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Sustainability is a paramount concern for manufacturing companies, necessitating the adoption of sustainable production and circular economy strategies. However, quantifying these sustainability efforts remains a formidable challenge due to the absence of a standardized framework, consequently hindering the development of effective strategies. This study presents a framework comprising 39 indicators, each accompanied by a descriptive calculation method, recommended units, and a suggested trend. These indicators were meticulously selected through a comprehensive literature review and refined via expert consensus during semi‐structured interviews. To establish a tangible connection between the operational world of companies and the Sustainable Development Goals (SDGs), we employ a visualization tool – the Sankey diagram. This diagram unravels the intricate links between the selected indicators and the SDGs. Both contributions provide manufacturers with a clear roadmap to quantify and align their actions with broader global objectives. [ABSTRACT FROM AUTHOR]

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. Plain Language Summary: 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. Key Points: 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 [ABSTRACT FROM AUTHOR]

(E) Cell growth analysis of Jurkat, K562 and Ba/F3 cells transduced with SEPTIN6:ABL2 (Ba/F3-SA) treated with Imatinib (0.1, 0.5 or 1 M; left), Nilotinib (10, 50, 100 nM; middle) and Dasatinib (1, 5, 10 nM; right) and referred to DMSO-treated cells. T-cell acute lymphoblastic leukaemia (T-ALL) arises from the malignant transformation of T-cell progenitors.[[1]] Current standard-of-care treatment for T-ALL consists of high-dose multi-agent chemotherapy followed by haematopoietic stem cell transplantation (HSCT) in standard-high risk patients.[3] Despite reasonable rates of initial complete responses (CR), patients who relapse or do not respond to first-line treatments show a dismal outcome with cure rates below 10% and limited therapeutic options.[2] Actually, since the approval of nelarabine in 2005 no pharmacological inhibitors have been approved for relapsed/refractory T-ALL patients.[4] Therefore, there is an urgent need to identify the molecular alterations that are present in such patients and that promote leukemogenesis in order to implement personalized-therapies with higher efficacy and fewer adverse effects.[5] Here, we identify and comprehensively characterize a novel, oncogenic and targetable I SEPTIN6 i : I ABL2 i fusion in a 16-year-old boy with T-ALL (Figure 1A). M07e cells transduced with I SEPTIN6 i : I ABL2 i showed significantly higher levels of cell growth and viability compared to cells transduced with the empty-vector or with I ABL2 i SP WT sp in the absence of cytokines (Figure 2A). We evaluated the mutational profile of the patient in matched tumour samples at diagnosis (Patient Dx) and relapse (Patient Rx) by paired-end 2 × 150 bp exome sequencing analysis. [Extracted from the article]

Background: Data for Spain from the Rome Foundation Global Epidemiology Study on the disorders of gut–brain interaction (DGBI) were used to assess the national and regional prevalence of all 22 DGBI, the percentage of respondents meeting diagnostic criteria for at least one DGBI, and the impact on burden of disease in our country. Methods: Data were collected through an anonymous, nationwide, and secure Internet survey with multiple built‐in quality‐assurance techniques that included the Rome IV diagnostic questionnaire and an in‐depth supplemental questionnaire. Key Results: The survey was completed by 2072 adult Spanish participants (50.2% female) with a mean age of 45.67 ± 15.44 years with a good representative national distribution. 43.6% (41.5%–45.8%) met diagnostic criteria for at least one DGBI, with 8.2% for any esophageal disorder, 12.1% for any gastroduodenal disorder, 30.1% for any bowel disorder, and 11.5% for any anorectal disorder. Functional constipation was the most prevalent DGBI in Spain (12.8%). We found that proctalgia fugax (9.3%), unspecified bowel disorders (10.8%), and functional dysphagia (5.6%) showed unexplained high rates in our country. DGBI rates were higher for women. Having any DGBI was negatively associated with psychosocial variables (including quality of life, somatization, and concern about digestive problems), and associated with increased healthcare utilization. Conclusions & Inferences: We provide the first comprehensive data on the prevalence and burden of all DGBI in Spain using the Rome IV criteria. The enormous burden of DGBI in Spain highlights the need for specialized training and future research. [ABSTRACT FROM AUTHOR]

Objective: Many studies have been published on disorders of the gut–brain interaction (DGBI) in Asia and Western Europe, but no previous study has directly assessed the difference between the two regions. The aim was to compare the prevalence of DGBI in Asia and Western Europe. Methods: We used data collected in a population‐based Internet survey, the Rome Foundation Global Epidemiology Study, from countries in Western Europe (Belgium, France, Germany, Netherlands, Italy, Spain, Sweden, and the United Kingdom) and Asia (China, Japan, South Korea, and Singapore). We assessed DGBI diagnoses (Rome IV Adult Diagnostic Questionnaire), anxiety/depression (Patient Health Questionnaire‐4, PHQ‐4), non‐GI somatic symptoms (PHQ‐12), and access to and personal costs of doctor visits. Results: The study included 9487 subjects in Asia and 16,314 in Western Europe. Overall, 38.0% had at least one DGBI; younger age, female sex, and higher scores on PHQ4 and PHQ12 were all associated with DGBI. The prevalence of having at least one DGBI was higher in Western Europe than in Asia (39.1% vs 36.1%, OR 1.14 [95% CI 1.08–1.20]). This difference was also observed for DGBI by anatomical regions, most prominently esophageal DGBI (OR 1.67 [1.48–1.88]). After adjustment, the difference in DGBI prevalence diminished and psychological (PHQ‐4) and non‐GI somatic symptoms (PHQ‐12) had the greatest effect on the odds ratio estimates. Conclusion: The prevalence of DGBI is generally higher in Western Europe compared to Asia. A considerable portion of the observed difference in prevalence rates seems to be explained by more severe psychological and non‐GI somatic symptoms in Western Europe. [ABSTRACT FROM AUTHOR]

