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Genomic DNA is folded into loops and topologically associating domains (TADs), which serve important structural and regulatory roles. It has been proposed that these genomic structures are formed by a loop extrusion process, which is mediated by structural maintenance of chromosomes (SMC) protein complexes. Recent single-molecule studies have shown that the SMC complexes condensin and cohesin are indeed able to extrude DNA into loops. In this Review, we discuss how the loop extrusion hypothesis can explain key features of genome architecture; cellular functions of loop extrusion, such as separation of replicated DNA molecules, facilitation of enhancer-promoter interactions and immunoglobulin gene recombination; and what is known about the mechanism of loop extrusion and its regulation, for example, by chromatin boundaries that depend on the DNA binding protein CTCF. We also discuss how the loop extrusion hypothesis has led to a paradigm shift in our understanding of both genome architecture and the functions of SMC complexes.

Radiolabeled leukocyte scans are used in nuclear medicine to detect sites of infection and inflammation. We have previously demonstrated the use of clinical grade immunomagnetic beads to isolate autologous eosinophils and image their distribution in healthy volunteers. Here we describe the use of radiolabeled eosinophils coupled to single-photon emission computed tomography (SPECT) to quantify eosinophil uptake in the lungs of healthy volunteers, patients with asthma, and patients with focal eosinophilic inflammation.

Genomic DNA is folded into loops and topologically associating domains (TADs), which serve important structural and regulatory roles. It has been proposed that these genomic structures are formed by a loop extrusion process, which is mediated by structural maintenance of chromosomes (SMC) protein complexes. Recent single-molecule studies have shown that the SMC complexes condensin and cohesin are indeed able to extrude DNA into loops. In this Review, we discuss how the loop extrusion hypothesis can explain key features of genome architecture; cellular functions of loop extrusion, such as separation of replicated DNA molecules, facilitation of enhancer-promoter interactions and immunoglobulin gene recombination; and what is known about the mechanism of loop extrusion and its regulation, for example, by chromatin boundaries that depend on the DNA binding protein CTCF. We also discuss how the loop extrusion hypothesis has led to a paradigm shift in our understanding of both genome architecture and the functions of SMC complexes.

This dialogue (trilogue) is an attempt to critically discuss the technoscientific convergence that is taking place with biodigital technologies in the postdigital condition. In this discussion, Sarah Hayes, Petar Jandrić and Michael A. Peters examine the nature of the convergences, their applications for bioeconomic sustainability and associated ecopedagogies. The dialogue paper raises issues of definition and places the technological convergence (‘nano-bio- info-cogno’) – of new systems biology and digital technologies at the nano level – in an evolutionary context to speculate, on the basis of the latest research, future possibilities. The paper also reviews these developments within familiar landscapes of posthumanism and postmodernism, raises the question of political bioeconomy and the role of postdigital education within it.

Today, we again need to anticipate the future and reinvent our theories and practices in and for the biodigital context. Under pandemic conditions, our work has been transformed by an increasing sense of global oneness and solidarity (Mañero, 2020 ; Suoranta, 2020), some environmental benefits such as a decrease in carbon emissions (Lewis, 2020), and also many losses from most obviously human lives, to the sorrows of living in a time of ‘no touch’ (Sapon- Shevin & SooHoo, 2020). Political responses to the pandemic vary from balanced approaches based on solidarity (Kerres, 2020) to the downright craziness of the Trump administration (McLaren, 2020), and we now see emerging initiatives such as the Global New Green Deal that may well herald a new green age that at last takes sustainability seriously. Yet in our age of bioinformational capitalism (Peters, 2012), all these changes and initiatives will be worthless without a solid material base. It is with this conclusion, that we urgently need to develop new understandings of bioeconomy fit for our biodigital moment in history.

Radiolabeled leukocyte scans are used in nuclear medicine to detect sites of infection and inflammation. We have previously demonstrated the use of clinical grade immunomagnetic beads to isolate autologous eosinophils and image their distribution in healthy volunteers. Here we describe the use of radiolabeled eosinophils coupled to single-photon emission computed tomography (SPECT) to quantify eosinophil uptake in the lungs of healthy volunteers, patients with asthma, and patients with focal eosinophilic inflammation.

‘Structural maintenance of chromosomes’ (SMC) complexes are required for the folding of genomic DNA into loops. Theoretical considerations and single-molecule experiments performed with the SMC complexes cohesin and condensin indicate that DNA folding occurs via loop extrusion. Recent work indicates that this process is essential for the assembly of antigen receptor genes by V(D)J recombination in developing B and T cells of the vertebrate immune system. Here, I review how recent studies of the mouse immunoglobulin heavy chain locus Igh have provided evidence for this hypothesis and how the formation of chromatin loops by cohesin and regulation of this process by CTCF and Wapl might ensure that all variable gene segments in this locus (VH segments) participate in recombination with a re-arranged DJH segment, to ensure generation of a maximally diverse repertoire of B-cell receptors and antibodies.

