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In the United States, hundreds of thousands of undocumented orphan wells have been abandoned, leaving the burden of managing environmental hazards to governmental agencies or the public. These wells, a result of over a century of fossil fuel extraction without adequate regulation, lack basic information like location and depth, emit greenhouse gases, and leak toxic substances into groundwater. For most of these wells, basic information such as well location and depth is unknown or unverified. Addressing this issue necessitates innovative and interdisciplinary approaches for locating, characterizing, and mitigating their environmental impacts. Our survey of the United States revealed the need for tools to identify well locations and assess conditions, prompting the development of technologies including machine learning to automatically extract information from old records (95%+ accuracy), remote sensing technologies like aero-magnetometers to find buried wells, and cost-effective methods for estimating methane emissions. Notably, fixed-wing drones equipped with magnetometers have emerged as cost-effective and efficient for discovering unknown wells, offering advantages over helicopters and quadcopters. Efforts also involved leveraging local knowledge through outreach to state and tribal governments as well as citizen science initiatives. These initiatives aim to significantly contribute to environmental sustainability by reducing greenhouse gases and improving air and water quality.

When teaching STEM courses, it is important to introduce state-of-the-art techniques. Students need to learn how to conduct experiments, analyse data and choose the most effective approaches to address meaningful situations. Here we present the assessment of the implementation of a structured inquiry-based activity aimed at teaching students about protein mass and size. This activity emerges as an intervention in our educational module, designed to create a cognitive conflict that effectively drives a conceptual change. To evaluate the efficacy of this module, we collected data on students’ perceived and actual knowledge through pre- and post-class surveys (n= 36 and 34, respectively, mean age 26 ± 2). Additionally, we evaluated lab reports using a detailed rubric. Results indicate that the practical innovation we propose is a challenging activity that promotes the accomplishment of our learning objectives. The activity led to improvements both in confidence and in actual mastery of theoretical concepts and techniques. After completing the activity, students were able to choose the most appropriate technique to solve specific problems. Furthermore, we found that the use of a structured questionnaire in lab reports helped students to accurately analyse and process experimental data. It also allows them to demonstrate understanding of technical limitations, while integrating the knowledge and skills acquired during the module. Overall, this activity provides notions that are conceivable and profitable, thus leading to successful conceptual changes.

Disorders of Gut‐Brain Interaction (DGBI) are highly prevalent worldwide, but their effect on work productivity has not gained much attention. We aimed to compare work productivity and activity impairment (WPAI) in persons with and without DGBI in a large population‐based cohort and identify factors independently associated with WPAI in subjects with DGBI. Data were collected from Germany, Israel, Italy, Japan, the Netherlands, Poland, Spain and Sweden via Internet surveys as part of the Rome Foundation Global Epidemiology Study. Apart from the Rome IV diagnostic questionnaire, questionnaires evaluating WPAI related to general health (WPAI:GH), psychological distress (PHQ‐4), somatic symptom severity (PHQ‐15) and other factors were assessed. Of the 16,820 subjects, 7111 met the criteria for DGBI according to the Rome IV diagnostic questionnaire. Subjects with DGBI were younger (median (interquartile range) age 43 (31–58) vs. 47 (33–62)) and more often female (59.0% vs. 43.7%) compared to subjects without DGBI. Subjects with DGBI had higher absenteeism, presenteeism (poor work productivity due to illness), overall work impairment and activity impairment (p< 0.001) compared with subjects without. For subjects with DGBI affecting more than one anatomical region, WPAI was incrementally higher for each additional region. There were significant differences in WPAI for subjects with DGBI in different countries. Subjects from Sweden had the highest overall work impairment and from Poland the lowest. Using multiple linear regression, male sex, fatigue, psychological distress, somatic symptom severity and number of anatomical regions were independently associated with overall work impairment (p< 0.05 for all). In the general population, people with DGBI have substantial WPAI compared with those without DGBI. The reasons for these findings should be explored further, but having multiple DGBI, psychological distress, fatigue and somatic symptom severity seem to contribute to this impairment associated with DGBI.

