Leveraging type 1 diabetes human genetic and genomic data in the T1D knowledge portal.

To address the challenge of translating genetic discoveries for type 1 diabetes (T1D) into mechanistic insight, we have developed the T1D Knowledge Portal (T1DKP), an open-access resource for hypothesis development and target discovery in T1D.

Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes.

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

The hepatocyte epidermal growth factor receptor (EGFR) pathway regulates the cellular interactome within the liver fibrotic niche.

Liver fibrosis is the consequence of chronic liver injury in the presence of an inflammatory component. Although the main executors of this activation are known, the mechanisms that lead to the inflammatory process that mediates the production of pro-fibrotic factors are not well characterized. Epidermal growth factor receptor (EGFR) signaling in hepatocytes is essential for the regenerative processes of the liver; however, its potential role in regulating the fibrotic niche is not yet clear. Our group generated a mouse model that expresses an inactive truncated form of the EGFR specifically in hepatocytes (ΔEGFR mice). Here, we have analyzed the response of WT and ΔEGFR mice to chronic treatment with carbon tetrachloride (CCl4), which induces a pro-inflammatory and fibrotic process in the liver. The results indicated that the hallmarks of liver fibrosis were attenuated in CCl4-treated ΔEGFR mice when compared with CCl4-treated WT mice, coinciding with a faster resolution of the fibrotic process and ameliorated damage. The absence of EGFR activity in hepatocytes induced changes in the pattern of immune cells in the liver, with a notable increase in the population of M2 macrophages, more related to fibrosis resolution, as well as in the population of lymphocytes related to eradication of the damage. Transcriptome analysis of hepatocytes, and secretome studies of extracellular media from in vitro experiments, allowed us to elucidate the specific molecular mechanisms regulated by EGFR that mediate hepatocyte production of both pro-fibrotic and pro-inflammatory mediators; these have consequences for the deposition of extracellular matrix proteins, as well as for the immune microenvironment. Overall, our study uncovered novel mechanistic insights regarding EGFR kinase-dependent actions in hepatocytes that reveal its key role in chronic liver damage. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Studying interactions among anthropogenic stressors in freshwater ecosystems: A systematic review of 2396 multiple-stressor experiments.

Understanding the interactions among anthropogenic stressors is critical for effective conservation and management of ecosystems. Freshwater scientists have invested considerable resources in conducting factorial experiments to disentangle stressor interactions by testing their individual and combined effects. However, the diversity of stressors and systems studied has hindered previous syntheses of this body of research. To overcome this challenge, we used a novel machine learning framework to identify relevant studies from over 235,000 publications. Our synthesis resulted in a new dataset of 2396 multiple-stressor experiments in freshwater systems. By summarizing the methods used in these studies, quantifying trends in the popularity of the investigated stressors, and performing co-occurrence analysis, we produce the most comprehensive overview of this diverse field of research to date. We provide both a taxonomy grouping the 909 investigated stressors into 31 classes and an open-source and interactive version of the dataset (https://jamesaorr.shinyapps.io/freshwater-multiple-stressors/). Inspired by our results, we provide a framework to help clarify whether statistical interactions detected by factorial experiments align with stressor interactions of interest, and we outline general guidelines for the design of multiple-stressor experiments relevant to any system. We conclude by highlighting the research directions required to better understand freshwater ecosystems facing multiple stressors.

Three perspectives on the prediction of chemical effects in ecosystems.