AIM The aim of this study was to evaluate a slope-intercept glomerular filtration rate (GFR) one-compartment correction method based exclusively on the rate constant (α2) of the exponential between 2 and 4 h post-injection that requires no scaling for BSA. METHODS The correction factor is 1/([C.α2]+1). C depends on the difference between one-compartment-corrected and uncorrected GFR, so varies with different correction procedures. Patients were in four groups: group 1 (Cr-EDTA; n = 141) and group 2 (Tc-DTPA; n = 47) had sampling at 2, 3 and 4 h. Groups 3A (Tc-DTPA; n = 168) and 3B (Tc-DTPA; n = 361) gave nine samples up to 480 min. C was calculated from GFR corrected using Brochner-Mortensen (BM) without prior BSA-scaling (CBM; GFRBM), after BSA-scaling then reverse-scaling as per British Nuclear Medicine Society (BNMS) guidelines (CBNMS; GFRBNMS), and after correction using the equations containing 'f' described by Fleming (CFlem; GFRFlem) and Jodal and Brochner-Mortensen (CJBM; GFRJBM). In group 3A, C (C9) was determined from GFR measured from all nine samples (GFR9) and from seven samples (C7) up to 240 min. In 3B, GFRC, corrected using 1/([C9.α2]+1), was compared with GFRBM, GFRBNMS, GFRFlem and GFRJBM against GFR9 (gold-standard). RESULTS C derived from these one-compartment correction formulae ranged from 25 to 32 min. In group 3, C7 and C9 were 28 ± 11 and 38 ± 14 min (P < 0.0001). Biases of GFRBM, GFRBNMS, GFRJBM, GFRFlem and GFRC against GFR9 were 2.7, 1.5, 4.2, 3.4 and 0.4 ml/min. Corresponding precisions were 9.3, 7.3, 7.0, 6.7 and 7.6 ml/min. CONCLUSION Correction using α2 avoids BSA scaling, has a low bias against gold-standard GFR and does not over-correct at high GFR.

© Copyright owned by the author(s) under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0). The first measurements of two-particle angular correlations for charged particles emitted in e+e collisions at a center-of-mass energy of 91 GeV are presented. The archived data are collected with the ALEPH detector at LEP. The correlation functions are measured over a broad range of pseudorapidity and azimuthal angle of the charged particles. Those results are compared to predictions from the PYTHIA event generator. In contrast to the results from high charged particle multiplicity nucleon-nucleon, nucleon-nucleus and nucleus-nucleus collisions, where longrange correlations with a large pseudorapidity gap are observed, no significant enhancement of long-range correlations is observed with respect to PYTHIA predictions, which do not include additional final state interactions of the outgoing partons.

Neutrophils play an important role in the lung tumour microenvironment. We hypothesised that radiolabelled neutrophils coupled to single-photon emission CT (SPECT) may non-invasively quantify neutrophil uptake in tumours from patients with non-small cell lung cancer. We demonstrated increased uptake of radiolabelled neutrophils from the blood into tumours compared with non-specific uptake using radiolabelled transferrin. Moreover, indium-111-neutrophil activity in the tumour biopsies also correlated with myeloperoxidase (MPO)-positive neutrophils. Our data support the utility of imaging with In-111-labelled neutrophils and SPECT-CT to quantify neutrophil uptake in lung cancer.

Eukaryotic genomes are compacted into loops and topologically associating domains (TADs)

Eukaryotic genomes are compacted into loops and topologically associating domains (TADs), which contribute to transcription, recombination and genomic stability. Cohesin extrudes DNA into loops that are thought to lengthen until CTCF boundaries are encountered. Little is known about whether loop extrusion is impeded by DNA-bound macromolecular machines. We demonstrate that the replicative helicase MCM is a barrier that restricts loop extrusion in G1 phase. Single-nucleus Hi-C of one-cell embryos revealed that MCM loading reduces CTCF-anchored loops and decreases TAD boundary insulation, suggesting loop extrusion is impeded before reaching CTCF. Single-molecule imaging shows that MCMs are physical barriers that frequently constrain cohesin translocationin vitro.Simulations are consistent with MCMs as abundant, random barriers. We conclude that distinct loop extrusion barriers contribute to shaping 3D genomes.One Sentence SummaryMCM complexes are obstacles that impede the formation of CTCF-anchored loops.

