Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma.

LINE-1 (L1) retrotransposons are mobile genetic elements comprising ~17% of the human genome. New L1 insertions can profoundly alter gene function and cause disease, though their significance in cancer remains unclear. Here, we applied enhanced retrotransposon capture sequencing (RC-seq) to 19 hepatocellular carcinoma (HCC) genomes and elucidated two archetypal L1-mediated mechanisms enabling tumorigenesis. In the first example, 4/19 (21.1%) donors presented germline retrotransposition events in the tumor suppressor mutated in colorectal cancers (MCC). MCC expression was ablated in each case, enabling oncogenic ß-catenin/Wnt signaling. In the second example, suppression of tumorigenicity 18 (ST18) was activated by a tumor-specific L1 insertion. Experimental assays confirmed that the L1 interrupted a negative feedback loop by blocking ST18 repression of its enhancer. ST18 was also frequently amplified in HCC nodules from Mdr2(-/-) mice, supporting its assignment as a candidate liver oncogene. These proof-of-principle results substantiate L1-mediated retrotransposition as an important etiological factor in HCC.

Tumor suppressive role of the antimicrobial lectin REG3A targeting the O -GlcNAc glycosylation pathway.

BACKGROUND AND AIMS: Antimicrobial proteins of the regenerating family member 3 alpha (REG3A) family provide a first line of protection against infections and transformed cells. Their expression is inducible by inflammation, which makes their role in cancer biology less clear since an immune-inflammatory context may preexist or coexist with cancer, as occurs in HCC. The aim of this study is to clarify the role of REG3A in liver carcinogenesis and to determine whether its carbohydrate-binding functions are involved. APPROACH AND RESULTS: This study provides evidence for a suppressive role of REG3A in HCC by reducing O -GlcNAcylation in 2 mouse models of HCC, in vitro cell studies, and clinical samples. REG3A expression in hepatocytes significantly reduced global O -GlcNAcylation and O -GlcNAcylation of c-MYC in preneoplastic and tumor livers and markedly inhibited HCC development in REG3A-c-MYC double transgenic mice and mice exposed to diethylnitrosamine. REG3A modified O -GlcNAcylation without altering the expression or activity of O-linked N-acetylglucosaminyltransferase, O-linked N-acetylglucosaminyl hydrolase, or glutamine fructose-6-phosphate amidotransferase. Reduced O -GlcNAcylation was consistent with decreased levels of UDP-GlcNAc in precancerous and cancerous livers. This effect was linked to the ability of REG3A to bind glucose and glucose-6 phosphate, suggested by a REG3A mutant unable to bind glucose and glucose-6 phosphate and alter O -GlcNAcylation. Importantly, patients with cirrhosis with high hepatic REG3A expression had lower levels of O -GlcNAcylation and longer cancer-free survival than REG3A-negative cirrhotic livers. CONCLUSIONS: REG3A helps fight liver cancer by reducing O -GlcNAcylation. This study suggests a new paradigm for the regulation of O -GlcNAc signaling in cancer-related pathways through interactions with the carbohydrate-binding function of REG3A.

Neuromodulation with aerobic exercise reduces fatigue in systemic lupus erythematosus: a randomised, sham-controlled, double-blind study.

OBJECTIVES: Transcranial direct current stimulation (tDCS) combined with aerobic exercise (tDCS-AE) effectively reduces fatigue in patients with fibromyalgia. However, no study has assessed this method in systemic lupus erythematosus (SLE) patients with significant fatigue. Therefore, we evaluated the safety and efficacy of tDCS-AE for significant fatigue symptoms in adult female SLE patients. METHODS: This randomised, sham-controlled, double-blind study included 25 patients with SLE in remission or low disease activity (SLEDAI-2K £4) and with significant fatigue [≥36 points on the Fatigue Severity Scale (FSS) or ≥38 points on the Modified Fatigue Scale (MFIS)]. The patients received sham or tDCS for five consecutive days. The anode and cathode were positioned at M1 and Fp2, respectively (international 10-20 EEG system). tDCS was applied at an intensity of 2mA, and density of 0.057mA/cm2 in the tDCS-AE group. Both groups underwent combined low-intensity treadmill exercise. FSS, MFIS, pain visual analogue scale, physical activity, and sleep quality were evaluated at baseline and on days 7, 30, and 60. Adherence and safety were assessed using a standardised questionnaire. RESULTS: Improvement in fatigue levels was observed in both groups. However, a sustained reduction in fatigue levels on days 30 and 60 occurred only with tDCS-AEs (p<0.05). No significant differences were observed in pain level, sleep quality, or physical activity. No disease flares occurred and the adverse effects were mild and transient. Finally, the patient's adherence to the treatment was satisfactory. CONCLUSIONS: Despite isolated AEs, there was an improvement in fatigue, however, only tDCS-AE maintained significant and sustained improvement.

