Pan-inhibition of super-enhancer-driven oncogenic transcription by next-generation synthetic ecteinascidins yields potent anti-cancer activity.

The plasticity of cancer cells facilitates their ability to adopt heterogeneous differentiation states, posing a significant challenge to therapeutic interventions. Specific gene expression programs, driven in part by super-enhancers (SEs), underlie cancer cell states. Here we successfully inhibit SE-driven transcription in phenotypically distinct metastatic melanoma cells using next-generation synthetic ecteinascidins.

Changes in AXL and/or MITF melanoma subpopulations in patients receiving immunotherapy.

Background: Tumor heterogeneity is a hurdle to effective therapy, as illustrated by the 'mixed responses' frequently seen in immunotherapy-treated patients. Previously, AXL+ tumor cells were identified to be highly resistant to targeted therapy, whereas more differentiated MITF+ tumor cells do respond to RAF and MEK inhibitors.

Patients And Methods: In this study, we analyzed tumor heterogeneity and explored the presence of the previously described AXL+ or MITF+ melanoma subpopulations in metastatic tissues by NanoString gene expression analysis, single-cell RNA sequencing and multiplex immunofluorescence.

All eukaryotic SMC proteins induce a twist of -0.6 at each DNA loop extrusion step.

Eukaryotes carry three types of structural maintenance of chromosome (SMC) protein complexes, condensin, cohesin, and SMC5/6, which are ATP-dependent motor proteins that remodel the genome via DNA loop extrusion (LE). SMCs modulate DNA supercoiling but remains incompletely understood how this is achieved. Using a single-molecule magnetic tweezers assay that directly measures how much twist is induced by individual SMCs in each LE step, we demonstrate that all three SMC complexes induce the same large negative twist (i.

Methodological approaches in 16S sequencing of female reproductive tract in fertility patients: a review.

Background: The female genital tract microbiome has become a particular area of interest in improving assisted reproductive technology (ART) outcomes with the emergence of next-generation sequencing (NGS) technology. However, NGS assessment of microbiomes currently lacks uniformity and poses significant challenges for accurate and precise bacterial population representation.

Objective: As multiple NGS platforms and assays have been developed in recent years for microbiome investigation-including the advent of long-read sequencing technologies-this work aimed to identify current trends and practices undertaken in female genital tract microbiome investigations.

Are factors that predict conversion to psychosis associated with initial transition to a high risk state? An adolescent brain cognitive development study analysis.

Objective: Previous work suggests that cognitive and environmental risk factors may predict conversion to psychosis in individuals at clinical high risk (CHRs) for the disorder. Less clear, however, is whether these same factors are also associated with the initial emergence of the high risk state in individuals who do not meet current threshold criteria for being considered high risk.

Method: Here, using data from the Adolescent Brain Cognitive Development (ABCD) study, we examined associations between factors previously demonstrated to predict conversion to psychosis in CHRs with transition to a "high risk" state, here defined as having a distress score between 2 and 5 on any unusual thought content question in the Prodromal Questionnaire-Brief Child version.

An atlas of the human liver diurnal transcriptome and its perturbation by hepatitis C virus infection.

Chronic liver disease and cancer are global health challenges. The role of the circadian clock as a regulator of liver physiology and disease is well established in rodents, however, the identity and epigenetic regulation of rhythmically expressed genes in human disease is less well studied. Here we unravel the rhythmic transcriptome and epigenome of human hepatocytes using male human liver chimeric mice.

Microlens Hollow-Core Fiber Probes for Operando Raman Spectroscopy.

We introduce a flexible microscale all-fiber-optic Raman probe which can be embedded into devices to enable operando in situ spectroscopy. The facile-constructed probe is composed of a nested antiresonant nodeless hollow-core fiber combined with an integrated high refractive index barium titanate microlens. Pump laser 785 nm excitation and near-infrared collection are independently characterized, demonstrating an excitation spot of full-width-half-maximum 1.

Handwriting speed in juvenile idiopathic arthritis using the detailed assessment of speed of handwriting.

