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Dahai Yu,1,2 Uchechukwu Levi Osuagwu,3,4 Karen Pickering,5 John Baker,5,6 Richard Cutfield,5,7 Zheng Wang,1 Yamei Cai,1,* Brandon J Orr-Walker,5,6 Gerhard Sundborn,8 Zhanzheng Zhao,1,* David Simmons1,3,4,* 1Department of Nephrology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 2Primary Care Centre Versus Arthritis, School of Medicine, Keele University, Keele, UK; 3Translational Health Research Institute (THRI), Western Sydney University, Sydney, NSW, Australia; 4School of Medicine, Western Sydney University, Sydney, NSW, Australia; 5Diabetes Foundation Aotearoa, Auckland, New Zealand; 6Department of Diabetes and Endocrinology, Counties Manukau Health, Auckland, New Zealand; 7Department of Diabetes and Endocrinology, Waitemata District Health Board, Auckland, New Zealand; 8Section of Pacific Health, The University of Auckland, Auckland, New Zealand*These authors contributed equally to this workCorrespondence: David Simmons; Zhanzheng Zhao, Department of Nephrology, The First Affiliated Hospital Zhengzhou University, Zhengzhou, 450052, People’s Republic of China, Tel +61 2 4620 3899 ; +86 139 3852 5666, Fax +61 2 4620 3890 ; +86 371 6698 8753, Email Da.Simmons@westernsydney.edu.au; zhanzhengzhao@zzu.edu.cnPurpose: The study aimed to examine the separate population-level contributions of the ethnic and socioeconomic disparities among people with type 2 diabetes mellitus (T2DM) and residence in New Zealand (NZ).Patients and Methods: A prospective cohort enrolled T2DM patients from 01/01/1994 into the Diabetes Care Support Service, a primary care audit program in Auckland, NZ. The cohort was linked to national registry databases (socioeconomic status, pharmaceutical claim, hospitalization, and death registration). Each cohort member was followed up till death or the study end time (31/12/2019), whichever came first. Incident clinical events (stroke, myocardial infarction (MI), heart failure (HF), end-stage renal disease (ESRD), and premature mortality (PM)) were used as outcomes. The attributable fractions (AFs) were estimated for the whole population and for specific population with NZ Europeans (NZE) and/or least deprived population as reference, both unadjusted and with adjustment for covariables by Cox Regression models.Results: Among 36,267 patients, adjusted population AFs indicated 6.6(− 30.8– 33.3)% of PM, 17.1(5.8– 27.0)% of MI, 35.3(22.6– 46.0)% of stroke, 14.3(3.2– 24.2)% of HF, and 15.9(6.7– 24.2)% of ESRD could be attributed to deprivation; while 14.3(3.3– 25.4)% of PM, − 3.3(− 8.3– 1.5)% of MI, − 0.5(− 6.7– 5.3)% of stroke, 4.7(0.3– 8.8)% of HF, 13.3(9.9– 16.6)% of ESRD could be attributed to ethnicity. Deprivation contributed a significant AF to stroke, while ethnicity was important for ESRD. Gradient of AF for deprivation indicated NZE and Asians were most affected by deprivation across outcomes. Conversely, Māori, with the highest AFs for ethnicity of PM and ESRD, were unaffected by deprivation. At same deprivations, the AFs of MI and stroke were greatest among NZE compared with other ethnic groups; the AF of ESRD was greatest among Māori and Pasifika.Conclusion: Both socioeconomic deprivation and ethnicity are strongly associated with outcomes in patients with T2DM in NZ, although the extent of the deprivation gradient is greatest among NZE and Asians, and least among Māori.Keywords: stroke, myocardial infarction, heart failure, end-stage renal disease, premature mortality, Māori