Summary: Despite the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway being frequently altered in T‐ALL/LBL, no specific therapy has been approved for T‐ALL/LBL patients with constitutive signalling by JAK/STAT, so there is an urgent need to identify pathway members that may be potential therapeutic targets. In the present study, we searched for JAK/STAT pathway members potentially modulated through aberrant methylation and identified SOCS3 hypermethylation as a recurrent event in T‐ALL/LBL. Additionally, we explored the implications of SOCS3 deregulation in T‐ALL/LBL and demonstrated that SOCS3 counteracts the constitutive activation of the JAK/STAT pathway through different molecular mechanisms. Therefore, SOCS3 emerges as a potential therapeutic target in T‐ALL/LBL. [ABSTRACT FROM AUTHOR]

Frataxin is a kinetic activator of the mitochondrial supercomplex for iron‐sulfur cluster assembly. Low frataxin expression or a decrease in its functionality results in Friedreich's Ataxia (FRDA). With the aim of creating new molecular tools to study this metabolic pathway, and ultimately, to explore new therapeutic strategies, we have investigated the possibility of obtaining small proteins exhibiting a high affinity for frataxin. In this study, we applied the ribosome display approach, using human frataxin as the target. We focused on Affi_224, one of the proteins that we were able to select after five rounds of selection. We have studied the interaction between both proteins and discussed some applications of this specific molecular tutor, concerning the modulation of the supercomplex activity. Affi_224 and frataxin showed a KD value in the nanomolar range, as judged by surface plasmon resonance analysis. Most likely, it binds to the frataxin acidic ridge, as suggested by the analysis of chemical shift perturbations (nuclear magnetic resonance) and computational simulations. Affi_224 was able to increase Cys NFS1 desulfurase activation exerted by the FRDA frataxin variant G130V. Importantly, Affi_224 interacts with frataxin in a human cellular model. Our results suggest quaternary addition may be a new tool to modulate frataxin function in vivo. Nevertheless, more functional experiments under physiological conditions should be carried out to evaluate Affi_224 effectiveness in FRDA cell models. [ABSTRACT FROM AUTHOR]

Objective: To compare perioperative outcomes and complications in robotically assisted laparoscopy (RAL) and standard laparoscopy (SLP) approaches in the treatment of endometrial cancer by body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters).Methods: A comparative study was carried out of women treated for endometrial cancer at the Hospital Clinico San Carlos from January 2012 to December 2016: 133 patients were operated by RAL and 101 by SLP. Demographic characteristics of the patients, perioperative outcomes and complications were compared in both approaches.Results: Hospital stay was significantly lower in patients with BMI ≤30 operated with RAL (2 days RAL vs 4 days SLP; P=0.002). Estimated blood loss was significantly lower in the group with BMI<25 (60 mL RAL vs 100 mL SLP; P=0.004) and in the group with BMI ≥30 (87.5 mL RAL vs 180 SLP; P=0.003) operated with RAL. RAL significantly reduced the conversion rate in patients with BMI ≥30 (2 [3.4%] patients RAL vs 6 [27.3%] patients SLP; P=0.004).Conclusions: RAL has demonstrated advantages in treating obese women with endometrial cancer by reducing blood loss and conversion to laparotomy. [ABSTRACT FROM AUTHOR]

Background: Gas‐related symptoms (GRS) are common in the general population (GPop) and among patients with disorders of gut‐brain interactions but there is no patient‐reported outcome evaluating these symptoms and their impact on daily life. We have previously developed a 43‐item intestinal gas questionnaire (IGQ). The aim of the present study is to perform a psychometric validation of this instrument. Methods: Participants (119 from the GPop and 186 irritable bowel syndrome (IBS) patients) were recruited from 3 countries (UK, Spain, France). IBS patients fulfilled ROME IV criteria with an IBS severity score between 150 and 300. Participants completed the IGQ, the functional Digestive Disorders Quality of Life (FDDQL), and the EQ‐5D. A subgroup (n = 90) repeated the IGQ completion after 7 days on paper or electronically. Results: From the original IGQ questionnaire, 26 items were deleted because of poor performance. Confirmatory factorial analysis on the remaining 17 items (7 symptom and 10 impact items) yielded a 6‐factor structure accounting for 67% of the variance for bloating (6 items), flatulence (3), belching (2), bad breath (2), stomach rumbling (2), and difficult gas evacuation (2). Global score (0‐100) was worse among IBS vs GPop (40 ± 15 vs 33 ± 17; p = 0.0016). At the second visit, the intraclass correlation coefficient of IGQ scores was between 0.71 and 0.86 (n = 67) for test‐retest reliability and 0.61‐0.87 (n = 64) for equivalence between electronic and paper versions of IGQ. Conclusion: The IGQ available in paper and electronic versions in 3 languages is a robust instrument for capturing and measuring GRS and their impact on daily life. [ABSTRACT FROM AUTHOR]

