Miracle-dz/UniFAR-FTUs huggingface dataset:
Biliary epithelial injury-induced regenerative response by IL-33 promotes cholangiocarcinogenesis from peribiliary glands

Significance Death-driven compensatory proliferation to repair tissue defects is an important promoter of inflammation-associated carcinogenesis. Our work using a mouse model demonstrates that a biliary epithelial injury-induced regenerative response mediated by IL-33 accelerates development of extrahepatic cholangiocarcinoma (ECC) from peribiliary glands, an effect that was suppressed by anti–IL-33 treatment. Thus, IL-33 is a potential therapeutic target for ECC, and the mouse model reported in this study will enable identification of the mechanisms of biliary injury-based carcinogenesis. The carcinogenic mechanism of extrahepatic cholangiocarcinoma (ECC) is unclear, due at least in part to the lack of an appropriate mouse model. Because human studies have reported frequent genetic alterations in the Ras- and TGFβ/SMAD-signaling pathways in ECC, mice with tamoxifen-inducible, duct-cell–specific Kras activation and a TGFβ receptor type 2 (TGFβR2) deletion were first generated by crossing LSL-KrasG12D, Tgfbr2flox/flox, and K19CreERT mice (KT-K19CreERT). However, KT-K19CreERT mice showed only mild hyperplasia of biliary epithelial cells (BECs) in the extrahepatic bile duct (EHBD) and died within 7 wk, probably a result of lung adenocarcinomas. Next, to analyze the additional effect of E-cadherin loss, KT-K19CreERT mice were crossed with CDH1flox/flox mice (KTC-K19CreERT). Surprisingly, KTC-K19CreERT mice exhibited a markedly thickened EHBD wall accompanied by a swollen gallbladder within 4 wk after tamoxifen administration. Histologically, invasive periductal infiltrating-type ECC with lymphatic metastasis was observed. Time-course analysis of EHBD revealed that recombined BECs lining the bile duct lumen detached due to E-cadherin loss, whereas recombined cells could survive in the peribiliary glands (PBGs), which are considered a BEC stem-cell niche. Detached dying BECs released high levels of IL-33, as determined by microarray analysis using biliary organoids, and stimulated inflammation and a regenerative response by PBGs, leading eventually to ECC development. Cell lineage tracing suggested PBGs as the cellular origin of ECC. IL-33 cooperated with Kras and TGFβR2 mutations in the development of ECC, and anti–IL-33 treatment suppressed ECC development significantly. Thus, this mouse model provided insight into the carcinogenic mechanisms, cellular origin, and potential therapeutic targets of ECC.
Engineering Contactless Particle–Particle Interactions in Active Microswimmers

Artificial self‐propelled colloidal particles have recently served as effective building blocks for investigating many dynamic behaviors exhibited by nonequilibrium systems. However, most studies have relied upon excluded volume interactions between the active particles. Experimental systems in which the mobile entities interact over long distances in a well‐defined and controllable manner are valuable so that new modes of multiparticle dynamics can be studied systematically in the laboratory. Here, a system of self‐propelled microscale Janus particles is engineered to have contactless particle–particle interactions that lead to long‐range attraction, short‐range repulsion, and mutual alignment between adjacent swimmers. The unique modes of motion that arise can be tuned by modulating the system's parameters.
Empirical prediction intervals improve energy forecasting

Significance While many forecasters are moving toward generating probabilistic predictions, energy forecasts typically still consist of point projections and scenarios without associated probabilities. Empirical density forecasting methods provide a probabilistic amendment to existing point forecasts. Here we lay the groundwork for evaluating the performance of these methods in the data-scarce setting of long-term forecasts. Results can give policy analysts and other users confidence in estimating forecast uncertainties with empirical methods. Hundreds of organizations and analysts use energy projections, such as those contained in the US Energy Information Administration (EIA)’s Annual Energy Outlook (AEO), for investment and policy decisions. Retrospective analyses of past AEO projections have shown that observed values can differ from the projection by several hundred percent, and thus a thorough treatment of uncertainty is essential. We evaluate the out-of-sample forecasting performance of several empirical density forecasting methods, using the continuous ranked probability score (CRPS). The analysis confirms that a Gaussian density, estimated on past forecasting errors, gives comparatively accurate uncertainty estimates over a variety of energy quantities in the AEO, in particular outperforming scenario projections provided in the AEO. We report probabilistic uncertainties for 18 core quantities of the AEO 2016 projections. Our work frames how to produce, evaluate, and rank probabilistic forecasts in this setting. We propose a log transformation of forecast errors for price projections and a modified nonparametric empirical density forecasting method. Our findings give guidance on how to evaluate and communicate uncertainty in future energy outlooks.
Patient-reported factors influencing return to work after joint replacement.