Single particle cavity ring-down spectroscopy (CRDS) allows direct and continuous measurements of the extinction cross-sections for levitated micron-scale aerosol particles of constant or evolving composition. Our recent interests have concerned single particle CRDS measurements for light-absorbing particles. These measurements are made on single, spherical particles evaporating over the radius range 1500–700 nm that are levitated within a 405-nm cavity ring-down spectrometer using a linear electrodynamic quadrupole trap. Here, we quantify the accuracy and precision of our cavity ring-down time measurements and the consequences of particle motion within our electrodynamic trap. Next, we estimate the uncertainty in our particle size retrievals from angularly resolved elastic light scattering measurements for particles with a range of absorption strengths. Finally, we assess the accuracy of complex refractive index values retrieved from simultaneous ring-down time and particle size measurements. The assessments account for the impacts of shot and detector noise in the measured ring-down times, the driven particle motion within the electrodynamic trap, and particle absorption strength (for imaginary refractive indices in the range ∼0.0–0.1). The real and imaginary refractive indices are retrieved to an accuracy better than 0.005 and 0.002, respectively, for almost all absorption strengths studied, and for particles of constant or evolving composition. Although particles confined in our electrodynamic quadrupole trap undergo considerable levels of driven motion (with oscillation amplitudes of several tens of micrometers), the contribution of this motion to uncertainty in retrieved refractive indices is negligible compared to contributions from particle sizing errors.

Regulating the central CO2-fixing enzyme Rubisco is as complex as its ancient reaction mechanism and involves interaction with a series of cofactors and auxiliary proteins that activate catalytic sites and maintain activity. A key component among the regulatory mechanisms is the binding of sugar phosphate derivatives that inhibit activity. Removal of inhibitors via the action of Rubisco activase is required to restore catalytic competency. In addition, specific phosphatases dephosphorylate newly released inhibitors, rendering them incapable of binding to Rubisco catalytic sites. The best studied inhibitor is 2-carboxy-d-arabinitol 1-phosphate (CA1P), a naturally occurring nocturnal inhibitor that accumulates in most species during darkness and low light, progressively binding to Rubisco. As light increases, Rubisco activase removes CA1P from Rubisco, and the specific phosphatase CA1Pase dephosphorylates CA1P to CA, which cannot bind Rubisco. Misfire products of Rubisco’s complex reaction chemistry can also act as inhibitors. One example is xylulose-1,5-bisphosphate (XuBP), which is dephosphorylated by XuBPase. Here we revisit key findings related to sugar phosphate derivatives and their specific phosphatases, highlighting outstanding questions and how further consideration of these inhibitors and their role is important for better understanding the regulation of carbon assimilation.

Examine factors impacting U.S. parents' intention to vaccinate their children against COVID-19.Data were collected February-May 2021 from parents living in six geographically diverse locations. The COVID-19 Exposure and Family Impact Survey assessed perceived susceptibility and severity to adverse outcomes from the pandemic. Semi-structured interviews assessed perceptions about benefits and risks of vaccinating children.Fifty parents of 106 children (newborn-17 years) were included; half were Spanish-speaking and half English-speaking. 62% were hesitant about vaccinating their children against COVID-19. Efficacy and safety were the main themes that emerged: some parents perceived them as benefits while others perceived them as risks to vaccination. Parent hesitancy often relied on social media, and was influenced by narrative accounts of vaccination experiences. Many cited the lower risk of negative outcomes from COVID-19 among children, when compared with adults. Some also cited inaccurate and constantly changing information about COVID-19 vaccines.Main drivers of parent hesitancy regarding child COVID-19 vaccination include perceived safety and efficacy of the vaccines and lower severity of illness in children.Many vaccine-hesitant parents may be open to vaccination in the future and welcome additional discussion and data.

The genomic architecture underlying the origins and maintenance of biodiversity is an increasingly accessible feature of species, due in large part to third-generation sequencing and novel analytical toolsets. Applying these techniques to woodrats (Neotoma spp.) provides a unique opportunity to study how herbivores respond to environmental change. Neotoma bryanti and N. lepida independently achieved a major dietary feat in the aftermath of a natural climate change event: switching to the novel, toxic food source creosote bush (Larrea tridentata). To better understand the genetic mechanisms underlying this ability, we employed a trio binning sequencing approach with a N. bryanti × N. lepida F