Electric fields near undulating dielectric membranes.

Dielectric interfaces are crucial to the behavior of charged membranes, from graphene to synthetic and biological lipid bilayers. Understanding electrolyte behavior near these interfaces remains a challenge, especially in the case of rough dielectric surfaces. A lack of analytical solutions consigns this problem to numerical treatments. We report an analytic method for determining electrostatic potentials near curved dielectric membranes in a two-dimensional periodic "slab" geometry using a periodic summation of Green's functions. This method is amenable to simulating arbitrary groups of charges near surfaces with two-dimensional deformations. We concentrate on one-dimensional undulations. We show that increasing membrane undulation increases the asymmetry of interfacial charge distributions due to preferential ionic repulsion from troughs. In the limit of thick membranes, we recover results mimicking those for electrolytes near a single interface. Our work demonstrates that rough surfaces generate charge patterns in electrolytes of charged molecules or mixed-valence ions.

Hydroelectric Plant Safety: Real-Time Monitoring Utilizing Fiber-Optic Sensors.

In the context of hydroelectric plants, this article emphasizes the imperative of robust monitoring strategies. The utilization of fiber-optic sensors (FOSs) emerges as a promising approach due to their efficient optical transmission, minimal signal attenuation, and resistance to electromagnetic interference. These optical sensors have demonstrated success in diverse structures, including bridges and nuclear plants, especially in challenging environments. This article culminates with the depiction of the development of an array of sensors featuring Fiber Bragg Gratings (FBGs). This array is designed to measure deformation and temperature in protective grids surrounding the turbines at the Santo Antônio Hydroelectric Plant. Implemented in a real-world scenario, the device identifies deformation peaks, indicative of water flow obstructions, thereby contributing significantly to the safety and operational efficiency of the plant.

In-fiber Mach-Zehnder interferometer as a promising tool for optical nose and odor prediction during the fermentation process.

In this paper, we present an in-fiber Mach-Zehnder interferometer (MZI) applied to coffee bean fermentation monitoring. Two MZIs, based on a combination of a fiber taper cascaded by a micro-tapered long-period fiber grating, were installed in a fermentation barrel to monitor the liquids and gases released during the fermentation process. During this process, a variety of odors arise due to the yeast activity and their classification is important to decide when to stop the fermentation process. In this work, we show that the in-fiber MZIs are good candidates for optical noses in this scenario.

Spiers Memorial Lecture: Towards understanding of iontronic systems: electroosmotic flow of monovalent and divalent electrolyte through charged cylindrical nanopores.