Hybridization is suggested to contribute to ecomorphological and taxonomic diversity in lacustrine East African cichlids. This is supported by studies demonstrating that genetic diversity within lake radiations has been influenced by hybridization events, leading to extensive phenotypic differentiation of genetically closely related species. Hybrid persistence and speciation in sympatry with gene flow can be explained by pleiotropy in traits involved in reproductive isolation; however, little attention has been given to how trait differentiation is established during hybrid ontogeny, and how this may relate to trophic and locomotor specialization. This study compares body shape changes in a Lake Victoria cichlid hybrid throughout its post‐hatch ontogeny to those of its parental species. Across the considered age/size categories, hybrids occupy a distinct and intermediate morphological space, yet where several transgressive traits emerge. A between‐group principal component analysis on body shapes across size categories reveals axes of shape variation exclusive to the hybrids in the youngest/smallest size categories. Shape differences in the hybrids involved morphological traits known to be implicated in trophic and locomotor specializations in the parental species. Combined, our findings suggest that phenotypic divergence in the hybrid can lead to functional differences that may potentially release them to some degree from competition with the parental species. These findings agree with recent literature that addresses the potential importance of hybridization for the unusually recent origin of the Lake Victoria cichlid super‐species flock. [ABSTRACT FROM AUTHOR]

Objectives: 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. Background: The establishment of a mandatory social isolation have generated a decrease in activities in cardiology units. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Small and medium enterprises (SMEs) are key actors in the implementation of the circular economy (CE) concept as a basis for creating sustainable societies. Thus, the main objective of this study is to identify key strategies and resources that may favor CE implementation in SMEs. These key strategies should encourage SMEs to develop eco‐innovations to gain competitive advantage and create and capture value that is coherent with nature. A mixed‐method approach that consisted of a literature review and a focus group for gathering qualitative data was used. This focus group was made up of experts such as researchers and practitioners from universities, sustainable SMEs, and consultancy firms in Spain. A set of strategies and internal and external factors were identified to help SMEs to implement the CE. Finally, some useful dynamic capabilities for implementing the CE in business performance were identified. [ABSTRACT FROM AUTHOR]

Peroxiredoxins are thiol‐dependent peroxidases that function in peroxide detoxification and H2O2 induced signaling. Among the six isoforms expressed in humans, PRDX1 and PRDX2 share 97% sequence similarity, 77% sequence identity including the active site, subcellular localization (cytosolic) but they hold different biological functions albeit associated with their peroxidase activity. Using recombinant human PRDX1 and PRDX2, the kinetics of oxidation and hyperoxidation with H2O2 and peroxynitrite were followed by intrinsic fluorescence. At pH 7.4, the peroxidatic cysteine of both isoforms reacts nearly tenfold faster with H2O2 than with peroxynitrite, and both reactions are orders of magnitude faster than with most protein thiols. For both isoforms, the sulfenic acids formed are in turn oxidized by H2O2 with rate constants of ca 2 × 103 M−1 s−1 and by peroxynitrous acid significantly faster. As previously observed, a crucial difference between PRDX1 and PRDX2 is on the resolution step of the catalytic cycle, the rate of disulfide formation (11 s−1 for PRDX1, 0.2 s−1 for PRDX2, independent of the oxidant) which correlates with their different sensitivity to hyperoxidation. This kinetic pause opens different pathways on redox signaling for these isoforms. The longer lifetime of PRDX2 sulfenic acid allows it to react with other protein thiols to translate the signal via an intermediate mixed disulfide (involving its peroxidatic cysteine), whereas PRDX1 continues the cycle forming disulfide involving its resolving cysteine to function as a redox relay. In addition, the presence of C83 on PRDX1 imparts a difference on peroxidase activity upon peroxynitrite exposure that needs further study. [ABSTRACT FROM AUTHOR]

Metabolic control analysis (MCA) is a promising approach in biochemistry aimed at understanding processes in a quantitative fashion. Here the contribution of enzymes and transporters to the control of a given pathway flux and metabolite concentrations is determined and expressed quantitatively by means of numerical coefficients. Metabolic flux can be influenced by a wide variety of modulators acting on one or more metabolic steps along the pathway. We describe a laboratory exercise to study metabolic regulation of human erythrocytes (RBCs). Within the framework of MCA, students use these cells to determine the sensitivity of the glycolytic flux to two inhibitors (iodoacetic acid: IA, and iodoacetamide: IAA) known to act on the enzyme glyceraldehyde‐3‐phosphate‐dehydrogenase. Glycolytic flux was estimated by determining the concentration of extracellular lactate, the end product of RBC glycolysis. A low‐cost colorimetric assay was implemented, that takes advantage of the straightforward quantification of the absorbance signal from the photographic image of the multi‐well plate taken with a standard digital camera. Students estimate flux response coefficients for each inhibitor by fitting an empirical function to the experimental data, followed by analytical derivation of this function. IA and IAA exhibit qualitatively different patterns, which are thoroughly analyzed in terms of the physicochemical properties influencing their action on the target enzyme. IA causes highest glycolytic flux inhibition at lower concentration than IAA. This work illustrates the feasibility of using the MCA approach to study key variables of a simple metabolic system, in the context of an upper level biochemistry course. © 2018 International Union of Biochemistry and Molecular Biology, 46(5):502–515, 2018. [ABSTRACT FROM AUTHOR]