Minority physicians have been persistently underrepresented in medicine (URiM) when compared with their representation in the general U.S.There is evidence that diversifying the physician workforce would have a positive impact on healthcare delivery. While programs have been implemented to diversify the physician workforce, there has been less emphasis and progress in diversifying academic medical centers (AMCs) at the faculty level. This review sought to provide an update in the literature on the published outcomes and components of programs designed to increase the racial/ethnic diversity of faculty at AMCs.A scoping review study design was used. Search terms-academic medical faculty, diversity, and recruitment or retention-were used to search literature published from August 2012 through February 4, 2021. Eligible studies (1) evaluate structured organization/institutional programs to increase the representation of faculty who identify as URiM; (2) include faculty who identify as URiM as defined by the Association of American Medical Colleges (individuals who identify as African Americans and/or Black, Hispanic/Latino, Native American (American Indians, Alaska Natives, and Native Hawaiians), Pacific Islander, and mainland Puerto Rican); (3) describe interventions for the academic medicine setting; and (4) report either quantitative or qualitative data.Ten papers describing eight programs were included in the review. Program components were heterogeneous. Most studies described funded research-focused programs and fewer studies were institution-wide efforts or included institutional culture (i.e., rules, values, beliefs, behaviors, and customs that shape how people behave within an organization) or climate (i.e., perception regarding the culture) efforts. Four studies reported outcomes that included changes in faculty representation and six included faculty retention efforts such as promotion, leadership positions, grants, and scholarly productivity.This review summarizes and updates the literature on programs to improve the diversity of faculty at AMCs. It includes specific recommendations for components that can provide a foundation for programs to improve faculty diversity. Future research should use high quality methods to compare different interventions to improve the diversity of faculty in AMCs.

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The antiapoptotic protein BCL2 plays critical roles in regulating lymphocyte development and immune responses, and has also been implicated in tumorigenesis and tumor survival. However, it is unknown whether BCL2 is critical for antitumor immune responses. We evaluated whether venetoclax, a selective small-molecule inhibitor of BCL2, would influence the antitumor activity of immune checkpoint inhibitors (ICI). We demonstrate in mouse syngeneic tumor models that venetoclax can augment the antitumor efficacy of ICIs accompanied by the increase of PD-1+ T effector memory cells. Venetoclax did not impair human T-cell function in response to antigen stimuli in vitro and did not antagonize T-cell activation induced by anti–PD-1. Furthermore, we demonstrate that the antiapoptotic family member BCL-XL provides a survival advantage in effector T cells following inhibition of BCL2. Taken together, these data provide evidence that venetoclax should be further explored in combination with ICIs for cancer therapy.Significance:The antiapoptotic oncoprotein BCL2 plays critical roles in tumorigenesis, tumor survival, lymphocyte development, and immune system regulation. Here we demonstrate that venetoclax, the first FDA/European Medicines Agency–approved BCL2 inhibitor, unexpectedly can be combined preclinically with immune checkpoint inhibitors to enhance anticancer immunotherapy, warranting clinical evaluation of these combinations.This article is highlighted in the In This Issue feature, p. 1

The affinities of extinct organisms are often difficult to resolve using morphological data alone. Chemical analysis of carbonaceous specimens can complement traditional approaches, but the search for taxon-specific signals in ancient, thermally altered organic matter is challenging and controversial, partly because suitable positive controls are lacking. Here, we show that non-destructive Fourier Transform Infrared Spectroscopy (FTIR) resolves in-situ molecular fingerprints in the famous 407 Ma Rhynie chert fossil assemblage of Aberdeenshire, Scotland, an important early terrestrial Lagerstätte. Remarkably, unsupervised clustering methods (principal components analysis and K-mean) separate the fossil spectra naturally into eukaryotes and prokaryotes (cyanobacteria). Additional multivariate statistics and machine-learning approaches also differentiate prokaryotes from eukaryotes, and discriminate eukaryotic tissue types, despite the overwhelming influence of silica. We find that these methods can clarify the affinities of morphologically ambiguous taxa; in the Rhynie chert for example, we show that the problematic “nematophytes” have a plant-like composition. Overall, we demonstrate that the famously exquisite preservation of cells, tissues and organisms in the Rhynie chert accompanies similarly impressive preservation of molecular information. These results provide a compelling positive control that validates the use of infrared spectroscopy to investigate the affinity of organic fossils in chert.

[Image: see text] The serotonin 5-HT(2) receptors are important pharmaceutical targets involved in signaling pathways underlying various neurological, psychiatric, and cardiac functions and dysfunctions. As such, numerous ligands for the investigation of these receptors’ activity and downstream effects have been developed synthetically or discovered in nature. For example, the heteroyohimbine natural product alstonine exhibits antispychotic activity mediated by 5-HT(2A/2C) agonism. In this work, we identified a heteroyohimbine metabolite containing a serotonin pharmacophore and truncated the scaffold, leading to the discovery of potent agonist activity of substituted tetrahydro-β-carbolines across the 5-HT(2) receptor family. Extensive SAR development resulted in compound 106 with EC(50) values of 1.7, 0.58, and 0.50 nM at 5-HT(2A), 5-HT(2B), and 5-HT(2C), respectively. Docking studies suggest a π-stacking interaction between the tetrahydro-β-carboline core and conserved residue Trp(6.48) as the structural basis for this activity. This work lays a foundation for future investigation of these compounds in neurological and psychiatric disorders.

