Miracle-dz/UniFAR-FTUs huggingface dataset:
Modulation of inflammatory response via α2‐adrenoceptor blockade in acute murine colitis

Inflammatory bowel disease (IBD) is characterized by heavy production of proinflammatory cytokines such as tumour necrosis factor (TNF)‐α and interleukin (IL)‐1β. Interactions of the autonomic nervous system with local immune cells play an important role in the development of IBD, and the balance of autonomic nerve function is broken in IBD patients with sympathetic overactivity. However, the function of catecholamines in the progress of colitis is unclear. In this study, we examined the role of catecholamines via α2‐adrenoreceptor in acute murine colitis. The expression of tyrosine hydroxylase (TH) and dopamine b‐hydroxylase (DBH), two rate‐limiting enzymes in catecholamine synthesis, was detected by immunohistochemistry in murine colitis. Murine colitis was induced by dextran sodium sulphate or trinitrobenzene sulphonic acid (TNBS), and the mice were administered RX821002 or UK14304, α2‐adrenoceptor antagonists or agonists. Colitis was evaluated by clinical symptoms, myeloperoxidase assay, TNF‐α and IL‐1β production and histology. Lamina propria mononuclear cells (LPMCs) from mice with TNBS colitis were cultured in the absence or presence of RX821002 or UK14304, and stimulated further by lipopolysaccharide. TH and DBH are induced in LPMCs of inflamed colon, the evidence of catecholamine synthesis during the process of colitis. RX821002 down‐regulates the production of proinflammatory cytokines from LPMCs, while UK14304 leads to exacerbation of colitis. Together, our data show a critical role of catecholamines via α2‐adrenoreceptors in the progress of acute colitis, and suggest that use of the α2‐adrenoceptor antagonist represents a novel therapeutic approach for the management of colitis.
Clostridium difficile infection as a novel marker for hospital quality, efficiency and other factors associated with prolonged inpatient length of stay

Excess inpatient length of stay (LOS) varies between hospitals and is burdensome to patients and the overall healthcare system. Variation in LOS has often been associated with hospital-level factors, such as hospital e ciency and quality. Clostridium di cile infection (CDI) is an increasingly common hospital-acquired (HA) infection. This thesis explores the connection between hospital incidence of CDI and excess LOS in patients without a CDI. It is hypothesized that HA-CDI incidence may act as a “proxy variable” to capture unobserved hospital characteristics, such as hospital quality or e ciency, associated with prolonged LOS. In addition, hospitals with longer LOS may tend to observe more HA-CDI cases prior to discharge. This thesis analyzes the ability of CDI incidence to capture excess LOS variation across hospitals, while controlling for CDI cases that occur after discharge. We use data on hospital inpatient visits, spanning the years 2005-2011, from three data sources distributed by the Healthcare Cost and Utilization Project: the Nationwide Inpatient Sample (NIS), and the State Inpatient Databases (SID) for California and New York. The NIS provides discharge records from a nationwide sampling of hospitals in a given year. The SIDs are longitudinal populations of inpatient records in each state, and patient records can be linked across stays. We compute a variety of di↵erent measures of hospital CDI incidence and identify HACDI cases that occur after a patient is discharged. Various multivariable regression models are analyzed to predict LOS at an
Identification of Cav2–PKCβ and Cav2–NOS1 complexes as entities for ultrafast electrochemical coupling

