.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student-submitted PDF version of thesis.Includes bibliographical references (pages 260-269).Collective Home Office is a collaborative practice whose working process tests the propositions it makes through architecture. As a group of friends, willing test subjects, a union of producers, a jury, a family, or an army, CHO explores the frictions and benefits of collectivity in both method and content. The three words that form its name provide a framework through which the practice engages with its context, questioning how the meanings of collective, home and office have been historically shaped. Targeting the agents most implicated in defining the current moment, namely the proto-state corporations, platforms and institutions that constitute Big Tech, CHO pitches a series of unsolicited projects to clients who are radically changing how we live and relate to one another. CHO believes that not only should these agents be held responsible for the drastic social and urban impacts they exert, but that they may become willing partners in designing new ways of living that respond to the social estrangement, imminent technological unemployment, and chronic housing crisis that have resulted from their unregulated conquest of market share. Far from neglecting the notion of collectivity, the tech world has appropriated its surplus value and replaced sharing with a sharing economy and then with a gig economy. The "capitalist collective" fails to recognize its misuse of the word; collectives differ greatly from memberships rosters. CHO believes that collectivity is a shared motivation towards a common goal. Fundamentally ideological, it is accrued over time through social intimacy built on shared experiences, both positive and negative. Spatially, this notion of the collective requires a new organizational strategy. Modeled on both the city and the home, forms of domestic urbanism are fostered by intimate encounters occurring at overlapping scales of interaction, redefining the notion of household. CHO focuses its practice on how this unlikely partnership can be used as an opportunity to rewire the collective with new priorities. Using the home office as a device, CHO emphasizes the increasing importance of care work and social grooming as means of coping with transitional post-work lifestyle no longer based on the binary of home and work.by Mary Lynch-Lloyd, Ching Ying Ngan [and] Maya Shopova.M. Arch

Structural Mimicry in Class A G Protein-coupled Receptor Rotamer Toggle Switches

In this study, we tested the hypothesis that a CB1 TMH3-4-5-6 aromatic microdomain, which includes F3.25(190), F3.36(201), W5.43(280), and W6.48(357), is centrally involved in CB1 receptor activation, with the F3.36(201)/W6.48(357) interaction key to the maintenance of the CB1-inactive state. We have shown previously that when F3.36(201), W5.43(280), and W6.48(357) are individually mutated to alanine, a significant reduction in ligand binding affinity is observed in the presence of WIN 55,212-2 and SR141716A but not CP55,940 and anandamide. In the work presented here, we report a detailed functional analysis of the F3.36(201)A, F3.25(190)A, W5.43(280)A, and W6.48(357)A mutant receptors in stable cell lines created in HEK cells for agonist-stimulated guanosine 5′-3-O-(thio)triphosphate (GTPγS) binding and GIRK1/4 channel current effects in Xenopus oocytes where the mutant proteins were expressed transiently. The F3.36(201)A mutation showed statistically significant increases in ligand-independent stimulation of GTPγS binding versus wild type CB1, although basal levels for the W6.48(357)A mutant were not statistically different from wild type CB1. F3.36(201)A demonstrated a limited activation profile in the presence of multiple agonists. In contrast, enhanced agonist activation was produced by W6.48(357)A. These results suggest that a F3.36(201)/W6.48(357)-specific contact is an important constraint for the CB1-inactive state that may need to break during activation. Modeling studies suggest that the F3.36(201)/W6.48(357) contact can exist in the inactive state of CB1 and be broken in the activated state via a χ1 rotamer switch (F3.36(201) trans, W6.48(357) g+) → (F3.36(201) g+, W6.48(357) trans). The F3.36(201)/W6.48(357) interaction therefore may represent a “toggle switch” for activation of CB1

Towards establishing consistency in triage in a tertiary specialty

Clinical Genetics services provide a diagnostic, counselling and genetic testing service for children and adults affected by, or at risk of, a genetic condition, most of which are rare, and/or genetically heterogeneous. Appropriate triage of referrals is crucial to ensure that the most urgent referrals are seen as quickly as possible, without negatively impacting the waiting times of less urgent cases. We aimed to examine triage practice in six Clinical Genetic centres across the United Kingdom and Ireland. Thirteen simulated referrals were drafted based on common referrals to Clinical Genetics. Copies of each referral were forwarded to each centre, where 10 nominated clinicians were asked to triage each referral. Triaged referrals were returned to the coordinating author for analysis. An electronic questionnaire was contemporaneously completed by clinical leads in each unit to gather local demographic details and local operating procedures relevant to triage. Widespread inconsistencies were noted both within and between units, with respect to the acceptance of referrals to the services, prioritisation and designated clinic type. Referral rates, staffing levels and waiting lists varied widely between units. Inconsistencies observed between units are likely influenced by a number of factors, including staffing levels, referral rates and average family size. Inconsistency within units likely reflects the complex nature of many Clinical Genetic referrals, and triage guidelines should help improve decision-making in this setting

Genetic variation in insulin-like growth factor signaling genes and breast cancer risk among BRCA1 and BRCA2 carriers

Abstract Introduction Women who carry mutations in BRCA1 and BRCA2 have a substantially increased risk of developing breast cancer as compared with the general population. However, risk estimates range from 20 to 80%, suggesting the presence of genetic and/or environmental risk modifiers. Based on extensive in vivo and in vitro studies, one important pathway for breast cancer pathogenesis may be the insulin-like growth factor (IGF) signaling pathway, which regulates both cellular proliferation and apoptosis. BRCA1 has been shown to directly interact with IGF signaling such that variants in this pathway may modify risk of cancer in women carrying BRCA mutations. In this study, we investigate the association of variants in genes involved in IGF signaling and risk of breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations. Methods A cohort of 1,665 adult, female mutation carriers, including 1,122 BRCA1 carriers (433 cases) and 543 BRCA2 carriers (238 cases) were genotyped for SNPs in IGF1, IGF1 receptor (IGF1R), IGF1 binding protein (IGFBP1, IGFBP2, IGFBP5), and IGF receptor substrate 1 (IRS1). Cox proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was assumed; and for single SNP analyses, no additivity assumptions were made. Results Among BRCA1 carriers, significant associations were found between risk of breast cancer and LD blocks in IGF1R (global P = 0.011 for LD block 2 and global P = 0.012 for LD block 11). Among BRCA2 carriers, an LD block in IGFBP2 (global P = 0.0145) was found to be associated with the time to breast cancer diagnosis. No significant LD block associations were found for the other investigated genes among BRCA1 and BRCA2 carriers. Conclusions This is the first study to investigate the role of genetic variation in IGF signaling and breast cancer risk in women carrying deleterious mutations in BRCA1 and BRCA2. We identified significant associations in variants in IGF1R and IRS1 in BRCA1 carriers and in IGFBP2 in BRCA2 carriers. Although there is known to be interaction of BRCA1 and IGF signaling, further replication and identification of causal mechanisms are needed to better understand these associations

Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, <scp>genotype–phenotype</scp> correlations and common mechanisms

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (&gt;60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS‐like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or “DTRs”). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype–phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group