BACKGROUND An increasing number of patients in the working population are undergoing total hip and knee replacement for osteoarthritis and the timing and success of return to work (RTW) is becoming increasingly important as a measure of success for these patients. There is limited understanding of the patient variables that determine the ability to RTW. AIMS To explore the factors influencing RTW following hip and knee replacement from the patient's perspective. METHODS A cross-sectional population-based postal survey carried out with patients of working age after hip and knee replacement surgery in a UK teaching hospital. Free text comments were collected regarding the experiences of patients returning to work following hip and knee replacement. Qualitative thematic analysis was undertaken to identify the factors influencing RTW from the patient's perspective. RESULTS From the patients' perspective three key factors were identified that influenced RTW. Patients reported an improved physical and psychological performance at work after surgery in comparison to pre-operative functioning, although there was a lack of informed advice regarding RTW after surgery. Workplace support and adaptation of the job role enhanced the experience of RTW. CONCLUSIONS Return to work is influenced by a combination of patient, clinician and occupational factors. The relationship between each of these needs to be explored in greater depth through further qualitative work to gain a wider understanding of the variables influencing patients' RTW following hip and knee replacement.
Low escape-rate genome safeguards with minimal molecular perturbation of Saccharomyces cerevisiae

Significance As the use of synthetic biology grows, there is an increasing need to ensure biocontainment both to protect engineered proprietary strains and to mitigate potential inadvertent or advertent release to the environment. Here, we screen for the best-performing construct for essential gene-dependent transcriptional safeguards (SGs) in yeast. We have engineered strains that have near-WT fitness and a low escape rate, and grow in the presence of a nanomolar concentration of essential supplement. We also improved our “safeguard” construct by promoter engineering, as well as by analyzing a series of potential “decoy molecules” that could be used to mask the existence of critical chemical ligands required to grow the SG strain. As the use of synthetic biology both in industry and in academia grows, there is an increasing need to ensure biocontainment. There is growing interest in engineering bacterial- and yeast-based safeguard (SG) strains. First-generation SGs were based on metabolic auxotrophy; however, the risk of cross-feeding and the cost of growth-controlling nutrients led researchers to look for other avenues. Recent strategies include bacteria engineered to be dependent on nonnatural amino acids and yeast SG strains that have both transcriptional- and recombinational-based biocontainment. We describe improving yeast Saccharomyces cerevisiae-based transcriptional SG strains, which have near-WT fitness, the lowest possible escape rate, and nanomolar ligands controlling growth. We screened a library of essential genes, as well as the best-performing promoter and terminators, yielding the best SG strains in yeast. The best constructs were fine-tuned, resulting in two tightly controlled inducible systems. In addition, for potential use in the prevention of industrial espionage, we screened an array of possible “decoy molecules” that can be used to mask any proprietary supplement to the SG strain, with minimal effect on strain fitness.
B12-dependent photoresponsive protein hydrogels for controlled stem cell/protein release

Significance Photoresponsive hydrogels have lately received ample attention because of their great potential in biomedical applications. However, the use of an entirely recombinant protein-based hydrogel with light-sensing abilities for stem cell applications has rarely been shown. Here, we created a B12-dependent light-sensing hydrogel by covalently stitching together the photoreceptor C-terminal adenosylcobalamin binding domain (CarHC) proteins under mild conditions. The polymeric CarHC proteins self-assemble into an elastic hydrogel in the presence of adenosylcobalamin in the dark and disassemble rapidly on light exposure. Such a photoresponsive protein hydrogel system enabled facile release/recovery of stem cells and protein molecules. This direct assembly of stimuli-responsive proteins into hydrogels represents a versatile strategy for designing “smart” materials and opens up enormous opportunities for future material biology. Thanks to the precise control over their structural and functional properties, genetically engineered protein-based hydrogels have emerged as a promising candidate for biomedical applications. Given the growing demand for creating stimuli-responsive “smart” hydrogels, here we show the synthesis of entirely protein-based photoresponsive hydrogels by covalently polymerizing the adenosylcobalamin (AdoB12)-dependent photoreceptor C-terminal adenosylcobalamin binding domain (CarHC) proteins using genetically encoded SpyTag-SpyCatcher chemistry under mild physiological conditions. The resulting hydrogel composed of physically self-assembled CarHC polymers exhibited a rapid gel-sol transition on light exposure, which enabled the facile release/recovery of 3T3 fibroblasts and human mesenchymal stem cells (hMSCs) from 3D cultures while maintaining their viability. A covalently cross-linked CarHC hydrogel was also designed to encapsulate and release bulky globular proteins, such as mCherry, in a light-dependent manner. The direct assembly of stimuli-responsive proteins into hydrogels represents a versatile strategy for designing dynamically tunable materials.
Systems analysis of protective immune responses to RTS,S malaria vaccination in humans

