EU-LIFE charter of independent life science research institutes.

The diverse range of organizations contributing to the global research ecosystem is believed to enhance the overall quality and resilience of its output. Mid-sized autonomous research institutes, distinct from universities, play a crucial role in this landscape. They often lead the way in new research fields and experimental methods, including those in social and organizational domains, which are vital for driving innovation. The EU-LIFE alliance was established with the goal of fostering excellence by developing and disseminating best practices among European biomedical research institutes. As directors of the 15 EU-LIFE institutes, we have spent a decade comparing and refining our processes. Now, we are eager to share the insights we've gained. To this end, we have crafted this Charter, outlining 10 principles we deem essential for research institutes to flourish and achieve ground-breaking discoveries. These principles, detailed in the Charter, encompass excellence, independence, training, internationality and inclusivity, mission focus, technological advancement, administrative innovation, cooperation, societal impact, and public engagement. Our aim is to inspire the establishment of new institutes that adhere to these principles and to raise awareness about their significance. We are convinced that they should be viewed a crucial component of any national and international innovation strategies.

Reporter cell lines to screen for inhibitors or regulators of the KRAS-RAF-MEK1/2-ERK1/2 pathway.

The RAS-regulated RAF-MEK1/2-ERK1/2 signalling pathway is activated in cancer due to mutations in RAS proteins (especially KRAS), BRAF, CRAF, MEK1 and MEK2. Whilst inhibitors of KRASG12C (lung adenocarcinoma) and BRAF and MEK1/2 (melanoma and colorectal cancer) are clinically approved, acquired resistance remains a problem. Consequently, the search for new inhibitors (especially of RAS proteins), new inhibitor modalities and regulators of this pathway, which may be new drug targets, continues and increasingly involves cell-based screens with small molecules or genetic screens such as RNAi, CRISPR or protein interference. Here we describe cell lines that exhibit doxycycline-dependent expression KRASG12V or BRAFV600E and harbour a stably integrated EGR1:EmGFP reporter gene that can be detected by flow cytometry, high-content microscopy or immunoblotting. KRASG12V or BRAFV600E-driven EmGFP expression is inhibited by MEK1/2 or ERK1/2 inhibitors (MEKi and ERKi). BRAFi inhibit BRAFV600E-driven EmGFP expression but enhance the response to KRASG12V, recapitulating paradoxical activation of wild type RAF proteins. In addition to small molecules, expression of iDab6, encoding a RAS-specific antibody fragment inhibited KRASG12V- but not BRAFV600E-driven EmGFP expression. Finally, substitution of EmGFP for a bacterial nitroreductase gene allowed KRASG12V or BRAFV600E to drive cell death in the presence of a pro-drug, which may allow selection of pathway inhibitors that promote survival. These cell lines should prove useful for cell-based screens to identify new regulators of KRAS- or BRAF-dependent ERK1/2 signalling (drug target discovery) as well as screening or triaging 'hits' from drug discovery screens.

Outcome prediction in dogs admitted through the emergency room: Accuracy of staff prediction and comparison with an illness severity stratification system for hospitalized dogs.

OBJECTIVE: To determine whether emergency staff and students can predict patient outcome within 24 hours of admission, comparing the accuracy of clinician prognostication with outcome prediction by Acute Patient Physiologic and Laboratory Evaluation (APPLE)fast scoring and identifying whether experience or mood would be associated with accuracy. DESIGN: Prospective observational study between April 2020 and March 2021. SETTING: University teaching hospital. ANIMALS: One hundred and sixty-one dogs admitted through an Emergency Service were assessed. Where data were available, an APPLEfast score was calculated per patient. An APPLEfast score of >25 was deemed a predictor for mortality. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Emergency staff and students were asked to complete surveys about dogs admitted to the emergency room. All clinicopathological data were available for review, and the animals were available for examination. Data collected included opinions on whether the patient would be discharged from hospital, a mood score, position, and experience in Emergency and Critical Care. One-hundred and twenty-five dogs (77.6%) were discharged; 36 dogs (22.4%) died or were euthanized. Two hundred and sixty-six responses were obtained; 202 responses (75.9%) predicted the correct outcome. Students, interns, residents, faculty, and nurses predicted the correct outcome in 81.4%, 58.3%, 83.3%, 82.1%, and 65.5% of cases, respectively. Of 64 incorrect predictions, 43 (67.2%) predicted death in hospital. APPLEfast scores were obtained in 121 cases, predicting the correct outcome in 83 cases (68.6%). Of 38 cases in which APPLEfast was incorrect, 27 (71.1%) were dogs surviving to discharge. Mean APPLEfast score was 22.9 (± 6.2). There was no difference in outcome prediction accuracy between staff and APPLEfast scores (P = 0.13). Neither experience nor mood score was associated with outcome prediction ability (P = 0.55 and P = 0.74, respectively). CONCLUSIONS: Outcome prediction accuracy by staff is not significantly different to APPLEfast scoring where a cutoff of >25 is used to predict mortality. When predictions were incorrect, they often predicted nonsurvival.