In many practical applications, ions are the primary charge carrier and must move through either semipermeable membranes or through pores, which mimic ion channels in biological systems. In analogy to electronic devices, the "iontronic" ones use electric fields to induce the charge motion. However, unlike the electrons that move through a conductor, motion of ions is usually associated with simultaneous solvent flow. A study of electroosmotic flow through narrow pores is an outstanding challenge that lies at the interface of non-equilibrium statistical mechanics and fluid dynamics. In this paper, we will review recent works that use dissipative particle dynamics simulations to tackle this difficult problem. We will also present a classical density functional theory (DFT) based on the hypernetted-chain approximation (HNC), which allows us to calculate the velocity of electroosmotic flows inside nanopores containing 1 : 1 or 2 : 1 electrolyte solution. The theoretical results will be compared with simulations. In simulations, the electrostatic interactions are treated using the recently introduced pseudo-1D Ewald summation method. The zeta potentials calculated from the location of the shear plane of a pure solvent are found to agree reasonably well with the Smoluchowski equation. However, the quantitative structure of the fluid velocity profiles deviates significantly from the predictions of the Smoluchowski equation in the case of charged pores with 2 : 1 electrolyte. For low to moderate surface charge densities, the DFT allows us to accurately calculate the electrostatic potential profiles and the zeta potentials inside the nanopores. For pores with 1 : 1 electrolyte, the agreement between theory and simulation is particularly good for large ions, for which steric effects dominate over the ionic electrostatic correlations. The electroosmotic flow is found to depend very strongly on the ionic radii. In the case of pores containing 2 : 1 electrolyte, we observe a reentrant transition in which the electroosmotic flow first reverses and then returns to normal as the surface change density of the pore is increased.

Effects of electrostatic coupling and surface polarization on polyelectrolyte brush structure.

In this work, we perform molecular dynamics simulations to study a spherical polyelectrolyte brush. We explore the effects of surface polarization and electrostatic coupling on brush size and distribution of counterions. The method of image charges is considered to take into account surface polarization, considering a metallic, an unpolarizable, and a dielectric nano-core. It is observed that, for all cases, a moderate shrinking-swelling effect appears with an increase in the electrostatic coupling parameter. This effect occurs under high Manning ratios. The curves relating the average size of polyelectrolyte brush as a function of coupling show a minimum. The results show that the grafting density of polyelectrolytes on the nano-core surface plays an important role in the polarization effect. We consider a modified Poisson-Boltzmann theory to describe the counterion profiles around the brush in the case of unpolarizable nano-cores and weak electrostatic coupling.

Identification of external media using a long-period grating and optical time-domain reflectometry.

The application of signal processing and feature extraction to reflectometry traces aiming at sensor interrogation is not sufficiently explored. In this work, traces produced by an optical time-domain reflectometer in experiments using a long-period grating in different external media are analyzed using signal processing techniques inspired by audio processing. The objective is to demonstrate that, using this type of analysis, it is possible to correctly identify the external medium through the characteristics of the reflectometry trace. Results show that the features extracted from the traces were able to produce good classifiers, one of them achieving 100% correct classification for the data set presently considered. This technology could be applied in scenarios where it is necessary to distinguish among a given set of gases or liquids nondestructively.

Immediate dentoskeletal and periodontal effects of miniscrew-assisted rapid palatal expansion: Comparison between young vs middle-aged adults.

INTRODUCTION: This study aimed to compare the dentoskeletal and periodontal changes after miniscrew-assisted rapid palatal expansion (MARPE) in patients aged 18-29 and 30-45 years. METHODS: The sample comprised 28 subjects with transverse maxillary discrepancy successfully treated with MARPE. The young adult (YA) group comprised 14 subjects (mean age, 22.8 years; 3 male, 11 female). The middle adult (MA) group comprised 14 subjects (mean age, 36.8 years; 6 male, 8 female). All patients were treated with a 4-miniscrew MARPE expander. The activation protocol was one quarter turn twice a day until the midline diastema opening, followed by one quarter turn a day until overcorrection. Cone-beam computed tomography (CBCT) scans taken before and immediately after the expansion was analyzed using OnDemand3D Dental software. Using CBCT coronal images, transversal dentoskeletal and periodontal variables were measured in the preexpansion and postexpansion. Intergroup comparisons of expansion changes were performed using t and Mann-Whitney tests (P <0.05). RESULTS: Groups were compatible at preexpansion for most CBCT measurements. A success rate of midpalatal suture opening of 100% and 81% was observed for YA and MA groups, respectively. No intergroup differences were found for the maxillary and dental arch widths increases. The buccal tip of anchorage teeth was observed similarly in both groups. The buccal bone thickness of posterior teeth decreased, and the palatal bone thickness increased after expansion with no difference between groups. CONCLUSIONS: After MARPE, the MA group showed similar dentoskeletal and periodontal changes compared to the YA group.