The increasing production, use and emission of synthetic chemicals into the environment represents a major driver of global change. The large number of synthetic chemicals, limited knowledge on exposure patterns and effects in organisms and their interaction with other global change drivers hamper the prediction of effects in ecosystems. However, recent advances in biomolecular and computational methods are promising to improve our capacity for prediction. We delineate three idealised perspectives for the prediction of chemical effects: the suborganismal, organismal and ecological perspective, which are currently largely separated. Each of the outlined perspectives includes essential and complementary theories and tools for prediction but captures only part of the phenomenon of chemical effects. Links between the perspectives may foster predictive modelling of chemical effects in ecosystems and extrapolation between species. A major challenge for the linkage is the lack of data sets simultaneously covering different levels of biological organisation (here referred to as biological levels) as well as varying temporal and spatial scales. Synthesising the three perspectives, some central aspects and associated types of data seem particularly necessary to improve prediction. First, suborganism- and organism-level responses to chemicals need to be recorded and tested for relationships with chemical groups and organism traits. Second, metrics that are measurable at many biological levels, such as energy, need to be scrutinised for their potential to integrate across levels. Third, experimental data on the simultaneous response over multiple biological levels and spatiotemporal scales are required. These could be collected in nested and interconnected micro- and mesocosm experiments. Lastly, prioritisation of processes involved in the prediction framework needs to find a balance between simplification and capturing the essential complexity of a system. For example, in some cases, eco-evolutionary dynamics and interactions may need stronger consideration. Prediction needs to move from a static to a real-world eco-evolutionary view.

A glomerular transcriptomic landscape of apolipoprotein L1 in Black patients with focal segmental glomerulosclerosis.

Apolipoprotein L1 (APOL1)-associated focal segmental glomerulosclerosis (FSGS) is the dominant form of FSGS in Black individuals. There are no targeted therapies for this condition, in part because the molecular mechanisms underlying APOL1's pathogenic contribution to FSGS are incompletely understood. Studying the transcriptomic landscape of APOL1 FSGS in patient kidneys is an important way to discover genes and molecular behaviors that are unique or most relevant to the human disease. With the hypothesis that the pathology driven by the high-risk APOL1 genotype is reflected in alteration of gene expression across the glomerular transcriptome, we compared expression and co-expression profiles of 15,703 genes in 16 Black patients with FSGS at high-risk vs 14 Black patients with a low-risk APOL1 genotype. Expression data from APOL1-inducible HEK293 cells and normal human glomeruli were used to pursue genes and molecular pathways uncovered in these studies. We discovered increased expression of APOL1 and nine other significant differentially expressed genes in high-risk patients. This included stanniocalcin, which has a role in mitochondrial and calcium-related processes along with differential correlations between high- and low-risk APOL1 and metabolism pathway genes. There were similar correlations with extracellular matrix- and immune-related genes, but significant loss of co-expression of mitochondrial genes in high-risk FSGS, and an NF-κB-down regulating gene, NKIRAS1, as the most significant hub gene with strong differential correlations with NDUF family (mitochondrial respiratory genes) and immune-related (JAK-STAT) genes. Thus, differences in mitochondrial gene regulation appear to underlie many differences observed between high- and low-risk Black patients with FSGS.

Binary-lens-embedded photonic crystals.

A binary-lens-embedded photonic crystal (B-LEPC) was designed for operation at 1550 nm and fabricated by multiphoton lithography. The lens is binary in the sense that optical path difference is generated using unit cells having just two distinct fill factors. The unit cells have a "rod-in-wall" structure that exhibits three-dimensional self-collimation. Simulations show that self-collimation forces light to move through the device without diffracting or focusing, even as the wavefront is reshaped by the lensing region. Upon exiting the device, the curved wavefront causes the light to focus. The thickness of a B-LEPC was reduced threefold by wrapping phase in the style of a Fresnel lens. Embedding a faster-varying phase profile enables tighter focusing, and numerical aperture NA = 0.59 was demonstrated experimentally.

A pharmacokinetic and pharmacodynamic analysis of drug forgiveness.