ERK1/2 inhibitors act as monovalent degraders inducing ubiquitylation and proteasome-dependent turnover of ERK2, but not ERK1.

Innate or acquired resistance to small molecule BRAF or MEK1/2 inhibitors (BRAFi or MEKi) typically arises through mechanisms that sustain or reinstate ERK1/2 activation. This has led to the development of a range of ERK1/2 inhibitors (ERKi) that either inhibit kinase catalytic activity (catERKi) or additionally prevent the activating pT-E-pY dual phosphorylation of ERK1/2 by MEK1/2 (dual-mechanism or dmERKi). Here, we show that eight different ERKi (both catERKi or dmERKi) drive the turnover of ERK2, the most abundant ERK isoform, with little or no effect on ERK1. Thermal stability assays show that ERKi do not destabilise ERK2 (or ERK1) in vitro, suggesting that ERK2 turnover is a cellular consequence of ERKi binding. ERK2 turnover is not observed upon treatment with MEKi alone, suggesting it is ERKi binding to ERK2 that drives ERK2 turnover. However, MEKi pre-treatment, which blocks ERK2 pT-E-pY phosphorylation and dissociation from MEK1/2, prevents ERK2 turnover. ERKi treatment of cells drives the poly-ubiquitylation and proteasome-dependent turnover of ERK2 and pharmacological or genetic inhibition of Cullin-RING E3 ligases prevents this. Our results suggest that ERKi, including current clinical candidates, act as 'kinase degraders', driving the proteasome-dependent turnover of their major target, ERK2. This may be relevant to the suggestion of kinase-independent effects of ERK1/2 and the therapeutic use of ERKi.

The development of an electronic geriatric assessment tool: Comprehensive health assessment for my plan (CHAMP).

INTRODUCTION: Geriatric assessment (GA) provides information on key health domains of older adults and is recommended to help inform cancer treatment decisions and cancer care. However, GA is not feasible in many health institutions due to lack of geriatric staff and/or resources. To increase accessibility to GA and improve treatment decision making for older adults with cancer (≥65 years), we developed a self-reported, electronic geriatric assessment tool: Comprehensive Assessment for My Plan (CHAMP). MATERIALS AND METHODS: Older adults with cancer were invited to join user-centered design sessions to develop the layout and content of the tool. Subsequently, they participated in usability testing to test the usability of the tool (ease of use, acceptability, etc.). Design sessions were also conducted with oncology clinicians (oncologists and nurses) to develop the tool's clinician interface. GA assessment questions and GA recommendations were guided by a systematic review and Delphi expert panel. RESULTS: A total of seventeen older adults participated in the study. Participants were mainly males (82.4%) and 75% were aged 75 years and older. Nine oncology clinicians participated in design sessions. Older adults and clinicians agreed that the tool was user-friendly. Domains in the final CHAMP tool (with questions and recommendations) included functional status, falls risk, cognitive impairment, nutrition, medication review, social supports, depression, substance use disorder, and miscellaneous items. DISCUSSION: CHAMP was designed for use by older adults and oncologists and may enhance access to GA for older adults with cancer. The next phase of the CHAMP study will involve field validation in oncology clinics.

Retrospective evaluation of the use of small-bore wire-guided catheters for the management of peritoneal effusion in cats and dogs.

