Tetrahydroisoquinolines affect the whole-cell phenotype of Mycobacterium tuberculosis by inhibiting the ATP-dependent MurE ligase

Objectives (S)-Leucoxine, isolated from the Colombian Lauraceae tree Rhodostemonodaphne crenaticupula Madriñan, was found to inhibit the growth of Mycobacterium tuberculosis H37Rv. A biomimetic approach for the chemical synthesis of a wide array of 1-substituted tetrahydroisoquinolines was undertaken with the aim of elucidating a common pharmacophore for these compounds with novel mode(s) of anti-TB action. Methods Biomimetic Pictet–Spengler or Bischler–Napieralski synthetic routes were employed followed by an evaluation of the biological activity of the synthesized compounds. Results In this work, the synthesized tetrahydroisoquinolines were found to inhibit the growth of M. tuberculosis H37Rv and affect its whole-cell phenotype as well as the activity of the ATP-dependent MurE ligase, a key enzyme involved in the early stage of cell wall peptidoglycan biosynthesis. Conclusions As the correlation between the MIC and the half-inhibitory enzymatic concentration was not particularly strong, there is a credible possibility that these compounds have pleiotropic mechanism(s) of action in M. tuberculosis

Talented suppliers? Strategic change and innovation in the UK aerospace industry

The 1990s marked the start of extensive re-structuring in the aerospace industry throughout the world. While the ensuing consolidation among prime contractors has been widely researched, the changes affecting the aerospace supply chain have received less attention. This study focuses on the re-structuring taking place within the supply chain of the UK aerospace industry. The findings point to extensive re-structuring. Unlike most earlier studies the lean supply model was found to be a powerful influence, with suppliers moving away from subcontractor status and instead taking on the mantle of ‘talented’ suppliers. While some of the implications of lean supply, in terms of the dynamics of innovation, were not apparent, there were modest signs of increased process innovation on the part of some suppliers

Foot pain and foot health in an educated population of adults: results from the Glasgow Caledonian University Alumni Foot Health Survey

Abstract Background Foot pain is common amongst the general population and impacts negatively on physical function and quality of life. Associations between personal health characteristics, lifestyle/behaviour factors and foot pain have been studied; however, the role of wider determinants of health on foot pain have received relatively little attention. Objectives of this study are i) to describe foot pain and foot health characteristics in an educated population of adults; ii) to explore associations between moderate-to-severe foot pain and a variety of factors including gender, age, medical conditions/co-morbidity/multi-morbidity, key indicators of general health, foot pathologies, and social determinants of health; and iii) to evaluate associations between moderate-to-severe foot pain and foot function, foot health and health-related quality-of-life. Methods Between February and March 2018, Glasgow Caledonian University Alumni with a working email address were invited to participate in the cross-sectional electronic survey (anonymously) by email via the Glasgow Caledonian University Alumni Office. The survey was constructed using the REDCap secure web online survey application and sought information on presence/absence of moderate-to-severe foot pain, patient characteristics (age, body mass index, socioeconomic status, occupation class, comorbidities, and foot pathologies). Prevalence data were expressed as absolute frequencies and percentages. Multivariate logistic and linear regressions were undertaken to identify associations 1) between independent variables and moderate-to-severe foot pain, and 2) between moderate-to-severe foot pain and foot function, foot health and health-related quality of life. Results Of 50,228 invitations distributed, there were 7707 unique views and 593 valid completions (median age [inter-quartile range] 42 [31–52], 67.3% female) of the survey (7.7% response rate). The sample was comprised predominantly of white Scottish/British (89.4%) working age adults (95%), the majority of whom were overweight or obese (57.9%), and in either full-time or part-time employment (82.5%) as professionals (72.5%). Over two-thirds (68.5%) of the sample were classified in the highest 6 deciles (most affluent) of social deprivation. Moderate-to-severe foot pain affected 236/593 respondents (39.8%). High body mass index, presence of bunions, back pain, rheumatoid arthritis, hip pain and lower occupation class were included in the final multivariate model and all were significantly and independently associated with moderate-to-severe foot pain (p < 0.05), except for rheumatoid arthritis (p = 0.057). Moderate-to-severe foot pain was significantly and independently associated lower foot function, foot health and health-related quality of life scores following adjustment for age, gender and body mass index (p < 0.05). Conclusions Moderate-to-severe foot pain was highly prevalent in a university-educated population and was independently associated with female gender, high body mass index, bunions, back pain, hip pain and lower occupational class. Presence of moderate-to-severe foot pain was associated with worse scores for foot function, foot health and health-related quality-of-life. Education attainment does not appear to be protective against moderate-to-severe foot pain

mTORC1 in the Paneth cell niche couples intestinal stem cell function to calorie intake

How adult tissue stem and niche cells respond to the nutritional state of an organism is not well understood. Here we find that Paneth cells, a key constituent of the mammalian intestinal stem-cell (ISC) niche, augment stem-cell function in response to calorie restriction. Calorie restriction acts by reducing mechanistic target of rapamycin complex 1 (mTORC1) signalling in Paneth cells, and the ISC-enhancing effects of calorie restriction can be mimicked by rapamycin. Calorie intake regulates mTORC1 in Paneth cells, but not ISCs, and forced activation of mTORC1 in Paneth cells during calorie restriction abolishes the ISC-augmenting effects of the niche. Finally, increased expression of bone stromal antigen 1 (Bst1) in Paneth cells—an ectoenzyme that produces the paracrine factor cyclic ADP ribose—mediates the effects of calorie restriction and rapamycin on ISC function. Our findings establish that mTORC1 non-cell-autonomously regulates stem-cell self-renewal, and highlight a significant role of the mammalian intestinal niche in coupling stem-cell function to organismal physiology.National Institutes of Health (U.S.) (CA103866)National Institutes of Health (U.S.) (CA129105)David H. Koch Institute for Integrative Cancer Research at MIT (Initiator Award)Ellison Medical FoundationNational Cancer Institute (U.S.) (NCI (T32CA09216) fellowship support)Academy of FinlandFoundations’ Postdoc PoolNational Institutes of Health (U.S.) (NIH (1F32AG032833-01A1))Jane Coffin Childs Memorial Fund for Medical Researc

Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators

A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu[superscript 230], located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs.Glenn Foundation for Medical ResearchEllison Medical FoundationJuvenile Diabetes Research Foundation InternationalUnited Mitochondrial Disease FoundationNational Institutes of Health (U.S.)National Institute of Allergy and Infectious Diseases (U.S.