Myocardial blood flow (MBF) is measured withPatients had myocardial perfusion imaging using adenosine (n = 45) or regadenoson (n = 33) for stressing. BloodBoth agents increased myocardial blood flow almost equally. ECV was ~ 35 ml/100 ml at rest, increasing to ~ 40 ml/100 ml after stress. Z/KGPR analysis offers promise as a valid and analytically simpler technique for measuring myocardial blood flow, which, as with any clearance measured from GPR analysis, has units of ml/min/ml total tissue volume, and merits development as a polar map display.

Coronavirus disease 2019 (COVID-19) can progress to cytokine storm that is associated with organ dysfunction and death. The purpose of the present study is to determine clinical characteristics associated with 28 day in-hospital survival in patients with coronavirus disease 2019 (COVID-19) that received tocilizumab. This was a retrospective observational cohort study conducted at a five hospital health system in Michigan, United States. Adult patients with confirmed COVID-19 that were admitted to the hospital and received tocilizumab for cytokine storm from March 1, 2020 through April 3, 2020 were included. Patients were grouped into survivors and non-survivors based on 28 day in-hospital mortality. Study day 0 was defined as the day tocilizumab was administered. Factors independently associated with in-hospital survival at 28 days after tocilizumab administration were assessed. Epidemiologic, demographic, laboratory, prognostic scores, treatment, and outcome data were collected and analyzed. Clinical response was collected and defined as a decline of two levels on a six-point ordinal scale of clinical status or discharged alive from the hospital. Of the 81 patients included, the median age was 64 (58–71) years and 56 (69.1%) were male. The 28 day in-hospital mortality was 43.2%. There were 46 (56.8%) patients in the survivors and 35 (43.2%) in the non-survivors group. On study day 0 no differences were noted in demographics, clinical characteristics, severity of illness scores, or treatments received between survivors and non-survivors. C-reactive protein was significantly higher in the non-survivors compared to survivors. Compared to non-survivors, recipients of tocilizumab within 12 days of symptom onset was independently associated with survival (adjusted OR: 0.296, 95% CI: 0.098–0.889). SOFA score ≥8 on day 0 was independently associated with mortality (adjusted OR: 2.842, 95% CI: 1.042–7.753). Clinical response occurred more commonly in survivors than non-survivors (80.4% vs. 5.7%; p, Highlights • Patients receiving tocilizumab within 12 days of COVID-19 symptom onset had an increase in 28 day in-hospital survival. • A higher severity of illness prior to tocilizumab administration was associated with increased mortality. • Secondary infections occurred in 22.2% receiving tocilizumab, but infection was not associated with increased mortality.

Tc-99m-methoxyisobutyl isonitrile (Tc-99m-MIBI) is a radiolabelled xenobiotic, the disappearance rate of which from lungs following inhalation as a radioaerosol correlates inversely with bronchopulmonary multidrug resistance protein 1 (MRP1) expression. Tc-99m-MIBI clearance has previously been shown to be delayed in cigarette smokers. The aim of the current study was to determine whether smoking correlates with bronchopulmonary MRP1 expression, to confirm that Tc-99m-MIBI disappearance rate from the lungs following inhalation is delayed in smokers, and to determine the effects of gender and age on disappearance rate. Participants underwent dynamic imaging for 40 min over the lungs following inhalation of Tc-99m-MIBI using a double-headed gamma camera. The half-time of clearance was obtained from geometric mean of anterior and posterior counts and averaged between the two lungs. Paraffin-embedded tissue obtained from healthy lung during surgery in 13 patients was graded immunohistochemically for MRP1 as negative (0), weak (1), moderate (2) or strong (3). In 4 non-smokers, grading was 1 in three and 0 in one. In 9 smokers, in contrast, expression was graded 2-3 in 8 and 1 in one (P

AIM It has previously been proposed that entero-hepatic bile acid recycling frequency is a major determinant of whole-body retention (WBR) of SeHCAT. Hepatocyte to terminal ileum accounts for almost the entire cycle. The study aim was to test this hypothesis by comparing WBR with an estimate of speed of transit of bile acids using Tc-HIDA scintigraphy performed on a separate occasion. METHODS Using an un-collimated gamma camera and patient-to-camera distance of 1.5 m, WBR at 7 days after oral SeHCAT administration was measured in 14 patients with chronic diarrhoea, of whom 10 had previous cholecystectomy. The distance reached within the intestine of Tc-HIDA at 1 h (n = 14) and 2 h (n = 7) following iv injection was graded as follows: grades 1 and 2: small bowel on left and right sides of abdomen, respectively; and grade 3: colon. Relationships between WBR and grade were assessed using Spearman rank correlation. RESULTS Interval between studies ranged from 3 to 1219 (median 330) days. Grading correlated with WBR at 1 h (rs = -0.63; P = 0.02) and weakly at 2 h (rs = -0.68; P = 0.09) post-injection of Tc-HIDA. In nine patients in whom Tc-HIDA and SeHCAT scans were performed within 1 year of each other, the correlation remained significant at 1 h (rs = -0.73; P = 0.03). There was no difference in WBR or grading between patients with or without a gall bladder. CONCLUSION Entero-hepatic bile acid recycling frequency is a major determinant of whole-body SeHCAT retention.