OBJECTIVE: To describe the use of small-bore wire-guided catheters in the management of peritoneal effusion in cats and dogs and to detail any associated adverse events. DESIGN: Retrospective study. SETTING: University teaching hospital ANIMALS: Forty-five client-owned animals that had peritoneal catheters placed for management of peritoneal effusion between July 2010 and June 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Forty-five cases were included (25 dogs and 20 cats). Twenty-eight animals had the catheter placed to aid management of a uroabdomen, 8 of which recovered without surgical management, 11 had the catheter placed to allow autotransfusion of hemoabdomen, 3 had peritonitis, and 3 had ascites secondary to cardiac disease. Twenty-seven cases (15 dogs and 12 cats) received sedation (n = 24) or local anesthesia alone (n = 3) to facilitate catheter placement, and 6 cases had the catheter placed while under general anesthesia. Median length of catheter persistence was 24 hours (range: 2-144 h). The most common adverse events reported were impaired drainage (n = 7) and leakage at the insertion site (n = 4). CONCLUSIONS: Peritoneal catheters can be inserted percutaneously for management of peritoneal effusion. Indications include stabilization and conservative management of uroabdomen, and autotransfusion. They can often be placed with minimal or no sedation and adverse events appear infrequent in occurrence.

Perspectives of digital agriculture in diverse types of livestock supply chain systems. Making sense of uses and benefits.

Digital technology is being introduced to global agriculture in a wide variety of forms that are collectively known as digital agriculture. In this paper we provide opportunities and value propositions of how this is occurring in livestock production systems, with a consistent emphasis on technology relating to animal health, animal welfare, and product quality for value creation. This is achieved by organizing individual accounts of digital agriculture in livestock systems according to four broad types-commodity-based; value seeking; subsistence and nature-based. Each type presents contrasting modes of value creation in downstream processing; as well as from the perspective of One Health. The ideal result of digital technology adoption is an equitable and substantial diversification of supply chains, increased monetization of animal product quality, and more sensitive management to meet customer demands and environmental threats. Such changes have a significance beyond the immediate value generated because they indicate endogenous growth in livestock systems, and may concern externalities imposed by the pursuit of purely commercial ends.

Escape from G1 arrest during acute MEK inhibition drives the acquisition of drug resistance.

Mutations and gene amplifications that confer drug resistance emerge frequently during chemotherapy, but their mechanism and timing are poorly understood. Here, we investigate BRAFV600E amplification events that underlie resistance to the MEK inhibitor selumetinib (AZD6244/ARRY-142886) in COLO205 cells, a well-characterized model for reproducible emergence of drug resistance, and show that BRAF amplifications acquired de novo are the primary cause of resistance. Selumetinib causes long-term G1 arrest accompanied by reduced expression of DNA replication and repair genes, but cells stochastically re-enter the cell cycle during treatment despite continued repression of pERK1/2. Most DNA replication and repair genes are re-expressed as cells enter S and G2; however, mRNAs encoding a subset of factors important for error-free replication and chromosome segregation, including TIPIN, PLK2 and PLK3, remain at low abundance. This suggests that DNA replication following escape from G1 arrest in drug is more error prone and provides a potential explanation for the DNA damage observed under long-term RAF-MEK-ERK1/2 pathway inhibition. To test the hypothesis that escape from G1 arrest in drug promotes de novo BRAF amplification, we exploited the combination of palbociclib and selumetinib. Combined treatment with selumetinib and a dose of palbociclib sufficient to reinforce G1 arrest in selumetinib-sensitive cells, but not to impair proliferation of resistant cells, delays the emergence of resistant colonies, meaning that escape from G1 arrest is critical in the formation of resistant clones. Our findings demonstrate that acquisition of MEK inhibitor resistance often occurs through de novo gene amplification and can be suppressed by impeding cell cycle entry in drug.

The Impact of Over-The-Counter Lactic Acid Containing Vaginal Gels on the Integrity and Inflammatory State of the Vaginal Epithelium in vitro.