Psychological stress and increased permeability are implicated as contributing factors in the initiation and worsening of gastrointestinal diseases. A link between stress and intestinal permeability has been shown in animal models as well as in human small intestine, but stress effects on the human colorectal mucosal barrier has not been reported. To investigate the potential effects of acute psychological stress on colorectal mucosal barrier function and to explore stress‐induced molecular events in the rectal mucosa under healthy conditions. Endoscopic biopsies were taken from the rectosigmoid region of healthy volunteers, who had been subjected to dichotomous listening stress and after a control session, respectively. Paracellular and transcellular permeability were assessed in modified Ussing chambers. RNA expression (microarray technology confirmed by quantitative real‐time polymerase chain reaction) and biological pathway analysis were used to investigate the local mucosal response to acute stress. Dichotomous listening stress induced a subjective and objective stress response, and significantly increased paracellular but not transcellular permeability. We also identified a stress‐induced reduction in RNA expression of genes related to immune cell activation and maturation (CR2, CD20, TCLA1, BANK1, CD22, FDCSP), signaling molecules of homing of immune cells to the gut (chemokines: CCL21, CXCL13, and CCL19, and receptors: CCR7, CXCR5), and innate immunity (DUOX2). Eight of the 10 top down‐regulated genes are directly involved in B cell activation, signaling and migration. The systemic stress response correlated positively with paracellular permeability and negatively with DUOX2expression. Dichotomous listening stress increases paracellular permeability and modulates immune cell activity in the rectal mucosa. Further studies are warranted to identify the primary mechanisms of stress‐mediated reduction of mucosal defensive activity and barrier dysfunction, and their potential implications for gastrointestinal disorders.

ObjectivesThe long-term consequences of COVID-19 infection on the gastrointestinal tract remain unclear. Here, we aimed to evaluate the prevalence of gastrointestinal symptoms and post-COVID-19 disorders of gut–brain interaction after hospitalisation for SARS-CoV-2 infection.DesignGI-COVID-19 is a prospective, multicentre, controlled study. Patients with and without COVID-19 diagnosis were evaluated on hospital admission and after 1, 6 and 12 months post hospitalisation. Gastrointestinal symptoms, anxiety and depression were assessed using validated questionnaires.ResultsThe study included 2183 hospitalised patients. The primary analysis included a total of 883 patients (614 patients with COVID-19 and 269 controls) due to the exclusion of patients with pre-existing gastrointestinal symptoms and/or surgery. At enrolment, gastrointestinal symptoms were more frequent among patients with COVID-19 than in the control group (59.3% vs 39.7%, p<0.001). At the 12-month follow-up, constipation and hard stools were significantly more prevalent in controls than in patients with COVID-19 (16% vs 9.6%, p=0.019 and 17.7% vs 10.9%, p=0.011, respectively). Compared with controls, patients with COVID-19 reported higher rates of irritable bowel syndrome (IBS) according to Rome IV criteria: 0.5% versus 3.2%, p=0.045. Factors significantly associated with IBS diagnosis included history of allergies, chronic intake of proton pump inhibitors and presence of dyspnoea. At the 6-month follow-up, the rate of patients with COVID-19 fulfilling the criteria for depression was higher than among controls.ConclusionCompared with controls, hospitalised patients with COVID-19 had fewer problems of constipation and hard stools at 12 months after acute infection. Patients with COVID-19 had significantly higher rates of IBS than controls.Trial registration numberNCT04691895.

A signaling molecule that plays a role in the innate immune system, stimulator of IFN genes (STING), is a crucial regulator of the cyclic GMP-AMP synthase (cGAS)-STING pathway. This signaling pathway regulates inflammation and energy homeostasis under conditions of obesity, kidney fibrosis, and AKI, but its exact role in the pathogenesis of glomerular diseases remains unclear. The authors found that activation of STING in wild-type mice is sufficient to cause albuminuria and podocyte loss, and that the cGAS-STING signaling pathway is upregulated in mice with experimental diabetic kidney disease and Alport syndrome. They also demonstrated that either genetic or pharmacologic STING inhibition confers protection from kidney disease progression. These findings suggest that this signaling pathway plays an important role in mediating glomerular dysfunction.

Hydrocarbon production from shale reservoirs is inherently inefficient and challenging since these are low permeability plays. In addition, there is a limited understanding of the fundamentals and the controlling mechanisms, further complicating how to optimize these plays. Herein, we summarize our experimental and computational efforts to reveal unconventional shale fundamentals and devise development strategies to enhance extraction efficiency with a minimal environmental footprint. Integrating these fundamentals with machine learning, we outline a pathway to improve the predictive power of our models, which enhances the forecast quality of production, thereby improving the economics of operations in unconventional reservoirs. We will discuss the main processes involving the matrix, hydraulic fractures, enhanced oil recovery, and carbon dioxide sequestration. In addition, we present science-informed workflows and platforms to optimize pressure-drawdown at a site, enable real-time reservoir management, accelerate numerical modeling and quantify uncertainty. We summarize our insights on pressure-drawdown optimization to maximize recovery while considering the lifetime of the well. In addition, we demonstrate our work on the hybridization of physics-based prediction and machine learning, whereby accurate synthetic data (combined with available site data) can enable the application of machine learning methods for rapid forecasting and optimization. Consequently, the workflow and platform are readily extendable to operations at other sites, plays and basins.