Nonadherence to medication is a major public health problem. To combat nonadherence, some clinicians have suggested using "forgiving" drugs, which maintain efficacy in spite of delayed or missed doses. What pharmacokinetic (PK) and pharmacodynamic (PD) factors make a drug forgiving? In this paper, we address this question by analyzing a linear PK/PD model for a patient with imperfect adherence. We assume that the drug effect is far from maximal and consider direct effect, effect compartment (biophase), and indirect response PD models. We prove that the average drug effect relative to the clinically desired effect is simply the fraction of prescribed doses actually taken by the patient. Hence, under these assumptions, drug forgiveness cannot be defined in terms of the average effect. We argue that forgiveness should instead be understood in terms of effect fluctuations. We prove that the rates of PK absorption, PK elimination, and PD elimination are exactly equivalent for determining effect fluctuations. We prove all the aforementioned results for any pattern of nonadherence, including late doses, missed doses, drug holidays, extra doses, etc. To obtain quantitative estimates of effect fluctuations, we consider a simple statistical pattern of nonadherence and analytically calculate the coefficient of variation of effect. We further show how effect fluctuations can be reduced by taking an extra "make up" dose following a missed dose if any one of the aforementioned PK/PD rates is sufficiently slow. We illustrate some of our results for a nonlinear indirect response model of metformin.

The Development of a Digital Twin Framework for an Industrial Robotic Drilling Process.

A digital twin is a digital representation of a physical entity that is updated in real-time by transfer of data between physical and digital (virtual) entities. In this manuscript we aim to introduce a digital twin framework for robotic drilling. Initially, a generic reference model is proposed to highlight elements of the digital twin relevant to robotic drilling. Then, a precise reference digital twin architecture model is developed, based on available standards and technologies. Finally, real-time visualisation of drilling process parameters is demonstrated as an initial step towards implementing a digital twin of a robotic drilling process.

Babesia vulpes in a dog from Prince Edward Island, Canada.

A 12-year-old neutered male American Staffordshire terrier dog was referred to the Atlantic Veterinary College, Prince Edward Island, Canada, for suspected immune-mediated hemolytic anemia. Babesiosis (Babesia vulpes) was confirmed using polymerase chain reaction testing. The dog was successfully treated with a 10-day protocol of atovaquone/proguanil (TEVA Pharmaceutical Industries, Toronto, Ontario), 13.5 mg/kg BW, PO, q8h and azithromycin (Pharmascience, Montreal, Quebec), 10 mg/kg BW, PO, q24h. To the authors' knowledge, this report is the first documented case of babesiosis caused by Babesia vulpes in a dog from Canada.

Babesia vulpes chez un chien de l'Île-du-Prince-Édouard, Canada. Un chien American Staffordshire terrier mâle castré de 12 ans a été référé au Atlantic Veterinary College, Île-du-Prince-Édouard, Canada, pour suspicion d'anémie hémolytique à médiation immunitaire. La babésiose (Babesia vulpes) a été confirmée à l'aide d'un test d'amplification en chaîne par la polymérase. Le chien a été traité avec succès avec un protocole de 10 jours d'atovaquone/proguanil (TEVA Pharmaceutical Industries, Toronto, Ontario), 13,5 mg/kg BW, PO, q8h et azithromycine (Pharmascience, Montréal, Québec), 10 mg/kg BW, PO, q24h. À la connaissance des auteurs, ce rapport est le premier cas documenté de babésiose causée par Babesia vulpes chez un chien du Canada.(Traduit par Dr Serge Messier).

Warming and imidacloprid pulses determine macroinvertebrate community dynamics in experimental streams.