The vaginal microbiome influences a wide range of health outcomes in women, where a microbiome dominated by Lactobacillus spp. is considered optimal and associated with reduced risk of pre-term birth and acquisition of sexually transmitted infections including HIV. Conversely, replacement of lactobacilli by non-optimal bacteria leads to the development of bacterial vaginosis, which is associated with increased risk of these outcomes. Lactobacilli produce the metabolite lactic acid (LA) which is a potent antibacterial and antiviral agent. The potential therapeutic benefits of LA have prompted the development of numerous over-the-counter LA-containing gels for use in the vagina, although a comprehensive analysis of the impact of these formulations on the cervicovaginal epithelium and pro-inflammatory cytokine/chemokine responses, has not been assessed. Here, we evaluated the properties of 11 over-the-counter gels, including 9 containing LA, marketed for use in the vagina. Ten of the 11 gels had an osmolality greater than vaginal fluid from women with Lactobacillus-dominated microbiota (370 ± 40 mOsmol/kg in women with Nugent score 0-3), with six gels that were hyperosmolal >2,000 mOsmol/kg. Using a reconstructed primary cell model of the vaginal epithelium, we found hyperosmolal gels had a detrimental impact on epithelial barrier integrity, resulting in substantial cellular toxicity (<10% viability as compared to untreated cells) and reduced epithelial barrier integrity [≈30% of untreated cells, assessed by transepithelial electrical resistance (TEER)]. Treatment of vaginal tissues with most of the gels elicited the production of pro-inflammatory factors including IL-1α (8 of 11) and IL-1ß (10 of 11) which are associated with heightened risk of HIV acquisition in vivo. The majority of the OTC gels elicited moderate tissue damage as determined by histology. The detrimental effects of these gels on the human vaginal epithelium in vitro may predict compromised epithelial barrier integrity and genital inflammation in vivo, which has implications for sexual and reproductive health. This study highlights the importance of evaluating the impact of intravaginal products on the integrity and inflammatory status of the mucosal epithelium to avoid unfavorable off target effects.

Assessment of climate change effects on vegetation and river hydrology in a semi-arid river basin.

Climate change plays a key role in changing vegetation productivity dynamics, which ultimately affect the hydrological cycle of a watershed through evapotranspiration (ET). Trends and correlation analysis were conducted to investigate vegetation responses across the whole Upper Jhelum River Basin (UJRB) in the northeast of Pakistan using the normalized difference vegetation index (NDVI), climate variables, and river flow data at inter-annual/monthly scales between 1982 and 2015. The spatial variability in trends calculated with the Mann-Kendall (MK) trend test on NDVI and climate data was assessed considering five dominant land use/cover types. The inter-annual NDVI in four out of five vegetation types showed a consistent increase over the 34-year study period; the exception was for herbaceous vegetation (HV), which increased until the end of the 1990s and then decreased slightly in subsequent years. In spring, significant (p<0.05) increasing trends were found in the NDVI of all vegetation types. Minimum temperature (Tmin) showed a significant increase during spring, while maximum temperature (Tmax) decreased significantly during summer. Average annual increase in Tmin (1.54°C) was much higher than Tmax (0.37°C) over 34 years in the UJRB. Hence, Tmin appears to have an enhancing effect on vegetation productivity over the UJRB. A significant increase in NDVI, Tmin and Tmax during spring may have contributed to reductions in spring river flow by enhancing evapotranspiration observed in the watershed of UJRB. These findings provide valuable information to improve our knowledge and understanding about the interlinkages between vegetation, climate and river flow at a watershed scale.

ERK5 Signalling and Resistance to ERK1/2 Pathway Therapeutics: The Path Less Travelled?

The RAS-regulated RAF-MEK1/2-ERK1/2 signalling pathway is frequently de-regulated in human cancer. Melanoma in particular exhibits a high incidence of activating BRAFV600E/K and NRASQ61L/K mutations and such cells are addicted to the activity of these mutant oncoproteins. As a result three different BRAF inhibitors (BRAFi) have now been approved for BRAFV600E/K- mutant melanoma and have transformed the treatment of this disease. Despite this, clinical responses are typically transient as tumour cells develop resistance. These resistance mechanisms frequently involve reinstatement of ERK1/2 signalling and BRAFi are now deployed in combination with one of three approved MEK1/2 inhibitors (MEKi) to provide more durable, but still transient, clinical responses. Furthermore, inhibitors to ERK1/2 (ERK1/2i) have also been developed to counteract ERK1/2 signalling. However, recent studies have suggested that BRAFi/MEKi and ERK1/2i resistance can arise through activation of a parallel signalling pathway leading to activation of ERK5, an unusual protein kinase that contains both a kinase domain and a transcriptional transactivation domain. Here we review the evidence supporting ERK5 as a mediator of BRAFi/MEKi and ERK1/2i resistance. We also review the challenges in targeting ERK5 signalling with small molecules, including paradoxical activation of the transcriptional transactivation domain, and discuss new therapeutic modalities that could be employed to target ERK5.