Professor A. David Buckingham CBE FRS FAA made fundamental theoretical and experimental contributions to the understanding of optical, electric and magnetic properties of molecules. Born in Australia, he was an undergraduate at the University of Sydney and took his PhD at the University of Cambridge, UK. He moved to Oxford in 1955 and then in 1965 became Professor of Theoretical Chemistry at the University of Bristol. Finally, he moved back to Cambridge in 1969 for twenty-eight years as Professor of Chemistry and head of a distinguished Department of Theoretical Chemistry. A man of broad interests and achievements, he played first class cricket in the 1950s.

Shelter has been described as one of the most 'intractable problems' in humanitarian aid and yet there is little clarity on the over-arching definition of shelter. The terminology for shelter and housing is often conflated, and further to this, the most prominently used definition does not fully reflect the recent progress the shelter and settlements sector has made. These progressions include a movement from 'product' to 'process', and a recognition of the wider impacts of shelter, including livelihoods, health, economic stimulation, education, and reduction of vulnerability. This paper explores the varying terminology utilised in definitions of shelter within humanitarian aid since 1990, reflecting on the concepts of 'shelter' and 'housing', alongside the surrounding perceptions of 'house' vs 'home, and related measures of adequacy. The current, most prolific definition is also deconstructed, demonstrating the ambiguity in some of the terminology such as 'dignity' and 'privacy', and identifying that the interpretation of this definition is dependent on the knowledge of the reader. Finally, a new definition of 'sheltering' is proposed, encompassing five key reflections: the concept of process over object; inclusion of communities as well as individuals; the commonality of long-term sheltering; the wider impacts of shelter; the impact on host communities and environment. This definition is proposed in conjunction with the needs defined in the UN-HABITAT definition of 'adequate shelter', with the caveat that adequacy of those needs, and the sheltering response, should be determined by the affected population.

David Buckingham was a chemical physicist and theoretical chemist who made fundamental contributions to the understanding of optical, electric and magnetic properties of molecules. Born in Australia, he was an undergraduate at the University of Sydney and the first PhD research student of John Pople (FRS 1961) at Cambridge, and there he made significant advances in the theory of intermolecular forces and nonlinear optics. He then moved to Oxford, where he and his group performed the first direct measurement of a molecular electric quadrupole moment. He was elected to the first chair of theoretical chemistry at the University of Bristol, where he wrote a particularly influential article on molecular moments, higher-order polarizabilities and intermolecular forces. His next appointment was at the University of Cambridge as the first holder of the 1968 Chair of Chemistry, and he was head of a distinguished department of theoretical chemistry for 28 years. With colleagues he pioneered experiment and theory on vibrational optical activity and developed a powerful model to predict the structures of weakly-bound molecules. A man of broad interests and achievements, he played first class cricket in the 1950s.

Invasive fungal disease (IFD) causes severe morbidity and mortality, and the number of IFD cases is increasing. Exposure to opportunistic fungal pathogens is inevitable, but not all patients with underlying diseases increasing susceptibility to IFD, develop it. IFD diagnosis currently uses fungal biomarkers and clinical risk/presentation to stratify high-risk patients and classifies them into possible, probable, and proven IFD. However, the fungal species responsible for IFD are highly diverse and present numerous diagnostic challenges, which culminates in the empirical anti-fungal treatment of patients at risk of IFD. Recent studies have focussed on host-derived biomarkers that may mediate IFD risk and can be used to predict, and even identify IFD. The identification of novel host genetic variants, host gene expression changes, and host protein expression (cytokines and chemokines) associated with increased risk of IFD has enhanced our understanding of why only some patients at risk of IFD actually develop disease. Furthermore, these host biomarkers when incorporated into predictive models alongside conventional diagnostic techniques enhance predictive and diagnostic results. Once validated in larger studies, host biomarkers associated with IFD may optimize the clinical management of populations at risk of IFD. This review will summarise the latest developments in the identification of host biomarkers for IFD, their use in predictive modelling and their potential application/usefulness for informing clinical decisions.