RationaleThere is a need to develop imaging protocols which assess neutrophilic inflammation in the lung.AimTo quantify whole lung neutrophil accumulation in (1) healthy volunteers (HV) following inhaled lipopolysaccharide (LPS) or saline and (2) patients with COPD using radiolabelled autologous neutrophils and single-photon emission computed tomography/CT (SPECT/CT).Methods20 patients with COPD (Global initiative for chronic obstructive lung disease (GOLD) stages 2–3) and 18 HVs were studied. HVs received inhaled saline (n=6) or LPS (50 µg, n=12) prior to the injection of radiolabelled cells. Neutrophils were isolated using dextran sedimentation and Percoll plasma gradients and labelled with 99mTechnetium (Tc)-hexamethylpropyleneamine oxime. SPECT was performed over the thorax/upper abdomen at 45 min, 2 hours, 4 hours and 6 hours. Circulating biomarkers were measured prechallenge and post challenge. Blood neutrophil clearance in the lung was determined using Patlak-Rutland graphical analysis.ResultsThere was increased accumulation of 99mTc-neutrophils in the lungs of patients with COPD and LPS-challenged subjects compared with saline-challenged subjects (saline: 0.0006±0.0003 mL/min/mL lung blood distribution volume [mean ±1 SD]; COPD: 0.0022±0.0010 mL/min/mL [pConclusionsThis study shows the ability to quantify ‘whole lung’ neutrophil accumulation in HVs following LPS inhalation and in subjects with COPD using autologous radiolabelled neutrophils and SPECT/CT imaging. Moreover, the reproducibility observed supports the feasibility of using this approach to determine the efficacy of therapeutic agents aimed at altering neutrophil migration to the lungs.

INTRODUCTION For assessment of lower extremity swelling using lymphoscintigraphy, several nuclear medicine departments in the UK have recently switched from Tc-Nanocoll to Tc-Nanoscan. The aim of the study was to compare quantitative and semiquantitative features of lymphoscintigraphy between these two tracers. METHODS Twenty patients received Tc-Nanocoll and 20 received Tc-Nanoscan either side of the switch-over in our department. Tracers were compared with respect to visualisation of the liver, para-aortic lymph nodes and urine (all graded by consensus from 0 to 3; invisible-to-very prominent); and with respect to ilio-inguinal nodal quantification and ratio of liver-to-summed bilateral ilio-inguinal nodal activity at 120 min postinjection (L/N120). Scans were deemed abnormal when there was lymph diversion through skin or deep system, no activity in ilio-inguinal nodes at 60 min or negligible ilio-inguinal activity (

The three-dimensional organization of the genome supports regulated gene expression, recombination, DNA repair, and chromosome segregation during mitosis. Chromosome conformation capture (Hi-C)1–3 has revealed a complex genomic landscape of internal chromosome structures in vertebrate cells4–11 yet how sister chromatids topologically interact in replicated chromosomes has remained elusive due to their identical sequences. Here, we present sister-chromatid-sensitive Hi-C (scsHi-C) based on nascent DNA labeling with 4-thio-thymidine. Genome-wide conformation maps of human chromosomes revealed that sister chromatid pairs interact most frequently at the boundaries of topologically associating domains (TADs). Continuous loading of a dynamic cohesin pool separates sister-chromatid pairs inside TADs and is required to focus sister chromatid contacts at TAD boundaries. We identified a subset of TADs that are overall highly paired, characterized by facultative heterochromatin, as well as insulated topological domains that form separately within individual sister chromatids. The rich pattern of sister chromatid topologies and our scsHi-C technology will make it possible to dissect how physical interactions between identical DNA molecules contribute to DNA repair, gene expression, chromosome segregation, and potentially other biological processes.

International audience; Chemical enhanced oil recovery (EOR) is a successful method for increasing crude oil recovery. However, chemicals commonly used for enhanced oil recovery operations possess adverse biological impacts. To meet the legislative requirement and environmental protection demands, the performance of a highly biodegradable nonionic surfactant derived from tannic acid, a possible alternative, was evaluated using a microfluidic technology for the replacement of chemically synthesis surfactant by green chemistry products. Aqueous microdroplets containing the surfactant in crude oils were used for measurements of interfacial tension (IFT) reduction. The degree of interfacial tension reduction by sodium dodecyl sulfate (SDS), one of the most popular conventional surfactants, was also quantified for performance comparison. The potential of the biosurfactant for IFT reduction of light crude oil was superior to that of SDS. To evaluate the feasibility of the biosurfactant in improvement of recovery efficiency, surfactant-assisted flooding was tested under a random microfluidic network at the optimal concentrations, and the results were in good agreement with IFT reduction tests. The utilization of the polymer in a biosurfactant synthesis process effectively enhanced high sweep efficiency by decreasing a viscous fingering effect. The biosurfactant proved to be adequate and can sufficiently alleviate environmental concerns adopted by chemical flooding EOR.