Parallel Optimization of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Kinase Domain Inhibitor.

The nonclassical extracellular signal-related kinase 5 (ERK5) mitogen-activated protein kinase pathway has been implicated in increased cellular proliferation, migration, survival, and angiogenesis; hence, ERK5 inhibition may be an attractive approach for cancer treatment. However, the development of selective ERK5 inhibitors has been challenging. Previously, we described the development of a pyrrole carboxamide high-throughput screening hit into a selective, submicromolar inhibitor of ERK5 kinase activity. Improvement in the ERK5 potency was necessary for the identification of a tool ERK5 inhibitor for target validation studies. Herein, we describe the optimization of this series to identify nanomolar pyrrole carboxamide inhibitors of ERK5 incorporating a basic center, which suffered from poor oral bioavailability. Parallel optimization of potency and in vitro pharmacokinetic parameters led to the identification of a nonbasic pyrazole analogue with an optimal balance of ERK5 inhibition and oral exposure.

Medical and surgical management of pancreatic fluid accumulations in dogs: A retrospective study of 15 cases.

BACKGROUND: Limited data exist on the diagnosis and successful medical management of suspected pancreatic abscessation, and the appropriate terminology of this condition. HYPOTHESIS/OBJECTIVES: To describe the diagnosis and management of pancreatic fluid accumulations in dogs where pancreatic fluid cytology results were available, to describe those medically and surgically managed at the same institution, and reconsider the terminology describing acute pancreatitis with pancreatic fluid accumulation. ANIMALS: Fifteen dogs treated for suspected pancreatic abscessation at a university teaching hospital between January 2010 and March 2020. METHODS: Retrospective descriptive study. RESULTS: Ultrasonographic findings described pancreatic fluid accumulations as hypoechoic in 10/15 and anechoic in 2/15 cases, ranging between 1.6 and 7 cm in diameter (median, 3.5 cm). No complications were documented after ultrasound guided fine-needle aspiration. Cytologically, all samples revealed a predominantly neutrophilic inflammation. 11/15 samples yielded a negative culture (9/11 received antimicrobials before sampling) and in 4 cases culture was positive. 7/15 were initially managed surgically including all 4 infected cases. 4/7 surgically managed cases were discharged, including 2 infected cases. The remaining 3/7 surgically managed cases were euthanized due poor quality of life. 8/15 cases were managed medically; 7/8 were discharged, 1 died. 3/7 then represented, and underwent successful surgical intervention after recrudescence of clinical signs, and all were discharged. The remaining 4 medically managed cases did not require further therapeutic intervention, with no clinical deterioration on reassessment. CONCLUSIONS AND CLINICAL IMPORTANCE: Medical management is a viable treatment option for some dogs with pancreatic fluid accumulation, or as a prequel to surgical management. Subclassifications of pancreatic fluid accumulations using diagnostic findings could enable more tailored management approaches and accurate prognostication.

IKKα plays a major role in canonical NF-κB signalling in colorectal cells.

Inhibitor of kappa B (IκB) kinase ß (IKKß) has long been viewed as the dominant IKK in the canonical nuclear factor-κB (NF-κB) signalling pathway, with IKKα being more important in non-canonical NF-κB activation. Here we have investigated the role of IKKα and IKKß in canonical NF-κB activation in colorectal cells using CRISPR-Cas9 knock-out cell lines, siRNA and selective IKKß inhibitors. IKKα and IKKß were redundant for IκBα phosphorylation and turnover since loss of IKKα or IKKß alone had little (SW620 cells) or no (HCT116 cells) effect. However, in HCT116 cells IKKα was the dominant IKK required for basal phosphorylation of p65 at S536, stimulated phosphorylation of p65 at S468, nuclear translocation of p65 and the NF-κB-dependent transcriptional response to both TNFα and IL-1α. In these cells, IKKß was far less efficient at compensating for the loss of IKKα than IKKα was able to compensate for the loss of IKKß. This was confirmed when siRNA was used to knock-down the non-targeted kinase in single KO cells. Critically, the selective IKKß inhibitor BIX02514 confirmed these observations in WT cells and similar results were seen in SW620 cells. Notably, whilst IKKα loss strongly inhibited TNFα-dependent p65 nuclear translocation, IKKα and IKKß contributed equally to c-Rel nuclear translocation indicating that different NF-κB subunits exhibit different dependencies on these IKKs. These results demonstrate a major role for IKKα in canonical NF-κB signalling in colorectal cells and may be relevant to efforts to design IKK inhibitors, which have focused largely on IKKß to date.