Sustainable management of freshwater and pesticide use is essential for mitigating the impacts of intensive agriculture in the context of a changing climate. To better understand how climate change will affect the vulnerability of freshwater ecosystems to chemical pollutants, more empirical evidence is needed on the combined effects of climatic and chemical stressors in environmentally realistic conditions. Our experiment provides the first empirical evaluation of stream macroinvertebrate community dynamics in response to one of the world's most widely used insecticides, imidacloprid, and increased water temperature. In a 7-week streamside experiment using 128 flow-through circular mesocosms, we investigated the effects of pulsed imidacloprid exposure (four environmentally relevant levels between 0 and 4.6 µg/L) and raised water temperature (ambient, 3°C above) on invertebrate communities representative of fast- and slow-flowing microhabitats. Invertebrate drift and insect emergence were monitored during three pesticide pulses (10 days apart), and benthic invertebrate communities were sampled after 24 days of heating and pesticide manipulations. All three manipulated factors strongly affected drift community composition. The first imidacloprid pulse and increased temperature had a greater impact on communities in fast-flowing mesocosms, which contained more pollution-sensitive EPT taxa (mayflies, stoneflies and caddisflies). Heating and imidacloprid caused increased emigration by drift, weak reductions in emergence, and negatively affected the benthic community. The combined effect of stressor manipulations and a 10-day natural heatwave drastically reduced relative abundances of EPT and insects overall and caused a shift to oligochaete-, crustacean- and gastropod-dominated communities. Contrary to our hypothesis, the very high yet realistic water temperatures reached in our experiment meant the negative effects of imidacloprid were clearest at ambient temperatures and fast flow. These findings demonstrate the potential combined impacts of imidacloprid contamination and heatwaves on freshwater invertebrate communities under future climate scenarios and highlight the need for more countries to take regulatory action to control neonicotinoid use.

Wide-band self-collimation in a low-refractive-index hexagonal lattice.

Wide-angle, broadband self-collimation (SC) is demonstrated in a hexagonal photonic crystal (PhC) fabricated in a low-refractive-index photopolymer by multiphoton lithography. The PhC can be described as a hexagonal array of cylindrical air holes in a block of dielectric material having a low-refractive index. Optical characterization shows that the device strongly self-collimates light at near-infrared wavelengths that span 1360 to 1610 nm. SC forces light to flow along the extrusion direction of the lattice without diffractive spreading, even when light couples into the device at high oblique angles. Numerical simulations corroborate the experimental findings.

Fine sediment and flow velocity impact bacterial community and functional profile more than nutrient enrichment.

Freshwater ecosystems face many simultaneous pressures due to human activities. Consequently, there has been a rapid loss of freshwater biodiversity and an increase in biomonitoring programs. Our study assessed the potential of benthic stream bacterial communities as indicators of multiple-stressor impacts associated with urbanization and agricultural intensification. We conducted a fully crossed four-factor experiment in 64 flow-through mesocosms fed by a pristine montane stream (21 d of colonization, 21 d of manipulations) and investigated the effects of nutrient enrichment, flow-velocity reduction and added fine sediment after 2 and 3 weeks of stressor exposure. We used high-throughput sequencing and metabarcoding techniques (16S rRNA genes), as well as curated biological databases (METAGENassit, MetaCyc), to identify changes in bacterial relative abundances and predicted metabolic functional profile. Sediment addition and flow-velocity reduction were the most pervasive stressors. They both increased α-diversity and had strong taxon-specific effects on community composition and predicted functions. Sediment and flow velocity also interacted frequently, with 88% of all bacterial response variables showing two-way interactions and 33% showing three-way interactions including nutrient enrichment. Changes in relative abundances of common taxa were associated with shifts in dominant predicted functions, which can be extrapolated to underlaying stream-wide mechanisms such as carbon use and bacterial energy production pathways. Observed changes were largely stable over time and occurred after just 2 weeks of exposure, demonstrating that bacterial communities can be well-suited for early detection of multiple stressors. Overall, added sediment and reduced flow velocity impacted both bacterial community structure and predicted function more than nutrient enrichment. In future research and stream management, a holistic approach to studying multiple-stressor impacts should include multiple trophic levels with their functional responses, to enhance our mechanistic understanding of complex stressor effects and promote establishment of more efficient biomonitoring programs.

A challenging case of Cushing's disease complicated with multiple thrombotic phenomena following trans-sphenoidal surgery; a case report.