Significance The RTS,S malaria vaccine is the most advanced malaria vaccine candidate to be tested in humans. Despite its promise, there is little understanding of its mechanism of action. In this work, we describe the use of a systems biological approach to identify “molecular signatures” that are induced rapidly after the standard RTS,S vaccination regimen, consisting of three RTS,S immunizations, or with a different regimen consisting of a primary immunization with recombinant adenovirus 35 (Ad35) expressing the circumsporozoite malaria antigen followed by two immunizations with RTS,S. These results reveal important insights about the innate and adaptive responses to vaccination and identify signatures of protective immunity against malaria. RTS,S is an advanced malaria vaccine candidate and confers significant protection against Plasmodium falciparum infection in humans. Little is known about the molecular mechanisms driving vaccine immunity. Here, we applied a systems biology approach to study immune responses in subjects receiving three consecutive immunizations with RTS,S (RRR), or in those receiving two immunizations of RTS,S/AS01 following a primary immunization with adenovirus 35 (Ad35) (ARR) vector expressing circumsporozoite protein. Subsequent controlled human malaria challenge (CHMI) of the vaccinees with Plasmodium-infected mosquitoes, 3 wk after the final immunization, resulted in ∼50% protection in both groups of vaccinees. Circumsporozoite protein (CSP)-specific antibody titers, prechallenge, were associated with protection in the RRR group. In contrast, ARR-induced lower antibody responses, and protection was associated with polyfunctional CD4+ T-cell responses 2 wk after priming with Ad35. Molecular signatures of B and plasma cells detected in PBMCs were highly correlated with antibody titers prechallenge and protection in the RRR cohort. In contrast, early signatures of innate immunity and dendritic cell activation were highly associated with protection in the ARR cohort. For both vaccine regimens, natural killer (NK) cell signatures negatively correlated with and predicted protection. These results suggest that protective immunity against P. falciparum can be achieved via multiple mechanisms and highlight the utility of systems approaches in defining molecular correlates of protection to vaccination.
Recent Advances in Wearable Transdermal Delivery Systems

Wearable transdermal delivery systems have recently received tremendous attention due to their noninvasive, convenient, and prolonged administration of pharmacological agents. Here, the material prospects, fabrication processes, and drug‐release mechanisms of these types of therapeutic delivery systems are critically reviewed. The latest progress in the development of multifunctional wearable devices capable of closed‐loop sensation and drug delivery is also discussed. This survey reveals that wearable transdermal delivery has already made an impact in diverse healthcare applications, while several grand challenges remain.
LATERAL FLORET 1 induced the three-florets spikelet in rice

Significance In cereal crops, the number of florets in a spikelet is an important factor affecting the grain number per panicle and then the grain yield. In wild-type rice, one spikelet produces one fertile floret. This study characterized a gain-of-function mutant lateral florets 1 (lf1) in rice. In lf1, the spikelet developed lateral florets with proper floral organ identities in the axil of the sterile lemma, showing that the rice spikelet has the potential to restore the “three-florets spikelet” which may have existed in ancestors. Therefore, it provides strong evidence supporting the three-florets spikelet hypothesis and presents a prospect for increasing grain number per panicle by breeding rice with three-floret spikelets. The spikelet is a unique inflorescence structure in grass. The molecular mechanisms behind the development and evolution of the spikelet are far from clear. In this study, a dominant rice mutant, lateral florets 1 (lf1), was characterized. In the lf1 spikelet, lateral floral meristems were promoted unexpectedly and could generally blossom into relatively normal florets. LF1 encoded a class III homeodomain-leucine zipper (HD-ZIP III) protein, and the site of mutation in lf1 was located in a putative miRNA165/166 target sequence. Ectopic expression of both LF1 and the meristem maintenance gene OSH1 was detected in the axil of the sterile lemma primordia of the lf1 spikelet. Furthermore, the promoter of OSH1 could be bound directly by LF1 protein. Collectively, these results indicate that the mutation of LF1 induces ectopic expression of OSH1, which results in the initiation of lateral meristems to generate lateral florets in the axil of the sterile lemma. This study thus offers strong evidence in support of the “three-florets spikelet” hypothesis in rice.
Biomedical Applications of Recombinant Silk‐Based Materials