Objective: To prospectively assess the impact of the fixed‐dose combination (FDC) of the 5α‐reductase inhibitor (5ARI), dutasteride 0.5 mg and the α1‐adrenoceptor antagonist, tamsulosin 0.4 mg (DUT‐TAM FDC) therapy on sexual function domain scores in sexually active men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH), using the Men's Sexual Health Questionnaire (MSHQ). Patients and Methods: This European and Australian double‐blind, placebo‐controlled, parallel‐group study was conducted at 51 centres. Inclusion criteria: age ≥50 years, International Prostate Symptom Score ≥12, prostate volume ≥30 cc, prostate‐specific antigen 1.5–10 ng/mL. Patients were randomised 1:1 to DUT‐TAM FDC therapy or placebo for 12 months. The change from baseline to Month 12 on the total MSHQ (primary endpoint) and MSHQ erection, ejaculation and satisfaction domains (secondary outcome) was assessed, using a mixed model repeated measures analysis. Safety was evaluated. Results: The intention‐to‐treat population included 489 patients (243 DUT‐TAM FDC therapy; 246 placebo). A significant decrease (worsening) was observed with DUT‐TAM FDC therapy versus placebo on the total MSHQ score (−8.7 vs −0.7; standard error [ se]: 0.81, 0.78; P < 0.001), and the ejaculation (−7.5 vs −0.6; se: 0.56, 0.55; P < 0.001) and satisfaction (−0.6 vs +0.3; se: 0.3, 0.29, P = 0.047) domains, but not the erection domain (−1.0 vs −0.5; se: 0.19, 0.19, P = 0.091). Conclusion: This is the first domain‐specific quantitative evaluation of DUT‐TAM FDC therapy on sexual function in men with LUTS secondary to BPH. The observed changes in the MSHQ with DUT‐TAM FDC therapy were mainly driven by changes in the ejaculation domain. These findings will help give context to erectile and ejaculatory dysfunction AEs reported spontaneously in earlier 5ARI studies. [ABSTRACT FROM AUTHOR]

Friedreich's ataxia is a disease caused by a decrease in the levels of expression or loss of functionality of the mitochondrial protein frataxin (FXN). The development of an active and stable recombinant variant of FXN is important for protein replacement therapy. Although valuable data about the mature form FXN81‐210 has been collected, not enough information is available about the conformation of the frataxin precursor (FXN1‐210). We investigated the conformation, stability and function of a recombinant precursor variant (His6‐TAT‐FXN1‐210), which includes a TAT peptide in the N‐terminal region to assist with transport across cell membranes. His6‐TAT‐FXN1‐210 was expressed in Escherichia coli and conditions were found for purifying folded protein free of aggregation, oxidation or degradation, even after freezing and thawing. The protein was found to be stable and monomeric, with the N‐terminal stretch (residues 1–89) mostly unstructured and the C‐terminal domain properly folded. The experimental data suggest a complex picture for the folding process of full‐length frataxin in vitro: the presence of the N‐terminal region increased the tendency of FXN to aggregate at high temperatures but this could be avoided by the addition of low concentrations of GdmCl. The purified precursor was translocated through cell membranes. In addition, immune response against His6‐TAT‐FXN1‐210 was measured, suggesting that the C‐terminal fragment was not immunogenic at the assayed protein concentrations. Finally, the recognition of recombinant FXN by cellular proteins was studied to evaluate its functionality. In this regard, cysteine desulfurase NFS1/ISD11/ISCU was activated in vitro by His6‐TAT‐FXN1‐210. Moreover, the results showed that His6‐TAT‐FXN1‐210 can be ubiquitinated in vitro by the recently identified frataxin E3 ligase RNF126, in a similar way as the FXN1‐210, suggesting that the His6‐TAT extension does not interfere with the ubiquitination machinery. [ABSTRACT FROM AUTHOR]