Significance Nitric oxide synthase (NOS1) and protein kinase Cβ (PKCβ), through their enzymatic activities, initiate a variety of intracellular signaling processes in the brain. For activation, both enzymes require intracellular calcium ions (Ca2+), which, for NOS1, may be provided via NMDA-type glutamate receptors. Activation by voltage-gated Ca2+ (Cav) channels has remained elusive. Here we report that both PKCβ and NOS1 form bimolecular complexes with Cav2.2 channels, thus placing themselves within less than 10 nm of a Ca2+ source. Within the framework of the channel–enzyme complexes, PKCβ and NOS1 are reliably activated even by periods of Ca2+ influx as short as 0.8 ms occurring during action potentials. Our results establish Cav2–enzyme complexes as molecular entities for fast and precisely timed electrochemical coupling. Voltage-activated calcium (Cav) channels couple intracellular signaling pathways to membrane potential by providing Ca2+ ions as second messengers at sufficiently high concentrations to modulate effector proteins located in the intimate vicinity of those channels. Here we show that protein kinase Cβ (PKCβ) and brain nitric oxide synthase (NOS1), both identified by proteomic analysis as constituents of the protein nano-environment of Cav2 channels in the brain, directly coassemble with Cav2.2 channels upon heterologous coexpression. Within Cav2.2–PKCβ and Cav2.2–NOS1 complexes voltage-triggered Ca2+ influx through the Cav channels reliably initiates enzymatic activity within milliseconds. Using BKCa channels as target sensors for nitric oxide and protein phosphorylation together with high concentrations of Ca2+ buffers showed that the complex-mediated Ca2+ signaling occurs in local signaling domains at the plasma membrane. Our results establish Cav2–enzyme complexes as molecular entities for fast electrochemical coupling that reliably convert brief membrane depolarization into precisely timed intracellular signaling events in the mammalian brain.
Quorum sensing controls the Pseudomonas aeruginosa CRISPR-Cas adaptive immune system

Significance The cell–cell communication process, called quorum sensing, activates all three key aspects of the prokaryotic adaptive immune system (termed CRISPR-Cas): expression, activity, and adaptation in the pathogen Pseudomonas aeruginosa. We show that pro- and antiquorum-sensing compounds activate and repress CRISPR-Cas, respectively, suggesting the exciting possibility of a combination quorum-sensing–inhibition-phage therapy cocktail. In P. aeruginosa, quorum-sensing inhibitors repress virulence, making P. aeruginosa more susceptible to elimination by the human immune system, while simultaneously making P. aeruginosa more prone to killing by phage therapy through inhibition of the CRISPR-Cas defense mechanism. Finally, because we show that quorum sensing activates adaptation by the CRISPR-Cas immune system, a quorum-sensing inhibitor should also reduce acquisition of resistance against the administered phage. CRISPR-Cas are prokaryotic adaptive immune systems that provide protection against bacteriophage (phage) and other parasites. Little is known about how CRISPR-Cas systems are regulated, preventing prediction of phage dynamics in nature and manipulation of phage resistance in clinical settings. Here, we show that the bacterium Pseudomonas aeruginosa PA14 uses the cell–cell communication process, called quorum sensing, to activate cas gene expression, to increase CRISPR-Cas targeting of foreign DNA, and to promote CRISPR adaptation, all at high cell density. This regulatory mechanism ensures maximum CRISPR-Cas function when bacterial populations are at highest risk for phage infection. We demonstrate that CRISPR-Cas activity and acquisition of resistance can be modulated by administration of pro- and antiquorum-sensing compounds. We propose that quorum-sensing inhibitors could be used to suppress the CRISPR-Cas adaptive immune system to enhance medical applications, including phage therapies.
Zero‐Depth Interfacial Nanopore Capillaries

High‐fidelity analysis of translocating biomolecules through nanopores demands shortening the nanocapillary length to a minimal value. Existing nanopores and capillaries, however, inherit a finite length from the parent membranes. Here, nanocapillaries of zero depth are formed by dissolving two superimposed and crossing metallic nanorods, molded in polymeric slabs. In an electrolyte, the interface shared by the crossing fluidic channels is mathematically of zero thickness and defines the narrowest constriction in the stream of ions through the nanopore device. This novel architecture provides the possibility to design nanopore fluidic channels, particularly with a robust 3D architecture maintaining the ultimate zero thickness geometry independently of the thickness of the fluidic channels. With orders of magnitude reduced biomolecule translocation speed, and lowered electronic and ionic noise compared to nanopores in 2D materials, the findings establish interfacial nanopores as a scalable platform for realizing nanofluidic systems, capable of single‐molecule detection.
Programmable and Multifunctional DNA‐Based Materials for Biomedical Applications