Geochemical soil dynamics on a bimodal post-collisional intrusive complex.

The importance of environmental quality for global social and ecological development, including soil degradation, cannot be overstated. Trace elements dispersed in the environment due to anthropogenic or geogenic activities can result in ecotoxicological impacts, negatively influencing environmental quality. The reference values for soil quality concerning trace elements are primarily based on geological, geomorphological, and pedological patterns. However, intrinsic geological factors may diverge some concentration levels from established norms. Therefore, conducting comprehensive surveys of environmental quality reference values becomes imperative, incorporating geological, geomorphological, and pedological patterns. A deeper understanding of the distribution of these elements is also required. Multivariate analysis proves crucial in compartmentalizing the most relevant factors, particularly in regions marked by bimodal magmatism arising from post-collisional distensional processes, such as the Santa Angélica intrusive suite in southeast Brazil. This study collected soil samples from pastures and natural grasslands with minimal anthropogenic intervention at two depths. These samples underwent various chemical and physical analyses. Statistical techniques such as correlation analysis, principal component analysis, hierarchical clustering, and geostatistics were utilized to interpret the data. The analysis revealed a correlation between the clay fraction and trace elements, demonstrating that clustering is an effective methodology for ascertaining landscape distribution patterns of these components. When compared to quality reference values, it was observed that most soil content levels exceeded both global and local standards. This study suggests that the presence of barium (Ba) in the soil might be due to the isomorphic replacement of feldspathic minerals in acidic and intermediate rocks, whereas molybdenum (Mo) seems to be associated with soils in the domain of porphyritic allanite granite. However, additional research is warranted to determine the concentration factor of Mo in this scenario accurately.

Systemic autoimmune myopathies: a prospective phase 4 controlled trial of an inactivated virus vaccine against SARS-CoV-2.

OBJECTIVES: To evaluate immunogenicity and safety of an inactivated SARS-CoV-2 vaccine in systemic autoimmune myopathies (SAMs) and the possible influence of baseline disease parameters, comorbidities and therapy on immune response. METHODS: This prospective controlled study included 53 patients with SAMs and 106 non-immunocompromised control group (CTRL). All participants received two doses of the Sinovac-CoronaVac vaccine (28-day interval). Immunogenicity was assessed by anti-SARS-CoV-2 S1/S2 IgG seroconversion (SC), anti-S1/S2 IgG geometric mean titre (GMT), factor increase GMT (FI-GMT), neutralizing antibodies (NAb) positivity, and median neutralizing activity after each vaccine dose (D0 and D28) and six weeks after the second dose (D69). Participants with pre-vaccination positive IgG serology and/or NAb and those with RT-PCR confirmed COVID-19 during the protocol were excluded from immunogenicity analysis. RESULTS: Patients and CTRL had comparable sex (P>0.99) and age (P=0.90). Immunogenicity of 37 patients and 79 CTRL-naïve participants revealed at D69, a moderate but significantly lower SC (64.9% vs 91.1%, P<0.001), GMT [7.9 (95%CI 4.7-13.2) vs 24.7 (95%CI 30.0-30.5) UA/ml, P<0.001] and frequency of NAb (51.4% vs 77.2%, P<0.001) in SAMs compared with CTRL. Median neutralizing activity was comparable in both groups [57.2% (interquartile range (IQR) 43.4-83.4) vs 63.0% (IQR 40.3-80.7), P=0.808]. Immunosuppressives were less frequently used among NAb+ patients vs NAb- patients (73.7% vs 100%, P=0.046). Type of SAMs, disease status, other drugs or comorbidities did not influence immunogenicity. Vaccine-related adverse events were mild with similar frequencies in patients and CTRL (P>0.05). CONCLUSION: Sinovac-CoronaVac is safe and has a moderate short-term immunogenicity in SAMs, but reduced compared with CTRL. We further identified that immunosuppression is associated with diminished NAb positivity. TRIAL REGISTRATION: COVID-19 CoronaVac in Patients With Autoimmune Rheumatic Diseases and HIV/AIDS (CoronavRheum), http://clinicaltrials.gov/ct2/show/NCT04754698.