Background and Aim Patients with functional bowel disorders develop gas retention and symptoms in response to intestinal gas loads that are well tolerated by healthy subjects. Stimulation of 5HT-4 receptors in the gut has both prokinetic and antinociceptive effects. The aim of this study is to determine the effect of prucalopride, a highly selective 5HT-4 agonist, on gas transit and tolerance in women with functional bowel disorders complaining of constipation. Methods Twenty-four women with functional bowel disorders complaining of constipation were included in the study. Patients were studied twice on separate days in a cross-over design. On each study day, an intestinal gas challenge test was performed. During the five previous days, prucalopride (2 mg/day) or placebo was administered. Abdominal symptoms, stool frequency, and stool consistency were recorded during the treatment period on daily questionnaires. Results During the gas challenge test, prucalopride did not decrease the volume of gas retained in the subset of patients who had significant gas retention (≥ 200 mL) while on placebo. However, in those patients who had increased symptoms during the gas test (≥ 3 on a 0 to 6 scale) when on placebo, prucalopride did significantly reduce the perception of symptoms (2.3 ± 0.5 mean score vs 3.5 ± 0.3 on placebo; P = 0.045). During the treatment period with prucalopride, patients exhibited an increase in the total number of bowel movements and decreased stool consistency compared with placebo. Conclusion Prucalopride reduces abdominal symptoms without modifying gas retention when patients with functional bowel disorders are challenged with the gas transit and tolerance test. European Clinical Trials Database (EudraCT2011-006354-86). [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome (IBS) is one of the most prevalent gastrointestinal disorders in developed countries. Its etiology remains unknown; however, a common finding, regardless of IBS subtype, is the presence of altered intestinal barrier. In fact, signaling and location of cell-to-cell adhesion proteins, in connection with increased immune activity, seem abnormal in the intestinal epithelium of IBS patients. Despite that most research is performed on distal segments of the intestine, altered permeability has been reported in both, the small and the large bowel of all IBS subtypes. The small intestine carries out digestion and nutrient absorption and is also the site where the majority of immune responses to luminal antigens takes place. In fact, the upper intestine is more exposed to environmental antigens than the colon and is also a site of symptom generation. Recent studies have revealed small intestinal structural alterations of the epithelial barrier and mucosal immune activation in association with intestinal dysfunction, suggesting the commitment of the intestine as a whole in the pathogenesis of IBS. This review summarizes the most recent findings on mucosal barrier alterations and its relationship to symptoms arising from the small intestine in IBS, including epithelial structural abnormalities, mucosal immune activation, and microbial dysbiosis, further supporting the hypothesis of an organic origin of IBS. [ABSTRACT FROM AUTHOR]

Background: Participants with functional gut disorders develop gas retention and symptoms in response to intestinal gas loads that are well tolerated by healthy subjects. To determine the role of cholecystokinin (CCK1) receptors on gas transit and tolerance in women with functional gut disorders. Methods: In 12 healthy women, and 24 women with functional gut disorders (12 dyspepsia and 12 constipation-predominant irritable bowel syndrome) gas was infused into the jejunum at 12 mL/min for 3 h with simultaneous duodenal lipid infusion (intralipid 1 kcal/min), while measuring anal gas evacuation and abdominal symptoms on a 0-6 score scale. Triple-blind paired studies during iv infusion of dexloxiglumide (2.5 mg/kg bolus plus 5 mg/kg h continuous infusion), a selective CCK1 inhibitor, or saline (control) were performed in random order. Results: During saline infusion participants with functional gut disorders developed significantly greater gas retention and abdominal symptoms than healthy subjects (394 ± 40 mL vs 265 ± 35 mL and 2.8 ± 0.3 vs 1.9 ± 0.4 highest abdominal symptom score, respectively; P < 0.05 for both). Dexloxiglumide increased gas retention in both groups (514 ± 35 mL and 439 ± 60 mL, respectively; P = 0.033 vs saline for both); however, despite the larger retention, dexloxiglumide reduced abdominal symptoms (2.3 ± 0.2 score and 0.8 ± 0.3 score, respectively; P = 0.05 vs saline for both). Post-hoc analysis showed that, the decrease in abdominal symptoms was more pronounced in those participants with functional gut disorders with higher basal abdominal symptoms than in the rest ( P = 0.037). Conclusion: Inhibition of CCK1 receptors by dexloxiglumide increases intestinal gas retention and reduces abdominal symptoms in response to by intestinal gas loads. European Clinical Trials Database (EudraCT 2005-003338-16). [ABSTRACT FROM AUTHOR]

Friedreich's ataxia ( FRDA) is linked to a deficiency of frataxin ( FXN), a mitochondrial protein involved in iron-sulfur cluster synthesis. FXN is a small protein with an α/β fold followed by the C-terminal region ( CTR) with a nonperiodic structure that packs against the protein core. In the present study, we explored the impact of the alteration of the CTR on the stability and dynamics of FXN. We analyzed several pathological and rationally designed CTR mutants using complementary spectroscopic and biophysical approaches. The pathological mutation L198R yields a global destabilization of the structure correlating with a significant and highly localized alteration of dynamics, mainly involving residues that are in contact with L198 in wild-type FXN. Variant FXN 90-195, which is closely related to the FRDA-associated mutant FXN 81-193, conserves a globular shape with a native-like structure. However, the truncation of the CTR results in an extreme alteration of global stability and protein dynamics over a vast range of timescales and encompassing regions far from the CTR, as shown by proton-water exchange rates and 15N-relaxation measurements. Increased sensitivity to proteolysis, observed in vitro for both mutants, suggests a faster degradation rate in vivo, whereas the enhanced tendency to aggregate exhibited by the truncated variant may account for the loss of functional FXN, with both phenomena providing an explanation as to why the alteration of the CTR causes FRDA. These results contribute to understanding how stability and activity are linked to protein motions and they might be useful for the design of target-specific ligands to control local protein motions for stability enhancement. [ABSTRACT FROM AUTHOR]