DNA encodes the genetic information; recently, it has also become a key player in material science. Given the specific Watson–Crick base‐pairing interactions between only four types of nucleotides, well‐designed DNA self‐assembly can be programmable and predictable. Stem‐loops, sticky ends, Holliday junctions, DNA tiles, and lattices are typical motifs for forming DNA‐based structures. The oligonucleotides experience thermal annealing in a near‐neutral buffer containing a divalent cation (usually Mg2+) to produce a variety of DNA nanostructures. These structures not only show beautiful landscape, but can also be endowed with multifaceted functionalities. This Review begins with the fundamental characterization and evolutionary trajectory of DNA‐based artificial structures, but concentrates on their biomedical applications. The coverage spans from controlled drug delivery to high therapeutic profile and accurate diagnosis. A variety of DNA‐based materials, including aptamers, hydrogels, origamis, and tetrahedrons, are widely utilized in different biomedical fields. In addition, to achieve better performance and functionality, material hybridization is widely witnessed, and DNA nanostructure modification is also discussed. Although there are impressive advances and high expectations, the development of DNA‐based structures/technologies is still hindered by several commonly recognized challenges, such as nuclease instability, lack of pharmacokinetics data, and relatively high synthesis cost.
Progress toward Catalytic Micro‐ and Nanomotors for Biomedical and Environmental Applications

Synthetic micro‐ and nanomotors (MNMs) are tiny objects that can autonomously move under the influence of an appropriate source of energy, such as a chemical fuel, magnetic field, ultrasound, or light. Chemically driven MNMs are composed of or contain certain reactive material(s) that convert chemical energy of a fuel into kinetic energy (motion) of the particles. Several different materials have been explored over the last decade for the preparation of a wide variety of MNMs. Here, the discovery of materials and approaches to enhance the efficiency of chemically driven MNMs are reviewed. Several prominent applications of the MNMs, especially in the fields of biomedicine and environmental science, are also discussed, as well as the limitations of existing materials and future research directions.
Three-dimensional culture system identifies a new mode of cetuximab resistance and disease-relevant genes in colorectal cancer

Significance By culturing a human colorectal cancer (CRC) cell line (HCA-7) in 3D, we have generated two cell lines (CC and SC) with distinct morphological, genetic, biochemical, and functional properties. Using this 3D system, we have discovered that increased tyrosine phosphorylation of MET and RON results in cetuximab resistance in the SC cell line that can be overcome by addition of the dual MET/RON tyrosine kinase inhibitor, crizotinib. We have also identified that increased epithelial, but not stromal, versican staining correlates with reduced survival in a clinically annotated CRC tissue microarray. We previously reported that single cells from a human colorectal cancer (CRC) cell line (HCA-7) formed either hollow single-layered polarized cysts or solid spiky masses when plated in 3D in type-I collagen. To begin in-depth analyses into whether clonal cysts and spiky masses possessed divergent properties, individual colonies of each morphology were isolated and expanded. The lines thus derived faithfully retained their parental cystic and spiky morphologies and were termed CC (cystic) and SC (spiky), respectively. Although both CC and SC expressed EGF receptor (EGFR), the EGFR-neutralizing monoclonal antibody, cetuximab, strongly inhibited growth of CC, whereas SC was resistant to growth inhibition, and this was coupled to increased tyrosine phosphorylation of MET and RON. Addition of the dual MET/RON tyrosine kinase inhibitor, crizotinib, restored cetuximab sensitivity in SC. To further characterize these two lines, we performed comprehensive genomic and transcriptomic analysis of CC and SC in 3D. One of the most up-regulated genes in CC was the tumor suppressor 15-PGDH/HPGD, and the most up-regulated gene in SC was versican (VCAN) in 3D and xenografts. Analysis of a CRC tissue microarray showed that epithelial, but not stromal, VCAN staining strongly correlated with reduced survival, and combined epithelial VCAN and absent HPGD staining portended a poorer prognosis. Thus, with this 3D system, we have identified a mode of cetuximab resistance and a potential prognostic marker in CRC. As such, this represents a potentially powerful system to identify additional therapeutic strategies and disease-relevant genes in CRC and possibly other solid tumors.
Metal–Organic Frameworks as Platforms for Catalytic Applications