The health care system and the provision of nursing care continually increase in complexity. Rapidly progressing technological advances affect almost every aspect of health professions. In a seminal article, Moore [...]

OBJECTIVE--Nephrin, an immunoglobulin-like protein essential for the function of the glomerular podocyte and regulated in diabetic nephropathy, is also expressed in pancreatic β-cells, where its function remains unknown. The aim of this study was to investigate whether diabetes modulates nephrin expression in human pancreatic islets and to explore the role of nephrin in β-cell function. RESEARCH DESIGN AND METHODS--Nephrin expression in human pancreas and in MIN6 insulinoma cells was studied by Western blot, PCR, confocal microscopy, subcellular fractionation, and immunogold labeling. Islets from diabetic (n = 5) and nondiabetic (n = 7) patients were compared. Stable transfection and siRNA knockdown in MIN-6 cells/human islets were used to study nephrin function in vitro and in vivo after transplantation in diabetic immunodeficient mice. Live imaging of green fluorescent protein (GFP)-nephrin-transfected cells was used to study nephrin endocytosis. RESULTS--Nephrin was found at the plasma membrane and on insulin vesicles. Nephrin expression was decreased in islets from diabetic patients when compared with nondiabetic control subjects. Nephrin transfection in MIN-6 cells/pseudoislets resulted in higher glucose-stimulated insulin release in vitro and in vivo after transplantation into immunodeficient diabetic mice. Nephrin gene silencing abolished stimulated insulin release. Confocal imaging of GFP-nephrin-transfected cells revealed nephrin endocytosis upon glucose stimulation. Actin stabilization prevented nephrin trafficking as well as nephrin-positive effect on insulin release. CONCLUSIONS--Our data suggest that nephrin is an active component of insulin vesicle machinery that may affect vesicle-actin interaction and mobilization to the plasma membrane. Development of drugs targeting nephrin may represent a novel approach to treat diabetes., In the U.S. alone, diabetes affects >20 million people. Although advances have been made in the clinical care of diabetes, one of the major limitations for finding a cure is [...]

Purpose: This research has the following specific objectives: provide an overview of the literature addressing operational excellence (OE) and OE in emerging countries; propose an integrative framework of OE attributes; and propose future research directions for the OE literature. Design/methodology/approach: To remain competitive in industry, many organizations are implementing OE initiatives. However, achieving OE in emerging markets has been a pressing challenge due to the scarce knowledge on how it works. Through a systematic review of the literature, this study aims to contribute to a deeper understanding of the concept of OE in emerging countries through the triple bottom line. Findings: This study has found nine attributes of OE based on the three pillars of sustainability or triple bottom line (economic, environmental and social). Four of them were the most cited and served to build the proposed framework. The analysis concludes that most of the studies related to OE in emerging countries have been carried out in Asia. Finally, based on the results obtained from the literature review, six points of future research are proposed based on three research directions: OE in emerging countries, active participation by employees and culture generation and finally, research methods. Originality/value: The gap that is filled in this study is that some authors have studied the application of OE in emerging countries, specifically on the Asian continent. In those cases, the literature is either oriented to describing OE from different perspectives or to its application in different companies, some of which are emerging countries. However, to the best of the authors’ knowledge, there is no study that describes the specific and complete aspects that make up a model of OE and which can show how this model can be applied in emerging countries.

Background: Traditionally, many patients with acute deep vein thrombosis (DVT) are treated not only by anticoagulation therapy but additionally by strict bed rest, which is aimed at reducing the risk [...]

Lean and green are major, compatible management initiatives because of their joint focus on waste reduction, efficient use of resources and emphasis on satisfying customer needs at the lowest possible cost (economic and environmental). From this angle, this paper presents a bibliometric analysis of the integration of lean and green management. To that end, this paper analyses 685 research papers retrieved from the Scopus database using the following parameters: year of publication, discipline, source, institution, country and citations. This final dataset was composed of articles from scientific journals published between 1992-2018. Furthermore, VOSviewer software was used to map the bibliographic material using the coupling of countries and the co-occurrence of keywords. The analysis indicates that research on lean and green topics has increased in recent years, and that moreover the topic is structured into three clusters: 1) manufacturing; 2) energy, emissions and costs; 3) Lean Six Sigma. These highlights can facilitate the development of future research on this topic.