Many researchers consider absenteeism to be a significant problem for employers. Absenteeism lowers the overall level of worker expertise, which may affect product quality and trigger an increase in customer complaints. This research was carried out in a prominent automobile manufacturing company, with an assembly line-driven rigid production process. This article gathered customer quality complaints registered during the 17 months after cars were delivered to customers, from one year of car production, to analyze how employee absenteeism affects customer quality complaints. The empirical evidence presented by this research in the automotive industry confirms that absenteeism does not lead, necessarily, to a decrease in quality. This evidence must make organization redefine the value of their expert workers. Moreover, these results could have an impact on assembly-line design and the use of worker job-rotation programs for technologically sophisticated assembly lines. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: The N-terminal stretch of human frataxin (hFXN) intermediate (residues 42–80) is not conserved throughout evolution and, under defined experimental conditions, behaves as a random-coil. Overexpression of hFXN56–210 in Escherichia coli yields a multimer, whereas the mature form of hFXN (hFXN81–210) is monomeric. Thus, cumulative experimental evidence points to the N-terminal moiety as an essential element for the assembly of a high molecular weight oligomer. The secondary structure propensity of peptide 56–81, the moiety putatively responsible for promoting protein–protein interactions, was also studied. Depending on the environment (TFE or SDS), this peptide adopts α-helical or β-strand structure. In this context, we explored the conformation and stability of hFXN56–210. The biophysical characterization by fluorescence, CD and SEC-FPLC shows that subunits are well folded, sharing similar stability to hFXN90–210. However, controlled proteolysis indicates that the N-terminal stretch is labile in the context of the multimer, whereas the FXN domain (residues 81–210) remains strongly resistant. In addition, guanidine hydrochloride at low concentration disrupts intermolecular interactions, shifting the ensemble toward the monomeric form. The conformational plasticity of the N-terminal tail might impart on hFXN the ability to act as a recognition signal as well as an oligomerization trigger. Understanding the fine-tuning of these activities and their resulting balance will bear direct relevance for ultimately comprehending hFXN function. [Copyright &y& Elsevier]

Serrated adenocarcinoma (SAC) is a recently recognized colorectal cancer (CRC) subtype accounting for 7.5 to 8.7% of CRCs. It has been shown that SAC has a poorer prognosis and has different molecular and immunohistochemical features compared with conventional carcinoma (CC) but, to date, only one previous study has analyzed its mRNA expression profile by microarray. Using a different microarray platform, we have studied the molecular signature of 11 SACs and compared it with that of 15 matched CC with the aim of discerning the functions which characterize SAC biology and validating, at the mRNA and protein level, the most differentially expressed genes which were also tested using a validation set of 70 SACs and 70 CCs to assess their diagnostic and prognostic values. Microarray data showed a higher representation of morphogenesis-, hypoxia-, cytoskeleton- and vesicle transport-related functions and also an overexpression of fascin1 (actin-bundling protein associated with invasion) and the antiapoptotic gene hippocalcin in SAC all of which were validated both by quantitative real-time PCR (qPCR) and immunohistochemistry. Fascin1 expression was statistically associated with KRAS mutation with 88.6% sensitivity and 85.7% specificity for SAC diagnosis and the positivity of fascin1 or hippocalcin was highly suggestive of SAC diagnosis (sensitivity = 100%). Evaluation of these markers in CRCs showing histological and molecular characteristics of high-level microsatellite instability (MSI-H) also helped to distinguish SACs from MSI-H CRCs. Molecular profiling demonstrates that SAC shows activation of distinct signaling pathways and that immunohistochemical fascin1 and hippocalcin expression can be reliably used for its differentiation from other CRC subtypes. [ABSTRACT FROM AUTHOR]

Thioredoxins (TRXs) constitute attractive α/β scaffolds for investigating molecular recognition. The interaction between the recombinant fragment spanning the sequence 1-93 of full-length TRX (TRX1-93) and the synthetic peptide comprising residues 94-108 (TRX94-108), plus a C-terminal tyrosine tag (the numbering scheme used in entry pdb 2TRX is used throughout the article, two complementary moieties of E. coli TRX, brings about the consolidation of a native-like complex. Despite its reduced thermodynamic stability, this complex is able to acquire fine structural features remarkably similar to those characteristic of full-length TRX, namely, hydrodynamic behavior, assessed by diffusion-ordered spectroscopy (DOSY)-NMR; the pattern of secondary structure, as revealed by three-bond HNHα coupling constants and secondary shifts for Hα/CO/Cα/Cβ; native-like tertiary structural signatures revealed by near-UV circular dichroism (CD) spectroscopy. The complex exhibits a relaxation behavior compatible with that expected for a native-like structure. However, heteronuclear nuclear Overhauser effect (NOE)s reveal an enhanced dynamics for the complex by comparison with full-length TRX. Furthermore, higher R2 values for residues 43-50 and 74-89 would likely result from an exchange process modulated by the peptide at the interface region. The slow kinetics of the consolidation reaction was followed by CD and real-time NMR. Equilibrium titration experiments by NMR yield a KD value of 1.4 ± 1.0 μ M and a second low-affinity (>150 μ M) binding event in the vicinity of the active site. Molecular dynamics simulations of both the isolated fragment TRX1-93 and the complex suggest the destabilization of α2 and α3 helical elements and the persistence of β-structure in the absence of TRX94-108. Altogether, structural and dynamic evidence presented herein points to the key role played by the C-terminal helix in establishing the overall fold. This critical switch module endows reduced TRX with the ability to act as a cooperative folding unit. Proteins 2012;. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