Background: Handwriting is a commonly reported functional limitation for children with juvenile idiopathic arthritis (JIA). The aim of this study was to evaluate handwriting in children with JIA.

Findings: Twelve children (mean age 13.

Transient gas-induced differential refractive index effects in as-drawn hollow core optical fibers.

When a hollow core fiber is drawn, the core and cladding holes within the internal cane geometry are pressurized with an inert gas to enable precise control over the internal microstructure of the fiber and counteract surface tension forces. Primarily by considering the temperature drop as the fiber passes through the furnace and the geometrical transformation of the internal microstructure from preform-to-fiber, we recently established that the gas pressure within the final 'as-drawn' fiber is substantially below atmospheric pressure. We have also established that slight changes in the gas refractive index within the core and surrounding cladding holes induced by changes in gas pressure are sufficient to significantly affect both the modality and loss of the fiber.

Context-dependent multimodal behaviour in a coral reef fish.

Animals are expected to respond flexibly to changing circumstances, with multimodal signalling providing potential plasticity in social interactions. While numerous studies have documented context-dependent behavioural trade-offs in terrestrial species, far less work has considered such decision-making in fish, especially in natural conditions. Coral reef ecosystems host 25% of all known marine species, making them hotbeds of competition and predation.

Double-Clad Antiresonant Hollow-Core Fiber and Its Comparison with Other Fibers for Multiphoton Micro-Endoscopy.

Label-free and multiphoton micro-endoscopy can transform clinical histopathology by providing an in situ tool for diagnostic imaging and surgical treatment in diseases such as cancer. Key to a multiphoton imaging-based micro-endoscopic device is the optical fiber, for distortion-free and efficient delivery of ultra-short laser pulses to the sample and effective signal collection. In this work, we study a new hollow-core (air-filled) double-clad anti-resonant fiber (DC-ARF) as a high-performance candidate for multiphoton micro-endoscopy.

Three stage HCF fabrication technique for high yield, broadband UV-visible fibers.

Hollow-core optical fibers can offer broadband, single mode guidance in the UV-visible-NIR wavelength range, with the potential for low-loss, solarization-free operation, making them desirable and potentially disruptive for a wide range of applications. To achieve this requires the fabrication of fibers with <300nm anti-resonant membranes, which is technically challenging. Here we investigate the underlying fluid dynamics of the fiber fabrication process and demonstrate a new three-stage fabrication approach, capable of delivering long (∼350m) lengths of fiber with the desired thin-membranes.

Anthropogenic Vector Ecology and Management to Combat Disease Spread in Aquaculture.

Anthropogenic vectors (transfer mechanisms) can facilitate the introduction and spread of aquatic disease in marine farming regions. Preventing or interrupting pathogen transfers associated with movements of these vectors is key to ensuring productivity and profitability of aquaculture operations. However, practical methods to identify and manage vector risks are lacking.

Virulence evaluation of Israeli Marek's disease virus isolates from commercial poultry using their meq gene sequence.

Fifty-seven Gallid alphaherpesvirus 2 (GaHV-2) isolates, collected during a 30-year period (1990-2019) from commercial poultry flocks affected by Marek's disease (MD), were molecularly characterised. The GaHV-2 meq gene was amplified and sequenced to evaluate the virus virulence, based on the number of PPPPs within the proline-rich repeats (PRRs) of its transactivation domain. The present illustration of virus virulence evaluation on a large scale of field virus isolates by molecular analysis exemplifies the practical benefit and usefulness of the molecular marker in commercial GaVH-2 isolates.

High power Raman second stokes generation in a methane filled hollow core fiber.

We demonstrate a multi-watt, picosecond pulse duration laser source by exploiting a cascaded Raman process to the second Stokes signal at a wavelength of 2.58 μm in a methane-filled Nested Anti-Resonant Nodeless fiber from a 1 μm disk laser source. A maximum average power of 2.

Mode attraction, rejection and control in nonlinear multimode optics.