BACKGROUND: Cushing's syndrome occurs due to overproduction of cortisol from adrenal glands. Endogenous hypercortisolemia can occur secondary to adrenocorticotropic hormone (ACTH) dependent as well as independent causes. The presence of non-specific symptoms and signs contributes to a delay in diagnosis. Early identification and prompt definitive management is crucial. It is important to be alert about the post-operative complications including multiple thrombotic phenomena, which can add to the mortality. We report a case of Cushing's disease in a young female managed with trans-sphenoidal surgery, followed by a challenging post-operative period complicated with multiple thrombotic phenomena, ultimately succumbed. CASE PRESENTATION: A 32-year-old Sri Lankan female presented with overt features of Cushing's syndrome and diagnosed to have ACTH dependent Cushing's disease with pituitary microadenoma. She underwent trans-sphenoidal surgery, following which she developed fatal multiple complications including diverticular rupture and ischemic colitis, needing hemicolectomy, followed by a parieto-occipital infarction. CONCLUSION: This case highlights important and aggressive complications associated with Cushing's syndrome giving rise to a challenging post-operative course. Diverticular rupture had been described in association with hypercortisolemia and this case adds to the existing literature. Post-operative ischemic colitis and stroke which contributed to the death of this patient could have been due to the procoagulant state associated with Cushing's syndrome, with a high risk during the immediate post-operative period. This emphasizes the need to consider post-operative thromboprophylaxis in patients undergoing surgery for Cushing's syndrome.

Arteriovenous Fistula for dialysis - Let's Google it. Readability and quality of online information.

BACKGROUND: This study evaluated the readability and quality of information regarding arteriovenous (AV) fistula for dialysis on the Internet in the English language. STUDY DESIGN: Using Google© search, the keywords "AV Fistula for dialysis" were searched. The top 75 ranking sites were analyzed. One website was excluded due to repetition. Each landing page was assessed independently by two authors (RB, LR) for readability using the Flesch Reading Ease Score (FRES) and Gunning Fog Index (GFI). Web site quality was assessed using the DISCERN instrument. The individual position of the top 15 websites in the search engine ranking order list was noted. The country of origin, organization type and issuance of Health on the Net (HoN) Certification was recorded. Statistical analyses were performed using unpaired t-tests and ANOVA variance. RESULTS: The mean GFI score was 9.2 and the mean FRES score was 50.6, indicating poor readability. The mean DISCERN score was 48.4, indicating weak quality of websites. Website quality was influenced by the academic/healthcare organization type (p = 0.012). Organization type was not found to impact GFI and FRES scores. Presence of a HoN Certification was not found to impact the quality of information. The majority of sites originated from the United States (61%). CONCLUSION: Our study demonstrates that internet information pertaining to AV fistula for dialysis is of poor quality necessitating improvements to readability and overall website quality to improve the patient experience. Further research into how to improve healthcare web information is needed.

Prevention and management of COVID-19 among patients with diabetes: an appraisal of the literature.

The coronavirus disease 2019 (COVID-19) pandemic has emerged as one of the greatest challenges faced by humankind in the recent past. People with diabetes and related comorbidities are at increased risk of its complications and of COVID-19-related death. Older age, multi-morbidity, hyperglycaemia, cardiac injury and severe inflammatory response are predictors of poor outcome. The complex interplay between COVID-19, diabetes and the effects of related therapies is being explored. Most patients experience a mild illness with COVID-19, while people with diabetes are at increased risk of severe disease. Optimising glycaemic control and adopting measures to prevent disease spread are critical aspects. The management of mild disease is supportive, while very many immunomodulatory and antiviral therapies are being investigated for the treatment of severe disease. Several of these agents have specific considerations for use in people with diabetes. Since mass population lockdowns are considered a key step in controlling disease spread, it follows that, in addition to the direct vulnerability to severe COVID-19, people with diabetes can be affected by limited access to healthcare, insulin, other medications and blood glucose monitoring equipment. Measures to prevent disease spread at the individual and community level are the key to mitigating the rapidly escalating pandemic, while agents for chemoprophylaxis and vaccines are being explored. People with diabetes should be recognised as a vulnerable group for complicated disease and are at risk during times of disturbed social systems. Strategies are needed to safeguard the health of patients with diabetes during the pandemic. This review summarises the current knowledge and perceived challenges for prevention and management of COVID-19 in people with diabetes.