Metal–organic frameworks (MOFs), also called porous coordination polymers, represent a class of crystalline porous materials built from organic linkers and metal ions/clusters. The unique features of MOFs, including structural diversity and tailorability as well as high surface area, etc., enable them to be a highly versatile platform for potential applications in many fields. Herein, an overview of recent developments achieved in MOF catalysis, including heterogeneous catalysis, photocatalysis, and eletrocatalysis over MOFs and MOF‐based materials, is provided. The active sites involved in the catalysts are particularly emphasized. The challenges, future trends, and prospects associated with MOFs and their related materials for catalysis are also discussed.
Single-cell functional and chemosensitive profiling of combinatorial colorectal therapy in zebrafish xenografts

Significance Despite advances in targeted cancer treatments, we still lack methods to predict how a specific cancer will respond to a given therapy. As a consequence, patients go through rounds of trial-and-error approaches based on guidelines to find the best treatment, often subjected to unnecessary toxicity. Using cell lines, we used zebrafish larvae xenografts as sensors for cancer behavior and therapy guideline screening. Our data show not only sufficient resolution to distinguish functional tumor behaviors in just 4 days but also differential sensitivity to colorectal cancer therapy. As proof-of-principle, we provide evidence for similar behavior response to therapies in patients as in zebrafish patient-derived xenografts. Altogether, our results suggest zebrafish larvae xenografts as a promising in vivo screening platform for precision medicine. Cancer is as unique as the person fighting it. With the exception of a few biomarker-driven therapies, patients go through rounds of trial-and-error approaches to find the best treatment. Using patient-derived cell lines, we show that zebrafish larvae xenotransplants constitute a fast and highly sensitive in vivo model for differential therapy response, with resolution to reveal intratumor functional cancer heterogeneity. We screened international colorectal cancer therapeutic guidelines and determined distinct functional tumor behaviors (proliferation, metastasis, and angiogenesis) and differential sensitivities to standard therapy. We observed a general higher sensitivity to FOLFIRI [5-fluorouracil(FU)+irinotecan+folinic acid] than to FOLFOX (5-FU+oxaliplatin+folinic acid), not only between isogenic tumors but also within the same tumor. We directly compared zebrafish xenografts with mouse xenografts and show that relative sensitivities obtained in zebrafish are maintained in the rodent model. Our data also illustrate how KRAS mutations can provide proliferation advantages in relation to KRASWT and how chemotherapy can unbalance this advantage, selecting for a minor clone resistant to chemotherapy. Zebrafish xenografts provide remarkable resolution to measure Cetuximab sensitivity. Finally, we demonstrate the feasibility of using primary patient samples to generate zebrafish patient-derived xenografts (zPDX) and provide proof-of-concept experiments that compare response to chemotherapy and biological therapies between patients and zPDX. Altogether, our results suggest that zebrafish larvae xenografts constitute a promising fast assay for precision medicine, bridging the gap between genotype and phenotype in an in vivo setting.
The Hospitals 1800–1948.