Novel fundamental notions helping in the interpretation of the complex dynamics of nonlinear systems are essential to our understanding and ability to exploit them. In this work we predict and demonstrate experimentally a fundamental property of Kerr-nonlinear media, which we name mode rejection and takes place when two intense counter-propagating beams interact in a multimode waveguide. In stark contrast to mode attraction phenomena, mode rejection leads to the selective suppression of a spatial mode in the forward beam, which is controlled via the counter-propagating backward beam.

Silencing of genes by promoter hypermethylation shapes tumor microenvironment and resistance to immunotherapy in clear-cell renal cell carcinomas.

The efficacy of immune checkpoint inhibitors varies in clear-cell renal cell carcinoma (ccRCC), with notable primary resistance among patients. Here, we integrate epigenetic (DNA methylation) and transcriptome data to identify a ccRCC subtype characterized by cancer-specific promoter hypermethylation and epigenetic silencing of Polycomb targets. We develop and validate an index of methylation-based epigenetic silencing (iMES) that predicts primary resistance to immune checkpoint inhibition (ICI) in the BIONIKK trial.

Super-enhancer-driven expression of BAHCC1 promotes melanoma cell proliferation and genome stability.

Super-enhancers (SEs) are stretches of enhancers ensuring a high level of expression of key genes associated with cell function. The identification of cancer-specific SE-driven genes is a powerful means for the development of innovative therapeutic strategies. Here, we identify a MITF/SOX10/TFIIH-dependent SE promoting the expression of BAHCC1 in a broad panel of melanoma cells.

Evaluating alternatives to dual-energy x-ray absorptiometry for assessing bone quality in patients undergoing spine surgery.

Objective: The purpose of this study was to compare and contrast lumbar bone quality and osteoporosis/osteopenia screening results via dual-energy x-ray absorptiometry (DEXA), CT, and MRI.

Methods: A consecutive series of 426 candidates screened for lumbar disc replacement over a 5-year period beginning in 2018 was reviewed. Patients with a preoperative lumbar spine DEXA scan and a CT and/or MRI scan were included.

Fiber-delivered heterodyne spectroscopy with a mid-infrared frequency comb.

By exploiting the excellent short-term phase stability between consecutive pulses from a free-running optical parametric oscillator frequency comb, we report the first example of hollow-core fiber-delivered heterodyne spectroscopy in the 3.1-3.8 µm wavelength range.

Quality standards for the management of alcohol-related liver disease: consensus recommendations from the British Association for the Study of the Liver and British Society of Gastroenterology ARLD special interest group.

Objective: Alcohol-related liver disease (ALD) is the most common cause of liver-related ill health and liver-related deaths in the UK, and deaths from ALD have doubled in the last decade. The management of ALD requires treatment of both liver disease and alcohol use; this necessitates effective and constructive multidisciplinary working. To support this, we have developed quality standard recommendations for the management of ALD, based on evidence and consensus expert opinion, with the aim of improving patient care.

On-target delivery of intense ultrafast laser pulses through hollow-core anti-resonant fibers.

We report the flexible on-target delivery of 800 nm wavelength, 5 GW peak power, 40 fs duration laser pulses through an evacuated and tightly coiled 10 m long hollow-core nested anti-resonant fiber by positively chirping the input pulses to compensate for the anomalous dispersion of the fiber. Near-transform-limited output pulses with high beam quality and a guided peak intensity of 3 PW/cm were achieved by suppressing plasma effects in the residual gas by pre-pumping the fiber with laser pulses after evacuation. This appears to cause a long-term removal of molecules from the fiber core.

Cohesin mediates DNA loop extrusion and sister chromatid cohesion by distinct mechanisms.

Cohesin connects CTCF-binding sites and other genomic loci in cis to form chromatin loops and replicated DNA molecules in trans to mediate sister chromatid cohesion. Whether cohesin uses distinct or related mechanisms to perform these functions is unknown. Here, we describe a cohesin hinge mutant that can extrude DNA into loops but is unable to mediate cohesion in human cells.