On-Farm Experimentation to transform global agriculture.

Restructuring farmer-researcher relationships and addressing complexity and uncertainty through joint exploration are at the heart of On-Farm Experimentation (OFE). OFE describes new approaches to agricultural research and innovation that are embedded in real-world farm management, and reflects new demands for decentralized and inclusive research that bridges sources of knowledge and fosters open innovation. Here we propose that OFE research could help to transform agriculture globally. We highlight the role of digitalization, which motivates and enables OFE by dramatically increasing scales and complexity when investigating agricultural challenges.

Retrospective evaluation of negative-pressure pulmonary edema in dogs (2006-2018): 35 cases.

OBJECTIVE: To describe the clinical characteristics and outcomes in a population of dogs with negative-pressure pulmonary edema (NPPE) and to identify the main causes of the disease. To evaluate any associations with morbidity and mortality. DESIGN: Retrospective study. SETTING: Three university teaching hospitals and 2 private referral centers in the United Kingdom. ANIMALS: Thirty-five client-owned dogs presented with NPPE. INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: Data collected included patient characteristics, clinical history, clinicopathological abnormalities, radiographic features, treatments, and outcomes. The median age was 4 months (range 2-90) and median weight was 7.1 kg (range 1.7-37.2). There were many causes of NPPE including leash tugs, near hanging, accidental choking, anatomical obstruction to airflow, and purposeful airway obstruction by people. The most common cause of NPPE was accidental choking (40% of cases). Dogs with an anatomical obstruction were older than 24 months. Hypoxemia with an increased alveolar-arterial gradient was common on presentation. The majority of thoracic radiographs (65.7%) showed an alveolar or interstitial pattern in the caudodorsal area as previously described in the literature. Oxygen therapy was administered to 33 (94.3%) dogs. Furosemide was administered to 18 (51.4%) dogs. The median length of hospitalization was 2 days (range 0-14). Twenty-eight (80%) dogs survived to discharge. Seven dogs were mechanically ventilated and only 2 of them (28.6%) survived to discharge. The requirement for mechanical ventilation was the only parameter associated with mortality (P < 0.001). CONCLUSIONS: Most cases of NPPE occur in juvenile dogs. Different incidents associated with upper airway obstruction can produce an episode of NPPE. Choking on food or toys and near hanging have not been previously described in the veterinary literature as inciting causes of NPPE. The overall prognosis is good.

Accelerated mass loss of Himalayan glaciers since the Little Ice Age.

Himalayan glaciers are undergoing rapid mass loss but rates of contemporary change lack long-term (centennial-scale) context. Here, we reconstruct the extent and surfaces of 14,798 Himalayan glaciers during the Little Ice Age (LIA), 400 to 700 years ago. We show that they have lost at least 40 % of their LIA area and between 390 and 586 km3 of ice; 0.92 to 1.38 mm Sea Level Equivalent. The long-term rate of ice mass loss since the LIA has been between - 0.011 and - 0.020 m w.e./year, which is an order of magnitude lower than contemporary rates reported in the literature. Rates of mass loss depend on monsoon influence and orographic effects, with the fastest losses measured in East Nepal and in Bhutan north of the main divide. Locally, rates of loss were enhanced with the presence of surface debris cover (by 2 times vs clean-ice) and/or a proglacial lake (by 2.5 times vs land-terminating). The ten-fold acceleration in ice loss we have observed across the Himalaya far exceeds any centennial-scale rates of change that have been recorded elsewhere in the world.

Healthcare providers' perception of faecal microbiota transplantation with clostridium difficile infection and inflammatory bowel disease: a quantitative systematic review.