Silk is mostly known as a luxurious textile, which originates from silkworms first cultivated in China. A deeper look into the variety of silk reveals that it can be used for much more, in nature and by humanity. For medical purposes, natural silks were recognized early as a potential biomaterial for surgical threads or wound dressings; however, as biomedical engineering advances, the demand for high‐performance, naturally derived biomaterials becomes more pressing and stringent. A common problem of natural materials is their large batch‐to‐batch variation, the quantity available, their potentially high immunogenicity, and their fast biodegradation. Some of these common problems also apply to silk; therefore, recombinant approaches for producing silk proteins have been developed. There are several research groups which study and utilize various recombinantly produced silk proteins, and many of these have also investigated their products for biomedical applications. This review gives a critical overview over of the results for applications of recombinant silk proteins in biomedical engineering.
Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNFα-mediated inflammation and apoptosis

Significance TNFα is the key cytokine implicated in inflammatory bowel disease. However, TNFα is not always proinflammatory, because TNFα-activated NF-κB induces prosurvival proteins, including c-FLIP, to constrain caspase 8 activation. Here we report that epithelial EZH2 integrates the multifaceted effects of TNFα signaling to promote inflammation and apoptosis in colitis. EZH2 reduction directly stimulates TRAF2/5 expression to enhance TNFα-induced NF-κB signaling. More importantly, EZH2 deficiency up-regulates the expression of the E3 ligase ITCH to degrade the c-FLIP protein, thereby antagonizing the prosurvival role of NF-κB. Taken together, our results indicate that EZH2 serves as an epigenetic brake to modulate TNFα functions in colitis. Moreover, the data suggest that patients with lower levels of EZH2 might have a better response to anti-TNFα therapy. Epithelial barrier disruption is a major cause of inflammatory bowel disease (IBD); however, the mechanism through which epigenetic regulation modulates intestinal epithelial integrity remains largely undefined. Here we show that EZH2, the catalytic subunit of polycomb repressive complex (PRC2), is indispensable for maintaining epithelial cell barrier integrity and homeostasis under inflammatory conditions. In accordance with reduced EZH2 expression in patients, the inactivation of EZH2 in IECs sensitizes mice to DSS- and TNBS-induced experimental colitis. Conversely, EZH2 overexpression in the intestinal epithelium renders mice more resistant to colitis. Mechanistically, the genes encoding TRAF2/5 are held in a finely tuned bivalent status under inflammatory conditions. EZH2 deficiency potentiates the expression of these genes to enhance TNFα-induced NF-κB signaling, thereby leading to uncontrolled inflammation. More importantly, we show that EZH2 depletion compromises the protective role of NF-κB signaling in cell survival by directly up-regulating ITCH, a well-known E3 ligase that degrades the c-FLIP protein. Thus, our findings highlight an epigenetic mechanism by which EZH2 integrates the multifaceted effects of TNFα signaling to promote the inflammatory response and apoptosis in colitis.
Innate and adaptive immune gene expression profiles as biomarkers in human type 1 diabetes

The mRNA levels of a set of immune‐related genes were analysed with peripheral blood samples from at‐risk, new‐onset and long‐term type 1 diabetes (T1D) patients, in comparison to those from healthy controls. The selected set includes T lymphocyte genes [CD3G and cytotoxic T lymphocyte‐associated antigen 4 (CTLA4)], B lymphocyte genes (CD19 and CD20) and myeloid cell‐related genes [CD11b, Toll‐like receptor (TLR)‐9, arginase (ARG1)]. Also included is a subset of the S100 family members that has been documented recently as regulatory elements of innate immunity. Samples from patients with long‐term T1D had a reduced level of mRNA for most of selected innate and adaptive immune genes. No such reduction was detected in samples collected from at‐risk or new‐onset T1D patients. Analyses of regulatory gene expression ratios revealed a dynamic disproportion of CTLA4 versus CD3G expression in samples from at‐risk, new‐onset and long‐term T1D patients. These changes could serve as immunological biomarkers for the status of the immune system during T1D progression and therapeutic interventions.
“Let's Talk About Drugs”: Pilot study of a community‐level drug prevention intervention based on motivational interviewing principles

Purpose – The feasibility of a community‐level drug prevention intervention based upon the principles of motivational interviewing within a further education college was investigated in a pilot study.Design/methodology/approach – The implementation over the course of a single term of “Let's Talk about Drugs” was studied with both action research methods and a quasi‐experimental design.Findings – Modest qualitative evidence of attitudinal and environmental benefit provides some optimism that intervention of greater duration may have the capacity to produce more substantial impact.Research limitations/implications – The sustainability of the achieved institutional changes following the delivery of this intervention, most notably centring upon a revised drug policy, is questionable. No quantitative data on reduced drug use behaviour or associated problems directly attributable to intervention was obtained.Originality/value – Further education colleges offer relatively unexplored opportunities for drug preven.