Defective cholesterol metabolism primarily linked to reduced ATP-binding cassette transporter A1 (ABCA1) expression is closely associated with the pathogenesis and progression of kidney diseases, including diabetic kidney disease and Alport Syndrome. However, whether the accumulation of free or esterified cholesterol contributes to progression in kidney disease remains unclear. Here, we demonstrate that inhibition of sterol-O-acyltransferase-1 (SOAT1), the enzyme at the endoplasmic reticulum that converts free cholesterol to cholesterol esters, which are then stored in lipid droplets, effectively reduced cholesterol ester and lipid droplet formation in human podocytes. Furthermore, we found that inhibition of SOAT1 in podocytes reduced lipotoxicity-mediated podocyte injury in diabetic kidney disease and Alport Syndrome in association with increased ABCA1 expression and ABCA1-mediated cholesterol efflux. In vivo, Soat1deficient mice did not develop albuminuria or mesangial expansion at 10-12 months of age. However, Soat1deficiency/inhibition in experimental models of diabetic kidney disease and Alport Syndrome reduced cholesterol ester content in kidney cortices and protected from disease progression. Thus, targeting SOAT1-mediated cholesterol metabolism may represent a new therapeutic strategy to treat kidney disease in patients with diabetic kidney disease and Alport Syndrome, like that suggested for Alzheimer’s disease and cancer treatments.

Predicting the spatial configuration of gas in nanopores of is relevant in applications such as fluid flow forecasting and hydrocarbon reserves estimation. For example, shale reservoirs have suffered from computationally intractable multiscale problems, since fluid properties such as viscosity, density, and adsorption must be calculated by using expensive molecular dynamics (MD) simulations within each nanopore, whereas flow through these connected nanopores must be simulated at the micrometer scale. We utilize machine learning techniques to quickly and accurately model nanoscale confinement effects as an important step toward bridging the nano and micro scales. Our workflow is based on building and training physics-based deep-neural-networks models by learning from a database of MD calculations. The model accounts for the adsorption phenomenon by predicting the statistical distribution of gas inside nanopores. Because large databases of MD calculations are expensive to create, we investigate active learning (AL) as a data set construction strategy. In this workflow, new data are selected based on the model uncertainty via the query-by-committee approach. We show that our workflow obtains accurate models that generalize to real scanning electron microscopy geometries with 1/10th of the number of MD calculations required vs random data set generation. Our method enables the possibility of modeling nanoconfinement effects at the mesoscale, where complex connected sets of nanopores affect flow.

The purpose of this article was to determine the change in the volume of pacemaker implantations with the COVID‐2019 pandemic and to assess the change in the number of pacemaker implants according to etiology during the pandemic. The establishment of a mandatory social isolation have generated a decrease in activities in cardiology units. Descriptive, cross‐sectional study that used a database of a Peruvian Hospital. Time was divided into three categories: Before COVID period and COVID period including Previous to Social isolation (SI) and Social Isolation. The number of pacemaker implantations were compared per the same amount of time. A reduction in the pacemaker implant of 73% (95% CI: 33‐113; P< .001) was observed during the COVID‐19 pandemic period, and a reduction of 78% of patients with the diagnosis of complete or high‐grade atrioventricular block and a reduction in the de‐novo pacemaker implant was observed, regardless of the etiology. Our results indicate a very significant reduction (73%) in de‐novo pacemaker implantation during the months of the COVID‐19 pandemic. The reduction in the number of de‐novo pacemaker occurred independent of the etiology. This article reports the reduction of de‐novo pacemaker implants in a Peruvian hospital due to the COVID‐19 pandemic. The reduction in the number of de‐novo pacemaker occurred independently of the etiology.

Tanto la diabetes mellitus como la enfermedad renal crónica aumentan el riesgo de fibrilación auricular. A su vez, la concomitancia de diabetes mellitus y enfermedad renal crónica incrementa de manera sinérgica el riesgo tromboembólico asociado con la fibrilación auricular, lo que pone al paciente en esta situación en especial riesgo y obliga a no fijar nuestra actuación solo en la reducción del riesgo embólico, sino a buscar una protección general. Aunque todos los anticoagulantes orales reducen eficazmente el riesgo de ictus en el paciente diabético con fibrilación auricular, hay datos que indican que el rivaroxabán podría disminuir además la mortalidad cardiovascular en esta población, ofreciendo una protección adicional. Por otra parte, se ha descrito un empeoramiento de la función renal con el empleo de los antagonistas de la vitamina K (nefropatía por warfarina). En consecuencia, sería deseable que el tratamiento anticoagulante no solo disminuyera el riesgo de complicaciones tromboembólicas, sino que además no se asociara con este deterioro de la función renal. En este sentido, parece que algunos anticoagulantes orales de acción directa, como el dabigatrán y el rivaroxabán, tendrían un menor riesgo de eventos renales adversos en comparación con warfarina.