BACKGROUND: Clostridioides difficile infection (CDI) and inflammatory bowel disease (IBD) are global gastroenterological diseases that cause considerable burden on human health, healthcare systems, and society. Faecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridioides Difficile Infection (rCDI) and a promising therapy for IBD. However, indication for FMT in IBD is still unofficial. Consequently, the National Institute for Health and Care Excellence (NICE) is seeking healthcare providers' advice on whether to update FMT guidelines. METHODS: A systematic review methodology was adopted for this study. Five databases (CINAHL, MEDLINE, Cochrane Library, Scopus, Web of Science) and grey literature were systematically searched for English language literature to 14 May 2021. The quality of the included studies was then appraised using the Institute for Public Health Sciences cross-sectional studies tool, after which the findings of the studies were narratively synthesised. RESULTS: Thirteen cross-sectional studies with 4110 validated questionnaire responses were included. Narrative synthesis found that 39.43% of respondents were familiar with FMT (N = 3746, 95%CI = 37.87%-41%), 58.81% of respondents would recommend FMT to their patients (N = 1141, 95%CI = 55.95%-61.67%), 66.67% of respondents considered lack of clinical evidence was the greatest concern regarding FMT (N = 1941, 95%CI = 64.57%-68.77%), and 40.43% respondents would not implement FMT due to concerns about infection transmission (N = 1128, 95%CI = 37.57%-43.29%). CONCLUSION: Healthcare providers' knowledge of FMT is relatively low and education is an effective strategy to improve it. As knowledge of FMT increases, willingness to recommend it also increases. Strengthening FMT clinical efficacy and reducing infection can enhance its public acceptance, application and popularity. However, further research is required to explore the donor screening procedure.

Active microbial ecosystem in glacier basal ice fuelled by iron and silicate comminution-derived hydrogen.

The basal zone of glaciers is characterized by physicochemical properties that are distinct from firnified ice due to strong interactions with underlying substrate and bedrock. Basal ice (BI) ecology and the roles that the microbiota play in biogeochemical cycling, weathering, and proglacial soil formation remain poorly described. We report on basal ice geochemistry, bacterial diversity (16S rRNA gene phylogeny), and inferred ecological roles at three temperate Icelandic glaciers. We sampled three physically distinct basal ice facies (stratified, dispersed, and debris bands) and found facies dependent on biological similarities and differences; basal ice character is therefore an important sampling consideration in future studies. Based on a high abundance of silicates and Fe-containing minerals and, compared to earlier BI literature, total C was detected that could sustain the basal ice ecosystem. It was hypothesized that C-fixing chemolithotrophic bacteria, especially Fe-oxidisers and hydrogenotrophs, mutualistically support associated heterotrophic communities. Basal ice-derived rRNA gene sequences corresponding to genera known to harbor hydrogenotrophic methanogens suggest that silicate comminution-derived hydrogen can also be utilized for methanogenesis. PICRUSt-predicted metabolism suggests that methane metabolism and C-fixation pathways could be highly relevant in BI, indicating the importance of these metabolic routes. The nutrients and microbial communities release from melting basal ice may play an important role in promoting pioneering communities establishment and soil development in deglaciating forelands.

Inhibitory feedback control of NF-κB signalling in health and disease.

Cells must adapt to changes in their environment to maintain cell, tissue and organismal integrity in the face of mechanical, chemical or microbiological stress. Nuclear factor-κB (NF-κB) is one of the most important transcription factors that controls inducible gene expression as cells attempt to restore homeostasis. It plays critical roles in the immune system, from acute inflammation to the development of secondary lymphoid organs, and also has roles in cell survival, proliferation and differentiation. Given its role in such critical processes, NF-κB signalling must be subject to strict spatiotemporal control to ensure measured and context-specific cellular responses. Indeed, deregulation of NF-κB signalling can result in debilitating and even lethal inflammation and also underpins some forms of cancer. In this review, we describe the homeostatic feedback mechanisms that limit and 're-set' inducible activation of NF-κB. We first describe the key components of the signalling pathways leading to activation of NF-κB, including the prominent role of protein phosphorylation and protein ubiquitylation, before briefly introducing the key features of feedback control mechanisms. We then describe the array of negative feedback loops targeting different components of the NF-κB signalling cascade including controls at the receptor level, post-receptor signalosome complexes, direct regulation of the critical 'inhibitor of κB kinases' (IKKs) and inhibitory feedforward regulation of NF-κB-dependent transcriptional responses. We also review post-transcriptional feedback controls affecting RNA stability and translation. Finally, we describe the deregulation of these feedback controls in human disease and consider how feedback may be a challenge to the efficacy of inhibitors.