García-Solano J, Conesa-Zamora P, Trujillo-Santos J, Mäkinen M J & Pérez-Guillermo M (2011) Histopathology 59, 1046-1056 Tumour budding and other prognostic pathological features at invasive margins in serrated colorectal adenocarcinoma: a comparative study with conventional carcinoma Aims: To assess the incidence of tumour budding (TB), cytoplasmic pseudo-fragments (CyPs), tumour growth pattern (TGP) and peritumoural lymphocytic infiltration (PLI) in a series of serrated adenocarcinoma (SAC) and conventional carcinomas (CCs) of the colorectum in order to ascertain whether such features could explain the worse prognosis of SAC and whether they have prognostic value in SACs. Methods and results: Tumour budding, CyPs, TGP and PLI were evaluated in 81 SACs and 81 matched CCs. Kaplan-Meier survival curves and Cox logistic regression analysis were obtained for histological parameters. SACs had more high-grade (HG) TB (HG-TB) (69.1%), HG-CyPs (47%), infiltrative TGP (42%) and weak PLI (W-PLI) (65.4%) than CCs (40.7%, P = 0.0003; 19.7%, P = 0.0002; 29.7%, P = 0.07; 45.7%, P = 0.0087). SACs with HG-TB ( P = 0.017), HG-CyPs ( P = 0.045), infiltrating TGP ( P < 0.001) and W-PLI ( P = 0.04) had a worse 5-year survival, as had SACs with infiltrating TGP ( P = 0.047) and W-PLI ( P = 0.04) compared with CCs. For SACs, infiltrative TGP and W-PLI were independent prognostic parameters on multivariate analysis, as was location and regional node status. Conclusion: Compared to CC, SAC displayed more HG-TB, HG-CyPs and fewer PLI at the invasive margins and this may account for its poorer clinical outcome. TB, CyPs, TGP and PLI are useful histological prognostic aids in SAC. [ABSTRACT FROM AUTHOR]

In this work, we studied how an amphipathic peptide of the surface of the globular protein thioredoxin, TRX94-108, acquires a native-like structure when it becomes involved in an apolar interaction network. We designed peptide variants where the tendency to form α-helical conformation is modulated by replacing each of the leucine amino acid residues by an alanine. The induction of structure caused by sodium dodecyl sulfate (SDS) binding was studied by capillary zone electrophoresis, circular dichroism, DOSY-NMR, and molecular dynamics simulations (MDS). In addition, we analyzed the strength of the interaction between a C18 RP-HPLC matrix and the peptides. The results presented here reveal that (a) critical elements in the sequence of the wild-type peptide stabilize a SDS/peptide supramolecular cluster; (b) the hydrophobic nature of the interaction between SDS molecules and the peptide constrains the ensemble of conformations; (c) nonspecific apolar surfaces are sufficient to stabilize peptide secondary structure. Remarkably, MDS shed light on a contact network formed by a limited number of SDS molecules that serves as a structural scaffold preserving the helical conformation of this module. This mechanism might prevail when a peptide with low helical propensity is involved in structure consolidation. We suggest that folding of peptides sharing this feature does not require a preformed tightly-packed protein core. Thus, the formation of specific tertiary interactions would be the consequence of peptide folding and not its cause. In this scenario, folding might be thought of as a process that includes unspecific rounds of structure stabilization guiding the protein to the native state. Proteins 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Abstract: The development of 2D graph-theoretic representations for DNA sequences was very important for qualitative and quantitative comparison of sequences. Calculation of numeric features for these representations is useful for DNA–QSAR studies. Most of all graph-theoretic representations identify each one of the four bases with a unitary walk in one axe direction in the 2D space. In the case of proteins, twenty amino acids instead of four bases have to be considered. This fact has limited the introduction of useful 2D Cartesian representations and the corresponding sequences descriptors to encode protein sequence information. In this study, we overcome this problem grouping amino acids into four groups: acid, basic, polar and non-polar amino acids. The identification of each group with one of the four axis directions determines a novel 2D representation and numeric descriptors for proteins sequences. Afterwards, a Markov model has been used to calculate new numeric descriptors of the protein sequence. These descriptors are called herein the sequence 2D coupling numbers (ζ k ). In this work, we calculated the ζ k values for 108 sequences of different polygalacturonases (PGs) and for 100 sequences of other proteins. A Linear Discriminant Analysis model derived here (PG=5.36· ζ 1 −3.98· ζ 3 −42.21) successfully discriminates between PGs and other proteins. The model correctly classified 100% of a subset of 81 PGs and 75 non-PG proteins sequences used to train the model. The model also correctly classified 51 out of 52 (98.07%) of proteins sequences used as external validation series. The uses of different group of amino acids and/or axes orientation give different results, so it is suggested to be explored for other databases. Finally, to illustrates the use of the model we report the isolation and prediction of the PG action for a novel sequence (AY908988) isolated by our group from Psidium guajava L. This prediction coincides very well with sequence alignment results found by the BLAST methodology. These findings illustrate the possibilities of the sequence descriptors derived for this novel 2D sequence representation in proteins sequence QSAR studies. [Copyright &y& Elsevier]