The evolution of antifreeze glycoproteins has enabled notothenioid fish to flourish in the freezing waters of the Southern Ocean. Whilst successful at the biodiversity level to life in the cold, paradoxically at the cellular level these stenothermal animals have problems producing, folding and degrading proteins at their ambient temperatures of down to −1.86°C. In this first multi-species transcriptome comparison of the amino acid composition of notothenioid proteins with temperate teleost proteins, we show that, unlike psychrophilic bacteria, Antarctic fish provide little evidence for the mass alteration of protein amino acid composition to enhance protein folding and reduce protein denaturation in the cold. The exception was the significant over-representation of positions where leucine in temperate fish proteins was replaced by methionine in the notothenioid orthologues. Although methionine may increase stability in critical proteins, we hypothesise that a more likely explanation for the extra methionines is that they have been preferentially assimilated into the genome because they act as redox sensors. This redox hypothesis is supported by the enrichment of duplicated genes within the notothenioid transcriptomes which centre around Mapk signalling, a major pathway in the cellular cascades associated with responses to environmental stress. Whilst notothenioid fish show cold-associated problems with protein homeostasis, they may have modified only a selected number of biochemical pathways to work efficiently below 0°C. Even a slight warming of the Southern Ocean might disrupt the critical functions of this handful of key pathways with considerable impacts for the functioning of this ecosystem in the future.

Aim To compare weight, lean body mass and body surface area for calculation of standardised uptake value (SUV) in fluorine-18-fluorodeoxyglucose PET/computed tomography, taking sex into account. Patients and methods This was a retrospective study of 161 (97 men) patients. Maximum standardised uptake value (SUVmax) and mean standardised uptake value (SUVmean) were obtained from a 3-cm region of interest over the right lobe of the liver and scaled to weight, scaled to lean body mass (SUL) and scaled to body surface area (SUA). Mean hepatic computed tomography density was used to adjust SUVmean for hepatic fat (SUVFA). Hepatic SUV indices were divided by SUV from left ventricular cavity, thereby, eliminating whole body metric, to obtain a surrogate of blood fluorine-18-fluorodeoxyglucose clearance into liver, and multiplied by blood glucose to give a surrogate of hepatic glucose uptake rate (mSUV). Results SULmax, SUAmax and all scaled to weight indices correlated strongly with weight. SULmean, SULFA, SUAmean and SUAFA, however, correlated weakly or not at all with weight, nor with their corresponding whole body metric in men or women, but correlated strongly when the sexes were combined into one group. This was the result of sex differences in SUL (greater in men) and SUA (greater in women). There was, however, no sex difference in mSUV. Conclusion Weight is unsuitable for calculating SUV. SUL and SUA are also inappropriate as maxima but appropriate as mean and fat-adjusted values. However, SUL is recommended for both sexes because SUA is influenced by both body fat and weight. Sex differences in SUL and SUA give rise to misleading correlations when sexes are combined into one group.

Firms differ substantially in their participation in foreign input markets. We develop a methodology to measure the aggregate effects of input trade that takes such heterogeneity into account. We provide a theoretical result that holds in a variety of settings: the firm-level data on value added and domestic expenditure shares in material spending is sufficient to compute the change in consumer prices due to a shock to the import environment. We characterize the bias of approaches that rely on aggregate statistics. In an application to French data, input trade reduces the prices of manufacturing products by 27 percent. (JEL D24, E31, F12, F14, L11, L25, L60)

Solar energy systems that are increasingly economic with regard to their design, delivery and operating costs, hold the potential to contribute considerably to a nation's energy mix. While solar generation comes in many forms, ‘shared solar’, or a community-based system with an array size intermediate between a large-field and an individual residential system, offers many advantages that utility-scale projects are not able to deliver. The aim of this paper is to examine the development of shared solar initiatives in the recent history of US energy policy in order to reveal lessons that could be applied to future renewable energy generation in other developed nations including the UK and other European countries. Specifically the paper offers original appraisal of the ‘solar gardens’ scheme being trialled in Minnesota, drawing on findings from a survey with over 650 respondents representing a range of local renewable energy organizations and their customers. We examine the salience and influence of four key factors, namely: (i) perceived individual benefits; (ii) sources and trustworthiness of information; (iii) location; and (iv) project financing. Taken together the findings contribute understanding on the potential for community solar projects to assist in the transition towards a more sustainable and resilient energy future.