X-ray-based quantitative osteoporosis imaging at the spine.

Osteoporosis is a metabolic bone disease with a high prevalence that affects the population worldwide, particularly the elderly. It is often due to fractures associated with bone fragility that the diagnosis of osteoporosis becomes clinically evident. However, early diagnosis would be necessary to initiate therapy and to prevent occurrence of further fractures, thus reducing morbidity and mortality. X-ray-based imaging plays a key role for fracture risk assessment and monitoring of osteoporosis. Whereas over decades dual-energy X-ray absorptiometry (DXA) has been the main method used and still reflects the reference standard, another modality reemerges with quantitative computed tomography (QCT) because of its three-dimensional advantages and the opportunistic exploitation of routine CT scans. Against this background, this article intends to review and evaluate recent advances in the field of X-ray-based quantitative imaging of osteoporosis at the spine. First, standard DXA with the recent addition of trabecular bone score (TBS) is presented. Secondly, standard QCT, dual-energy BMD quantification, and opportunistic BMD screening in non-dedicated CT exams are discussed. Lastly, finite element analysis and microstructural parameter analysis are reviewed.

Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico.

Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others, with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. Here we analysed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and other Latin Americans: 3,848 with type 2 diabetes and 4,366 non-diabetic controls. In addition to replicating previous findings, we identified a novel locus associated with type 2 diabetes at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P = 3.9 × 10(-13); odds ratio (OR) = 1.29). The association was stronger in younger, leaner people with type 2 diabetes, and replicated in independent samples (P = 1.1 × 10(-4); OR = 1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at ~50% frequency in Native American samples and ~10% in east Asian, but is rare in European and African samples. Analysis of an archaic genome sequence indicated that the risk haplotype introgressed into modern humans via admixture with Neanderthals. The SLC16A11 messenger RNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite type 2 diabetes having been well studied by genome-wide association studies in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for type 2 diabetes with a possible role in triacylglycerol metabolism.

Independent control of phase and power in spatially variant self-collimating photonic crystals.

Self-collimating photonic crystals are a promising technology to control waves in optical devices. A technique was recently developed that can bend, twist, and otherwise spatially vary a photonic crystal without deforming the unit cells, as this would weaken or destroy the optical properties. Applying this to self-collimating photonic crystals allows us to control multiple properties of light at the same time. A spatially variant self-collimating photonic crystal is shown that decouples the phase and power of the wave and controls them independently and at the same time within the same volume. This creates new physical mechanisms from which to design optical systems. Some possible applications include miniaturization of optical systems, integrated optics, beam steering, and imaging, among others.

Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms.

To gain insight into potential regulatory mechanisms through which the effects of variants at four established type 2 diabetes (T2D) susceptibility loci (CDKAL1, CDKN2A-B, IGF2BP2 and KCNQ1) are mediated, we undertook transancestral fine-mapping in 22 086 cases and 42 539 controls of East Asian, European, South Asian, African American and Mexican American descent. Through high-density imputation and conditional analyses, we identified seven distinct association signals at these four loci, each with allelic effects on T2D susceptibility that were homogenous across ancestry groups. By leveraging differences in the structure of linkage disequilibrium between diverse populations, and increased sample size, we localised the variants most likely to drive each distinct association signal. We demonstrated that integration of these genetic fine-mapping data with genomic annotation can highlight potential causal regulatory elements in T2D-relevant tissues. These analyses provide insight into the mechanisms through which T2D association signals are mediated, and suggest future routes to understanding the biology of specific disease susceptibility loci.