Two genetically engineered variants of the Bacillus licheniformis β-lactamase gene were expressed in Escherichia coli. One variant coded for the exo-small mature enzyme without the signal peptide. The other coded for the exo-large mature enzyme preceded by 10, mostly polar, residues from an incomplete heterologous signal. As observed following the extraction by a lysozyme-EDTA treatment, the signal-less variant was exported to the periplasm with nearly 20% efficiency, whereas the variant with the N-terminal extension was translocated to a lesser degree; interestingly, nearly all of the former and half of the latter were extracted by osmotic shock, which may be of importance for our understanding of cellular compartments. The fact that a signal-less protein is translocated with substantial yields raises questions about the essential role of signal peptides for protein export. As folding and export are related processes, we investigated the folding in vitro of the two variants. No differences were found between them. In the absence of denaturant, they are completely folded, fully active and have a large ΔG of unfolding. Under partially denaturing conditions they populate several partially folded states. The absence of significant amounts of a non-native state under native conditions makes a thermodynamic partitioning between folding and export less likely. In addition, kinetic measurements indicated that these B. licheniformis lactamases fold much faster than E. coli β-lactamase. This behavior suggests that they are exported by a kinetically controlled process, mediated by one or more still unidentified interactions that slow folding and allow a folding intermediate to enter the export pathway. [ABSTRACT FROM AUTHOR]

Introduction Single-nucleotide polymorphisms (SNPs) in the region of the Interleukin 28B (IL28B) gene on chromosome 19, coding for the interferon (IFN)-λ3, are involved in hepatitis c virus (HCV), spontaneous clearance. There is little information on the degree of liver fibrosis (LF) in HIV patients, who have had spontaneous clearance of HCV. Our objective in this study is to assess the degree of liver fibrosis in this population, as well as to identify key genetic characteristics associated with spontaneous clearance. Materials and Methods Retrospective descriptive study that evaluated from 1 January 2013 to 30 May 2014, the HIV-HCV coinfected patients in which it has been demonstrated spontaneous clearance of HCV infection. The main variables analyzed were (1) genetics: Haplotype determination of genetic polymorphism SNP rs12979860 in the region of IL 28B gene and (2) grade of LF measured in kilopascals (kPa) by transient elastography (TE). Results We evaluated 205 patients with HIV and HCV coinfection, of whom, 17 patients (8.3%), presented spontaneous clearance. Fourteen patients (82.4%) had HIV CV<20 copies/mL, while the mean CD4 cell count was 396 (SD: 245) cells/mcL. Nine (53%) patients were analyzed for SNP rs12979860 of IL 28B gene. Nine patients (100%) had the CC haplotypes, and no cases of CT and TT haplotypes were detected (p<0.001). LF was measured by TE in 12 (70.6%) patients. The median of LF (Kpa) was 5.95 (IQR 4.78). In four patients (33.3%) were observed significant LF (F3-F4). In the univariate analysis, no significant differences in the median of LF (Kpa) of HIV patients with spontaneous clearance of HCV were observed with respect to the coinfected HIV-HCV patients with SVR to antiviral therapy (N=34; median 9.6 Kpa; IQR: 10.7; p=0.92) or the coinfected HIV-HCV group who did not receive antiviral therapy (N=124; median 8.5 kPa; IQR: 7.65; p=0.85). Conclusions Spontaneous clearance of HCV in our series of patients coinfected with HIV infection represents an uncommon clinical phenomenon. The immune status was preserved and most patients had HIV virological suppression. In all patients in which the IL 28B genetic polymorphism was determined, CC haplotypes were found. The degree of LF (Kpa) in this population was low (<9.5 Kpa) and a low proportion of subjects showed significant LF (F3-F4). No differences in the degree of LF were found in this group compared to coinfected patients receiving HCV treatment with SVR and compared to untreated patients coinfected with HIV-HCV. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome (IBS) is a gut-brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and the tagging SNP rs2020938 seems to associate with constipation-predominant IBS (IBS-C) in females. rs2020938 validation was performed in 1978 additional IBS patients and 6,038 controls from eight countries. Meta-analysis on data from 2,175 IBS patients and 6,128 controls confirmed the association with female IBS-C. Expression analyses revealed that the P2 promoter drives SLC6A4 expression primarily in the small intestine. Gene reporter assays showed a functional impact of SNPs in the P2 region. In silico analysis of the polymorphic promoter indicated differential expression regulation. Further follow-up revealed that the major allele of the tagging SNP rs2020938 correlates with differential SLC6A4 expression in the jejunum and with stool consistency, indicating functional relevance. Our data consolidate rs2020938 as a functional SNP associated with IBS-C risk in females, underlining the relevance of SLC6A4 in IBS pathogenesis., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)