Topographic measures are frequently used in a variety of landscape ecology applications, in their simplest form as elevation, slope, and aspect, but increasingly more complex measures are being employed. We explore terrain metric similarity with changes in scale, both grain and extent, and examine how selecting the best measures is sensitive to changes in application. There are three types of topographic measures: 1) those that relate to orientation for approximating solar input, 2) those that capture variability in terrain configuration, and 3) those that provide metrics about landform features. Many biodiversity hotspots and predators have been found to coincide with areas of complexity, yet most complexity measures cannot differentiate between terrain steepness and uneven and broken terrain. Currently characterizing terrain in landscape-level analyses can be challenging, especially at coarser spatial resolutions but developing methods that improve landscape-level assessments include multivariate approaches and the use of neighborhood statistics. Some measures are sensitive to the spatial grain of calculation, the physiography of the landscape, and the scale of application. We show which measures have the potential to be multi-collinear, and illustrate with a case study how the selection of the best measures can change depending on the question at hand using mountain lion (Puma concolor) occurrence data. The case study showed a combination of infrequently employed metrics, such as view-shed analysis and focal statistics, outperform more commonly employed singular metrics. The use of focal statistics as a measure of topographic complexity shows promise for improving how mountain lions use terrain features.

Climate Change communication to the Public is in general presented in a negative fashion and often depicts the resultant costs and impacts as distant. Its substantial gloom together with the less immediate consequences significantly weaken responses. Narratives and stories are potent arbiters of meaningful communication and are an important vehicle for communication in our information rich lives. Importantly, they reduce jargon, gather and translate information, provide insight, reframe evidence and engage audiences. It has been argued by many observers that stories are potentially useful in driving change; presenting a way to value what is gone, expressing emotions, and helping us assert our determination to salvage something and work towards the future. \ud This paper details the methods utilised by the authors to generate stories and case studies in a community in Ireland over a 4 year research period. The aim of the work was to identify and assess the salience and potency of storytelling – as part of a ‘co-creation’ process – with regard to galvanising local action in the generation of sustainable models of lifestyle practice for residents. In this paper co-creation includes the planning phase of co-design and the implementation phase of co-production. The demonstration of these sustainable lifestyle practices were a strong driver for the sustainable transition of this community supporting the reduction of its ecological footprint by 28% over 4 years, evidence of which is highlighted in this paper.

The effects of different thermal (raw versus autoclaving or boiling for 5 and 20 min) and soaking (with or without) treatments on the in vitro hindgut fermentation in pigs of undigested residue collected after in vitro foregut digestion of tropical legumes' grains (Canavalia brasiliensis; Lablab purpureus; pink, red and white Vigna unguiculata) were investigated. The undigested residue was fermented with a pig fecal inoculum to determine fermentability, gas, and short-chain fatty acid (SCFA) productions. Soaked raw legumes increased the production of SCFAs (e.g., butyric acid) and fermentability, while autoclaving reduced them. The productions of butyric acid and energy derived from SCFAs differed between legumes, with canavalia and lablab having the lowest and highest values, respectively. SCFAs and energy productions were highly related to the predicted nutrients entering the hindgut. In conclusion, different heating and soaking treatments can be applied to legumes to modulate the production of target SCFAs.

Summary Structural maintenance of chromosomes (SMC) complexes organize genome topology in all kingdoms of life and have been proposed to perform this function by DNA loop extrusion. How this process works is unknown. Here, we have analyzed how loop extrusion is mediated by human cohesin-NIPBL complexes, which enable chromatin folding in interphase cells. We have identified DNA binding sites and large-scale conformational changes that are required for loop extrusion and have determined how these are coordinated. Our results suggest that DNA is translocated by a spontaneous 50 nm-swing of cohesin’s hinge, which hands DNA over to the ATPase head of SMC3, where upon binding of ATP, DNA is clamped by NIPBL. During this process, NIPBL “jumps ship” from the hinge toward the SMC3 head and might thereby couple the spontaneous hinge swing to ATP-dependent DNA clamping. These results reveal mechanistic principles of how cohesin-NIPBL and possibly other SMC complexes mediate loop extrusion., Graphical abstract, Highlights • Identification of cohesin’s DNA binding sites and movements needed for loop extrusion • A DNA binding site on the hinge might translocate DNA by ATP-independent swinging • DNA clamping on the ATPase heads is regulated by ATP-dependent engagement cycles • NIPBL couples ATP-independent and -dependent DNA translocation events, Cohesin hands DNA over long distances from one binding site to another, explaining how SMC complexes might fold genomes in all kingdoms of life.

Mammalian genomes are spatially organized into compartments, topologically associating domains (TADs), and loops to facilitate gene regulation and other chromosomal functions. How compartments, TAD ...