genius-deserve special attention. Melancholy, regarded as evil during the Middle Ages, was revalued in the Renaissance: on Ficino's showing it was a 'unique and divine gift', even as Saturn was now not only the mightiest star, but also the noblest (p. 259), and it was Ficino who first identified Aristotle's attribution of high intellect to melancholy with Plato's 'divine frenzy'. Agrippa of Nettesheim accepted this Ficinian doctrine and systematized it-distinguishing three grades of Saturnine and melancholic inspiration. It is thefirst of these grades which is portrayed in Durer's Melancholia I, and thus the riddle of the 'I' which has exercised the minds of Renaissance scholars for so many years meets its most convincing and brilliant solution. It is the realm ofthe lower spirits which are operative through imagination and responsible for creative achievement in the mechanical arts (notably architecture and painting) and the correct prophecy of natural events such as cloudburst and famine. Indeed there is 'no work of art which corresponds more nearly to Agrippa's notion of melancholy than Durer's engraving, and there is no text with which Diirer's engraving accords more nearly than Agrippa's chapters on melancholy' (p. 360). We must content ourselves with these few hints to a store-house of information and historical wisdom. It is, of course, not primarily a historical-medical production and cannot be expected to cover all medical aspects ofthe subject, as for example the role attributed to black bile and the spleen in gastric digestion and its connection with the anti-humoralistic tendencies and ideas in sixteenthand seventeenth-century medicine. Nor has it been possible to discuss the extensive literature of the last two decades, owing to the long time which has elapsed between the completion of the script of the book (I939) and its appearance in print. The book is generously illustrated and beautifully produced.
Standards for 'Health for Health Professionals' services in the UK.

BACKGROUND Doctors are more likely to suffer from work-related mental ill-health than other professions in the UK and internationally. Services to support doctors with health problems are emerging in the UK and have diverse models of delivery and funding. Services should be able to demonstrate agreed standards of practice for those who wish to commission, develop or access them. AIMS To develop consensus about standards for 'Health for Health Professionals' (HHP) services in the UK through a modified Delphi study. METHODS We conducted a two-stage Delphi study over 6 months. The questionnaire development took place during the UK Association of Physician Health (UKAPH) meeting in London in 2012, an invited meeting for clinicians with a specific interest in the area of physician health. The final questionnaire was disseminated via the UKAPH database. RESULTS Forty-four people took part in round 1 and 40 in round 2. Participants were mainly GPs, occupational physicians and psychiatrists. Consensus was reached on major criteria for HHP services, with greatest consensus (45% agreement or greater) for four statements concerning the clarity and transparency of the services offered and one statement that anyone working within the service should have received suitable training in physician health. Consensus about some statements varied among the three specialities. CONCLUSIONS This study will assist discussion about providing and improving consistent services across the UK, while recognizing the flexibility required in view of geographical differences.
Psychosocial work conditions associated with sickness absence among hospital employees.

BACKGROUND Meaningfulness of the job, collaboration among colleagues, trustworthiness of the closest superior and bullying have previously been shown to be major covariates of intention to quit the job. AIMS To test if these elements of the psychosocial work environment are also the most essential covariates of sickness absence. METHODS A cross-sectional questionnaire study of hospital employees which sought information on elements of the psychosocial work environment, general health status, life style, age, gender and profession. Data on sickness absence were obtained from the employer's salary database. RESULTS A total of 1809 hospital employees took part with a response rate of 65%. The mean age was 43 (range: 20-69) and 75% were female. Totally, 363 study participants (20%) had at least 14 days sickness absence (defined as high absence) during the preceding year. Associations between high sickness absence and 29 psychosocial work elements were analysed, adjusting for relevant confounders. Following multiple logistic regression analysis, three elements had an independent statistically significant association with high sickness absence: no exposure to bullying (odds ratio (95% confidence interval) 0.50 (0.33-0.77)), high meaningfulness of the job (0.71 (0.52-0.97)) and high trustworthiness of the closest superior (0.70 (0.54-0.92)). CONCLUSIONS Elements of the psychosocial work environment which have previously been shown to have a significant independent association with intention to quit the job were also the most essential covariates of high sickness absence.
Hybrid 3D Printing of Soft Electronics

Hybrid 3D printing is a new method for producing soft electronics that combines direct ink writing of conductive and dielectric elastomeric materials with automated pick‐and‐place of surface mount electronic components within an integrated additive manufacturing platform. Using this approach, insulating matrix and conductive electrode inks are directly printed in specific layouts. Passive and active electrical components are then integrated to produce the desired electronic circuitry by using an empty nozzle (in vacuum‐on mode) to pick up individual components, place them onto the substrate, and then deposit them (in vacuum‐off mode) in the desired location. The components are then interconnected via printed conductive traces to yield soft electronic devices that may find potential application in wearable electronics, soft robotics, and biomedical devices.