La identificación y el tratamiento del síndrome de sobrecrecimiento bacteriano intestinal (SIBO) son materias sujetas a controversia. Los síntomas que han orientado la búsqueda del trastorno adolecen de falta de especificidad, especialmente en ausencia de factores predisponentes bien definidos. La precisión de los procedimientos diagnósticos ha sido cuestionada y las terapias propuestas alcanzan cifras de efectividad en general bajas, con grandes diferencias entre los estudios disponibles. También se desconoce si la normalización de los test es realmente garantía de curación.

Protein dynamics, folding, and thermodynamics represent a central aspect of biophysical chemistry. pH, temperature, and denaturant perturbations inform our understanding of diverse contributors to stability and rates. In this work, we performed a thermodynamic analysis using a combined experimental and computational approach to gain insights into the role of electrostatics in the folding reaction of a psychrophile frataxin variant from Psychromonas ingrahamii. This folding reaction is strongly modulated by pH with a single, narrow, and well-defined transition state with ∼80% compactness, ∼70% electrostatic interactions, and ∼60% hydration shell compared to the native state (αD= 0.82, αH= 0.67, and αΔCp= 0.59). Our results are best explained by a two-proton/two-state model with very different pKavalues of the native and denatured states (∼5.5 and ∼8.0, respectively). As a consequence, the stability strongly increases from pH 8.0 to 6.0 (|ΔΔG°| = 5.2 kcal mol–1), mainly because of a decrease in the TΔS°. Variation of ΔH° and ΔS° at pH below 7.0 is dominated by a change in ΔHf⧧and ΔSf⧧, while at pH above 7.0, it is governed by ΔHu⧧and ΔSu⧧. Molecular dynamics simulations showed that these pH modulations could be explained by the fluctuations of two regions, rich in electrostatic contacts, whose dynamics are pH-dependent and motions are strongly correlated. Results presented herein contribute to the understanding of the stability and dynamics of this frataxin variant, pointing to an intrinsic feature of the family topology to support different folding mechanisms.

In recent years, the mammalian mitochondrial protein complex for iron–sulfur cluster assembly has been the focus of important studies. This is partly because of its high degree of relevance in cell metabolism and because mutations of the involved proteins are the cause of several human diseases. Cysteine desulfurase NFS1 is the key enzyme of the complex. At present, it is well-known that the active form of NFS1 is stabilized by the small protein ISD11. In this work, the structure of the human mitochondrial ACP-ISD11 heterodimer was determined at 2.0 Å resolution. ACP-ISD11 forms a cooperative unit stabilized by several ionic interactions, hydrogen bonds, and apolar interactions. The 4′-phosphopantetheine-acyl chain, which is covalently bound to ACP, interacts with several residues of ISD11, modulating together with ACP the foldability of ISD11. Recombinant human ACP-ISD11 was able to interact with the NFS1 desulfurase, thus yielding an active enzyme, and the NFS1/ACP-ISD11 core complex was activated by frataxin and ISCU proteins. Internal motions of ACP-ISD11 were studied by molecular dynamics simulations, showing the persistence of the interactions between both protein chains. The conformation of the dimer is similar to that found in the context of the (NFS1/ACP-ISD11)2supercomplex core, which contains the Escherichia coliACP instead of the human variant. This fact suggests a sequential mechanism for supercomplex consolidation, in which the ACP-ISD11 complex may fold independently and, after that, the NFS1 dimer would be stabilized.