Student politics, teaching politics, black politics: an interview with Ansel Wong

Ansel Wong is the quiet man of British black politics, rarely in the limelight and never seeking political office. And yet his ‘career’ here – from Black Power firebrand to managing a multimillion budget as head of the Greater London Council’s Ethnic Minority Unit in the 1980s – spells out some of the most important developments in black educational and cultural projects. In this interview, he discusses his identification with Pan-Africanism, his involvement in student politics, his role in the establishment of youth projects and supplementary schools in the late 1960s and 1970s, and his involvement in black radical politics in London in the same period, all of which took place against the background of revolutionary ferment in the Third World and the world of ideas, and were not without their own internal class and ethnic conflicts

Supporting SMEs through Government Purchasing Activity

As major consumers of goods and services, governments have an opportunity to support SMEs directly through their purchasing policies. This study examines the experience of SMEs in the north-east of England in their attempt to supply UK public sector organizations, and finds that, despite recent initiatives, barriers are being experienced by the majority of SMEs surveyed. The findings suggest that both government and small business sectors face challenges, such as resolving policy conflicts, managing resource demands and facilitating organizational change, in overcoming these barriers. Further investigation is required to inform the resolution of these demands

Characteristics of Severe Acute Respiratory Syndrome Coronavirus-2 Infection and Comparison With Influenza in Children Admitted to U.K. PICUs

Objectives: Severe acute respiratory syndrome coronavirus-2 affects adults disproportionately more than children. A small proportion of children with severe acute respiratory syndrome coronavirus-2 required admission to a PICU. We describe the nationwide U.K. PICU experience of severe acute respiratory syndrome coronavirus-2 infection during the first wave of the pandemic and compare this with the critical care course of the 2019 influenza cohort. Design: Prospective nationwide cohort study of characteristics of severe acute respiratory syndrome coronavirus-2–positive children. Data collection utilized routine Pediatric Intensive Care Audit Network and severe acute respiratory syndrome coronavirus-2–specific data. Setting: All U.K. PICUs. Patients: Children less than 18 years old, admitted to U.K. PICUs between March 14, 2020, and June 13, 2020, and a positive severe acute respiratory syndrome coronavirus-2 polymerase chain reaction. Children admitted to U.K. PICUs in 2019 with influenza provided comparison. Interventions: None. Measurements and Main Results: We identified 76 PICU admissions among 73 children with a positive severe acute respiratory syndrome coronavirus-2 polymerase chain reaction test. Prevalence of PICU admissions per million was 5.2 for children versus 260 for adults. Ten children (14%) were identified on routine screening. Seventeen children (23%) had pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus-2. Seventeen (23%) had coinfections. Invasive ventilation was required in seven of 17 children (41%) with pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus-2 versus 38 of 56 other severe acute respiratory syndrome coronavirus-2 positive children (68%), with 77% requiring vasoactive support versus 43%, respectively. Seven children (10%) died. In comparison with influenza children, severe acute respiratory syndrome coronavirus-2 children were older (median [interquartile range]: 10 [1–13] vs 3 yr [1–8 yr]), more often Black or Asian (52% v 18%), higher weight z score (0.29 [–0.80 to 1.62] vs –0.41 [–1.37 to 0.63]), and higher deprivation index (3.3 [–1 to 6.3] vs 1.2 [–1.8 to 4.4]). Comorbidities, frequency of organ supports, and length of stay were similar. Conclusions: This nationwide study confirms that PICU admissions with severe acute respiratory syndrome coronavirus-2 infections were infrequent. We have reported similarities and differences in sociodemographic characteristics, organ support interventions, and outcomes of children affected by severe acute respiratory syndrome coronavirus-2 compared with influenza

A toolbox for the longitudinal assessment of healthspan in ageing mice

The number of people aged over 65 is expected to double in the next 30 years. For many, living longer will mean spending more years with the burdens of chronic diseases such as Alzheimer’s, cardiovascular disease, and diabetes. Although researchers have made rapid progress in developing geroprotective interventions that target mechanisms of ageing and delay or prevent the onset of multiple concurrent age-related diseases, a lack of standardized techniques to assess healthspan in preclinical murine studies has resulted in reduced reproducibility and slowed progress. To overcome this, major centres in Europe and the USA skilled in healthspan analysis came together to agree upon a toolbox of techniques which can be used to consistently assess the healthspan of mice. Here, we describe the agreed toolbox which contains protocols for echocardiography, novel object recognition, grip strength, rotarod, glucose and insulin tolerance tests, body composition, and energy expenditure. They can be performed longitudinally in the same mouse over a period of 4-6 weeks to test how candidate geroprotectors affect cardiac, cognitive, neuromuscular and metabolic health

Endurance Exercise as a Countermeasure for Aging

OBJECTIVE— We determined whether reduced insulin sensitivity, mitochondrial dysfunction, and other age-related dysfunctions are inevitable consequences of aging or secondary to physical inactivity