We analyze the academic matching market by considering a simple model in which applicants who face an application cost strategically choose portfolios of applications. Universities then play a decentralized offer game in which unaccepted offers result in failure to trade on both sides of the market. We characterize a basic equilibrium to illustrate the sorting role that application costs play. In a numeric example, we illustrate how reduced application costs can result in increased matching frictions.

Purpose The process of developing objective and measurable postgraduate year 1 (PGY1) residency graduation requirements and a progress tracking system is described. Summary The PGY1 residency accreditation standard requires that programs establish criteria that must be met by residents for successful completion of the program (i.e., graduation requirements), which should presumably be aligned with helping residents to achieve the purpose of residency training. In addition, programs must track a resident’s progress toward fulfillment of residency goals and objectives. Defining graduation requirements and establishing the process for tracking residents’ progress are left up to the discretion of the residency program. To help standardize resident performance assessments, leaders of an academic medical center–based PGY1 residency program developed graduation requirement criteria that are objective, measurable, and linked back to residency goals and objectives. A system for tracking resident progress relative to quarterly progress targets was instituted. Leaders also developed a focused, on-the-spot skills assessment termed “the Thunderdome,” which was designed for objective evaluation of direct patient care skills. Quarterly data on residents’ progress are used to update and customize each resident’s training plan. Implementation of this system allowed seamless linkage of the training plan, the progress tracking system, and the specified graduation requirement criteria. Conclusion PGY1 residency requirements that are objective, that are measurable, and that attempt to identify what skills the resident must demonstrate in order to graduate from the program were developed for use in our residency program. A system for tracking the residents’ progress by comparing residents’ performance to predetermined quarterly benchmarks was developed.

Splenic pathophysiology has been relatively unstudied, but recently, the spleen has received more attention as a result of the discovery of the 'cardiosplenic axis'. This term describes a role that the spleen plays in the progression of atherosclerosis following acute myocardial infarction. Human studies of this axis have largely used fluorine-18-fluorodeoxyglucose (F-FDG) PET/CT to quantify peri-infarction inflammation, arterial wall inflammation and splenic metabolic activity. Most of these studies have quantified arterial wall inflammation and splenic metabolic activity using the standardized uptake value, but this is a semiquantitative measurement with several drawbacks, including overestimation of metabolic activity in overweight individuals and a dependence on blood glucose levels. A better approach to the measurement of metabolic activity using F-FDG is to measure tissue F-FDG clearance from dynamic imaging and Patlak-Rutland graphical analysis. This is the preferred approach for future human studies of the cardiosplenic axis that will be required to better define the nature of the spleen's role.

Aims The aims of this study were to improve the quantification of lower extremity lymphoscintigraphy, determine its value and lower limit of normal, and determine whether intermediate postinjection time imaging is necessary. Patients and methods This was a study of 102 consecutive patients undergoing routine lower extremity lymphoscintigraphy using subcutaneous Tc-99m-nanocolloid with imaging at 5, 45 and 150 min after injection. Abnormal imaging criteria were delay (no activity in ilio-inguinal nodes at 45 min or negligible activity at 150 min), lymph diversion (through skin or deep system) and focal accumulation suggesting cellulitis. Lymphatic function was quantified as % injected activity in ilio-inguinal nodes at 150 min (IIQ) using a standard placed, by image guidance, exactly over the nodes. Results Forty-one patients had bilateral normal scintigraphy. IIQ was normally distributed in 15 limbs, with IIQ of 1-7.5%. In contrast, it was log-normally distributed in 68 limbs, with IIQ of at least 7.5%, suggesting 8% as the lower limit of normal. In 57 limbs, delay was the only scintigraphic abnormality at 45 min. Of these, 33 were abnormal at 150 min. Of the remaining 24 limbs, 17 had reduced IIQ; thus, 50 of these 57 (88%) limbs had lymphatic dysfunction. The seven limbs that remained normal at 150 min were in six patients. The contralateral limb was abnormal in five of these six patients; hence, lymphatic dysfunction would have been missed in only one patient without 45 min imaging. Conclusion IIQ is strongly recommended. Isolated delay at 45 min is abnormal. However, 45 min imaging is not necessary if IIQ is performed.

Eutectic freeze crystallization (EFC) is a treatment technology for saline streams that can recover both water and dissolved salts (or acids). It works by cooling the stream to the eutectic temperature, at which point both ice and salt (or acid) will crystallize. The ice, being less dense than the solution, floats, and the salt, being denser, will sink – thus effecting a gravity separation. Theoretically, EFC can result in zero liquid discharge (ZLD) and has several advantages over conventional separation techniques, including low energy consumption; high quality products and requires no additional chemicals. It can also be combined with other separation technologies to optimise separation processes. EFC can be applied to binary, ternary and multicomponent streams and thermodynamic modelling can be used to predict the eutectic temperature, eutectic composition, nucleation temperatures of ice and salt components, ice and salt recoveries and order of crystallization for crystal products. EFC is a classic coupled heat and mass transfer problem and, when operated as a continuous process, is suitable for the treatment of large volumes of saline streams. EFC has been developed from a laboratory curiosity to the point where commercialisation is currently under way.