Irritable bowel syndrome (IBS) is highly prevalent and presents a clinical challenge. Gelsectan is a medical device containing xyloglucan (XG), pea protein and tannins (PPT) from grape seed extract, and xylo-oligosaccharides (XOS), which act together to protect and reinforce the intestinal barrier. The objective of this study is to evaluate the efficacy and safety of XG?+?PPT?+?XOS in patients with diarrhoea-predominant IBS (IBS-D). In this double-blind study, 60 patients were randomly assigned to receive XG?+?PPT?+?XOS or placebo for 28 days, then crossed over to the alternative treatment. Patients were followed for 60 days. At Day 28, a significantly higher proportion of patients starting treatment with XG?+?PPT?+?XOS than placebo (87 vs 0%; p?=?0.0019) presented normal stools (Bristol Stool Form Scale type 3-4). At Day 56, a significantly higher proportion of patients who crossed over to XG?+?PPT?+?XOS than placebo (93% vs 23%; p?=?0.0001) presented normal stools. In the group allocated to receive XG?+?PPT?+?XOS after placebo, benefits of XG?+?PPT?+?XOS were maintained during follow-up. Subjective assessments of abdominal pain, bloating, quality of life and general health indicated significant improvement with XG?+?PPT?+?XOS over placebo. There were no related adverse events. XG?+?PPT?+?XOS effectively controlled diarrhoea and alleviated clinical symptoms in patients with IBS-D, and was well tolerated.

FBXW7is a driver gene in T-cell lymphoblastic neoplasia acting through proteasome degradation of key proto-oncogenes. FBXW7 encodes three isoforms, α, β and γ, which differ only in the N-terminus. In this work, massive sequencing revealed significant downregulation of FBXW7in a panel of primary T-cell lymphoblastic lymphomas characterised by the absence of mutations in its sequence. We observed that decreased expression mainly affected the FBXW7βisoform and to a lesser extent FBXW7αand may be attributed to the combined effect of epigenetic changes, alteration of upstream factors and upregulation of miRNAs. Transient transfections with miRNA mimics in selected cell lines resulted in a significant decrease of total FBXW7expression and its different isoforms separately, with the consequent increment of critical substrates and the stimulation of cell proliferation. Transient inhibition of endogenous miRNAs in a T-cell lymphoblastic-derived cell line (SUP-T1) was capable of reversing these proliferative effects. Finally, we show how FBXW7 isoforms display different roles within the cell. Simultaneous downregulation of the α and γ isoforms modulates the amount of CCNE1, whilst the β-isoform alone was found to have a prominent role in modulating the amount of c-MYC. Our data also revealed that downregulation of all isoforms is a sine qua noncondition to induce a proliferative pattern in our cell model system. Taking these data into account, potential new treatments to reverse downregulation of all or a specific FBXW7isoform may be an effective strategy to counteract the proliferative capacity of these tumour cells.

While it is known that energy efficiency (EE) lowers power sector demand and emissions, study of the air quality and public health impacts of EE has been limited. Here, we quantify the air quality and mortality impacts of a 12% summertime (June, July, and August) reduction in baseload electricity demand. We use the AVoided Emissions and geneRation Tool (AVERT) to simulate plant-level generation and emissions, the Community Multiscale Air Quality (CMAQ) model to simulate air quality, and the Environmental Benefits Mapping and Analysis Program (BenMAP) to quantify mortality impacts. We find EE reduces emissions of NOxby 13.2%, SO2by 12.6%, and CO2by 11.6%. On a nationwide, summer average basis, ambient PM2.5is reduced 0.55% and O3is reduced 0.45%. Reduced exposure to PM2.5avoids 300 premature deaths annually (95% CI: 60 to 580) valued at $2.8 billion ($0.13 billion to $9.3 billion), and reduced exposure to O3averts 175 deaths (101 to 244) valued at $1.6 billion ($0.15 billion to $4.5 billion). This translates into a health savings rate of $0.049/kWh ($0.031/kWh for PM2.5and $0.018/kWh for O3). These results illustrate the importance of capturing the health benefits of EE and its potential as a strategy to achieve air standards.

ABSTRACTNowadays companies are trying to become ‘greener’, which requires integrating the environmental dimension into their traditional performance metrics. However, managers may not have the complete information and data for their environmental problems and, crucially, there is a lack of knowledge about how these environmental issues affect a company’s productivity. Even though the availability of technology has increased and it is easier than ever to obtain all kinds of data, there is a lack of agreement on how to correctly measure environmental performance, and companies could suffer from an overload of environmental information. The biggest challenge, therefore, lies in how to measure and obtain the appropriate environmental data and how to interpret and relate these data to the company’s productivity. In this context, this paper presents a new and innovative approach, called Plug&Glean, for diagnosing and improving productivity and environmental performance in a defined production system. The approach is applied to a case study in the north of Spain. The findings suggest that it is possible to improve productivity and environmental performance at the same time, as well as reinforce the notion that waste elimination has a positive impact on improving environmental performance.

The importance of Discoidin Domain Receptor 1 (DDR1) in renal fibrosis has been shown via gene knockout and use of antisense oligonucleotides; however, these techniques act via a reduction of DDR1 protein, while we prove the therapeutic potential of inhibiting DDR1 phosphorylation with a small molecule. To date, efforts to generate a selective small-molecule to specifically modulate the activity of DDR1 in an in vivomodel have been unsuccessful. We performed parallel DNA encoded library screens against DDR1 and DDR2, and discovered a chemical series that is highly selective for DDR1 over DDR2. Structure-guided optimization efforts yielded the potent DDR1 inhibitor 2.45, which possesses excellent kinome selectivity (including 64-fold selectivity over DDR2 in a biochemical assay), a clean in vitrosafety profile, and favorable pharmacokinetic and physicochemical properties. As desired, compound 2.45modulates DDR1 phosphorylation in vitroas well as prevents collagen-induced activation of renal epithelial cells expressing DDR1. Compound 2.45preserves renal function and reduces tissue damage in Col4a3–/–mice (the preclinical mouse model of Alport syndrome) when employing a therapeutic dosing regime, indicating the real therapeutic value of selectively inhibiting DDR1 phosphorylation in vivo. Our results may have wider significance as Col4a3–/–mice also represent a model for chronic kidney disease, a disease which affects 10% of the global population.

Sustainability and Industry 4.0 are trending concepts today. It is expected that Industry 4.0 brings a multitude of benefits toward more sustainable operations such as manufacturing. In manufacturing, monitoring and control approaches are the most common tools included in the Industry 4.0 strategy. In this context, this paper presents a literature review concerning to control and monitoring techniques for sustainable-manufacturing decision making in the era of Industry 4.0. The objectives of this paper are to evaluate the state-of-the-art of this trending topic and to propose new opportunities and challenges that should be addressed in future research.

We model flow and transport in fracture networks with varying degrees of fracture‐to‐fracture aperture heterogeneity and network intensity to show how changes in these properties can cause the emergence of anomalous flow and transport behavior. If fracture‐to‐fracture aperture heterogeneity is increased in sparse networks, velocity fluctuations inhibit high flow rates and solute transport can be delayed. Surprisingly, transport can be slowed even in cases where hydraulic aperture is monotonically increased. As the intensity of the networks is increased, more connected pathways allow for particles to bypass these effects. There exists transition behavior where with relatively few connected pathways in a network, first arrival times of particles are not heavily affected by fracture‐to‐fracture aperture heterogeneity, but the scaling behavior of the tails is strongly influenced. These results reinforce the importance of considering multi‐scale effects in fractured systems and can inform flow and transport processes in both natural and engineered fractured systems. Fractured rocks are important to study to understand subsurface geology, hydrology, and engineered systems. Individual fractures often form connected networks with other fractures, which complicates the prediction of flow and transport behavior. In this work, we study how changes in fracture network properties such as the variability of fracture apertures and the number of fractures in a network, affect flow and transport observables, such as the amount of actively flowing network structure, as well as the arrival times of solutes. Our results point to rich behavior where there is a close link between how much variability exists between individual fracture apertures, the network intensity, and the behavior of the solute transport. When fracture networks have relatively few fractures, increases in the magnitude of the fracture apertures and the variability between individual apertures can cause unusual changes in the flow and transport, causing delays in solute transport times. However, these effects are gradually lost as the number of fractures in the network is increased. Our results can inform both natural hydrological processes, as well as engineered systems, such as enhanced geothermal systems and hydraulic fracturing because these systems often create high aperture fractures that connect to natural fractures with lower aperture. We investigate the influence of multi‐scale heterogeneity in fracture networks on flow and transport using discrete fracture network modelsHigh aperture heterogeneity across a sparse fracture network results in counter‐intuitive flow and transport behaviorEffects of fracture‐to‐fracture aperture heterogeneity are limited at high network intensities We investigate the influence of multi‐scale heterogeneity in fracture networks on flow and transport using discrete fracture network models High aperture heterogeneity across a sparse fracture network results in counter‐intuitive flow and transport behavior Effects of fracture‐to‐fracture aperture heterogeneity are limited at high network intensities