It is currently assumed that 3D chromosomal organisation plays a central role in transcriptional control. However, recent evidence shows that steady-state transcription of only a minority of genes is affected by depletion of architectural proteins such as cohesin and CTCF. Here, we have used Capture Hi-C to interrogate the dynamics of chromosomal contacts of all human gene promoters upon rapid architectural protein degradation. We show that promoter contacts lost in these conditions tend to be long-range, with at least one interaction partner localising in the vicinity of topologically associated domain (TAD) boundaries. In contrast, many shorter-range chromosomal contacts, particularly those that connect active promoters with each other and with active enhancers remain unaffected by cohesin and CTCF depletion. We demonstrate that the effects of cohesin depletion on nascent transcription can be explained by changes in the connectivity of their enhancers. Jointly, these results provide a mechanistic explanation to the limited, but consistent effects of cohesin and CTCF on steady-state transcription and point towards the existence of alternative enhancer-promoter pairing mechanisms that are independent of these proteins.

Empirical researchers often have to map data provided for a "reporting" spatial unit, say counties in 1900, to a "reference" one, say, counties in 2010. We discuss a general method to create such crosswalks: computing the share of the area of each reporting unit nested in a given reference unit. Using these shares, data can be re-aggregated from the reporting to the reference units. We apply the method to construct a crosswalk for US county-level data since 1790 to present-day counties or commuting zones. We also provide the code to generate other crosswalks given maps of reporting and reference units.

Argatroban is a parenteral direct thrombin inhibitor that requires close monitoring to ensure safety and efficacy. Limited data exist to describe its effect in critically ill patients. This was a retrospective, single-center, cohort study that aimed to compare argatroban dosing requirements in those receiving extracorporeal life support (ECLS), continuous renal replacement therapy (CRRT), or neither. Organ dysfunction was assessed using a modified version of the Sequential Organ Failure Assessment (modSOFA) that incorporated the use of extracorporeal support systems. Eighty patients were included in the study (n = 20, 20, 40 in the ECLS, CRRT, and support-free groups, respectively). The majority of patients were Child-Pugh classification B (73%). Median modSOFA scores were higher in the ECLS (16.5) and CRRT (15.5) groups than in the support-free group (7.5) (P .001). There was no difference in the primary outcome of first therapeutic argatroban dose between the three groups (0.5 μg/kg/min for each; IQRs 0.25-0.50, 0.11-0.50, and 0.25-0.50, respectively; P = .455). The ECLS group had the lowest mean (0.39 μg/kg/min), minimum (0.20 μg/kg/min), and final (0.43 μg/kg/min) doses. ECLS patients had more supratherapeutic aPTTs and dose changes overall, supporting the need for more frequent anticoagulation monitoring or dose reductions in this population. Total modSOFA score demonstrated a moderate inverse correlation with first therapeutic dose (dose = 0.54 - (modSOFA score × 0.012); R = -0.342, P = .002). Overall, initial argatroban doses of 0.3-0.5 μg/kg/min appear to achieve therapeutic aPTT values in the studied populations.

This work highlights the degradation of STAG1 and inhibition of its interaction with cohesin as promising therapeutic strategies for exploiting synthetic lethality to treat STAG2-mutated tumors and lays the groundwork for the discovery of STAG1-directed small molecules., The cohesin subunit STAG2 has emerged as a recurrently inactivated tumor suppressor in human cancers. Using candidate approaches, recent studies have revealed a synthetic lethal interaction between STAG2 and its paralog STAG1. To systematically probe genetic vulnerabilities in the absence of STAG2, we have performed genome-wide CRISPR screens in isogenic cell lines and identified STAG1 as the most prominent and selective dependency of STAG2-deficient cells. Using an inducible degron system, we show that chemical genetic degradation of STAG1 protein results in the loss of sister chromatid cohesion and rapid cell death in STAG2-deficient cells, while sparing STAG2–wild-type cells. Biochemical assays and X-ray crystallography identify STAG1 regions that interact with the RAD21 subunit of the cohesin complex. STAG1 mutations that abrogate this interaction selectively compromise the viability of STAG2-deficient cells. Our work highlights the degradation of STAG1 and inhibition of its interaction with RAD21 as promising therapeutic strategies. These findings lay the groundwork for the development of STAG1-directed small molecules to exploit synthetic lethality in STAG2-mutated tumors.