Studies suggest that altered renal lipid metabolism plays a role in the pathogenesis of diabetic kidney disease and that genetic or pharmacological induction of cholesterol efflux protects from the development of diabetic kidney disease and focal segmental glomerulosclerosis (FSGS). Here we tested whether altered lipid metabolism contributes to renal failure in the Col4a3 knockout mouse model for Alport Syndrome. There was an eight-fold increase in the cholesterol content in renal cortexes of mice with Alport Syndrome. This was associated with increased glomerular lipid droplets and cholesterol crystals. Treatment of mice with Alport Syndrome with hydroxypropyl-β-cyclodextrin (HPβCD) reduced cholesterol content in the kidneys of mice with Alport Syndrome and protected from the development of albuminuria, renal failure, inflammation and tubulointerstitial fibrosis. Cholesterol efflux and trafficking-related genes were primarily affected in mice with Alport Syndrome and were differentially regulated in the kidney cortex and isolated glomeruli. HPβCD also protected from proteinuria and mesangial expansion in a second model of non-metabolic kidney disease, adriamycin-induced nephropathy. Consistent with our experimental findings, microarray analysis confirmed dysregulation of several lipid-related genes in glomeruli isolated from kidney biopsies of patients with primary FSGS enrolled in the NEPTUNE study. Thus, lipid dysmetabolism occurs in non-metabolic glomerular disorders such as Alport Syndrome and FSGS, and HPβCD improves renal function in experimental Alport Syndrome and FSGS.

Gastrointestinal infection is an important risk factor for developing irritable bowel syndrome (IBS). Our aim was to characterise post-infectious IBS (PI-IBS) compared to other IBS patients. An internet survey of IBS patients using Rome III diagnostic questionnaire, Hospital Anxiety and Depression Scale (HADS) and Patient Health Questionnaire-12 Somatic Symptom (PHQ12-SS) scale score documenting the mode of onset was conducted. A total of 7811 participants (63.2% female), of whom 1004 (13.3%) met criteria for PI-IBS, were studied. Seventy per cent of PI-IBS patients described sudden onset, 35% onset while travelling, 49.6% vomiting, 49.9% fever and 20.3% bloody diarrhoea. Compared to other IBS individuals, PI-IBS was significantly associated with living in Northern Europe and North America, having a hysterectomy, not having an appendicectomy, higher PHQ12-SS score and having more than one toilet in the family home. PI-IBS patients had more frequent stools. At one year recovery rate in the PI-IBS and non-PI-IBS group was 19.7% and 22.2%, p?=?0.15. Recovery rates were lower for females (20.7%) vs males (38.8%), those with somatisation (23.0%) vs those without (33.2%) and those living in North America or Northern Europe (21.1%) vs living elsewhere (33.9%) p?=?0.001. PI-IBS accounts for around 13% of all IBS in this internet sample, with some distinctive features but a similar prognosis to the remainder.

Iron–sulfur clusters are essential cofactors in many biochemical processes. ISD11, one of the subunits of the protein complex that carries out the cluster assembly in mitochondria, is necessary for cysteine desulfurase NFS1 stability and function. Several authors have recently provided evidence showing that ISD11 interacts with the acyl carrier protein (ACP). We carried out the coexpression of human mitochondrial ACP and ISD11 in E. coli. This work shows that ACP and ISD11 form a soluble, structured, and stable complex able to bind to the human NFS1 subunit modulating its activity. Results suggest that ACP plays a key-role in ISD11 folding and stability in vitro. These findings offer the opportunity to study the mechanism of interaction between ISD11 and NFS1.

Background and goal Diarrhoea-predominant irritable bowel syndrome (IBS-D) exhibits intestinal innate immune and mucosal mast cell (MC) activation. MC stabilisers have been shown to improve IBS symptoms but the mechanism is unclear. Our primary aim was to investigate the effect of oral disodium cromoglycate (DSCG) on jejunal MC activation and specific innate immune signalling pathways in IBS-D, and secondarily, its potential clinical benefit.Study Mucosal MC activation (by ultrastructural changes, tryptase release and gene expression) and innate immune signalling (by protein and gene expression) were quantified in jejunal biopsies from healthy (HS; n= 16) and IBS-D subjects after six months of either treatment with DSCG (600 mg/day, IBS-D-DSCG group; n= 18) or without treatment (IBS-D-NT group; n= 25). All IBS-D patients recorded abdominal pain and bowel habits at baseline and in the last 10 days prior to jejunal sampling.Results IBS-D-NT exhibited significant MC activation and over-expression of immune-related genes as compared to HS, whereas in IBS-D-DSCG MC activity and gene expression were similar to HS. Furthermore, DSCG significantly reduced abdominal pain and improved stool consistency.Conclusion Oral DSCG modulates mucosal immune activity and improves gut symptoms in IBS-D patients. Future placebo-controlled clinical trials are needed for confirmation of clinical benefit of DSCG for IBS-D.