Reversal of Electroosmotic Flow in Charged Nanopores with Multivalent Electrolyte.

We study the reversal of electroosmotic flow in charged cylindrical nanopores containing multivalent electrolyte. Dissipative particle dynamics is used to simulate the hydrodynamics of the electroosmotic flow. The electrostatic interactions are treated using 3D Ewald summation, corrected for a pseudo-one-dimensional geometry of the pore. We observe that, for sufficiently large surface charge density, condensation of multivalent counterions leads to the reversal of the pore's surface charge. This results in the reversal of electroosmotic flow. Our simulations show that the Smoluchowski equation is able to quantitatively account for the electroosmotic flow through the nanopore, if the shear plane is shifted from the position of the Stern contact surface.

Physical exercise for the management of systemic autoimmune myopathies: recent findings, and future perspectives.

PURPOSE OF REVIEW: The aim of this review is to present the main pieces of evidence, recent literature and to present future perspectives on the use of exercise/physical training in the treatment and improvement of the quality of life of patients with systemic autoimmune myopathies. RECENT FINDINGS: In the last decades, knowledge about the relevance of physical exercise training in preventing and treating chronic diseases and improving quality of life has grown. Following the global trend exemplified by the expression 'exercise is medicine', the importance of exercise/physical training has also grown in myopathies. However, the science of exercise has a lot to collaborate on and improve patients' quality of life with myopathies by appropriating new technological tools, including accessible and low-cost devices and smartphone apps. SUMMARY: Physical exercise, as already consolidated in the literature, is an effective, well tolerated, and low-cost strategy for patients with myopathies. The use of wearable devices, smartphone apps, and online training prescriptions must accompany the global scenario, bringing new research fields and expanding the options for access to training for the individualized basis, and prescribed by qualified professionals.

Identification of Four Immune Subtypes Characterized by Distinct Composition and Functions of Tumor Microenvironment in Intrahepatic Cholangiocarcinoma.

BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (ICC) is a severe malignant tumor in which the standard therapies are mostly ineffective. The biological significance of the desmoplastic tumor microenvironment (TME) of ICC has been stressed but was insufficiently taken into account in the search for classifications of ICC adapted to clinical trial design. We investigated the heterogeneous tumor stroma composition and built a TME-based classification of ICC tumors that detects potentially targetable ICC subtypes. APPROACH AND RESULTS: We established the bulk gene expression profiles of 78 ICCs. Epithelial and stromal compartments of 23 ICCs were laser microdissected. We quantified 14 gene expression signatures of the TME and those of 3 functional indicators (liver activity, inflammation, immune resistance). The cell population abundances were quantified using the microenvironment cell population-counter package and compared with immunohistochemistry. We performed an unsupervised TME-based classification of 198 ICCs (training set) and 368 ICCs (validation set). We determined immune response and signaling features of the different immune subtypes by functional annotations. We showed that a set of 198 ICCs could be classified into 4 TME-based subtypes related to distinct immune escape mechanisms and patient outcomes. The validity of these immune subtypes was confirmed over an independent set of 368 ICCs and by immunohistochemical analysis of 64 ICC tissue samples. About 45% of ICCs displayed an immune desert phenotype. The other subtypes differed in nature (lymphoid, myeloid, mesenchymal) and abundance of tumor-infiltrating cells. The inflamed subtype (11%) presented a massive T lymphocyte infiltration, an activation of inflammatory and immune checkpoint pathways, and was associated with the longest patient survival. CONCLUSION: We showed the existence of an inflamed ICC subtype, which is potentially treatable with checkpoint blockade immunotherapy.

Electroosmotic Flow Grows with Electrostatic Coupling in Confining Charged Dielectric Surfaces.

In this work, the effects of polarization of confining charged planar dielectric surfaces on induced electroosmotic flow are investigated. To this end, we use dissipative particle dynamics to model solvent and ionic particles together with a modified Ewald sum method to model electrostatic interactions and surfaces polarization. A relevant difference between counterions number density profiles, velocity profiles, and volumetric flow rates obtained with and without surface polarization for moderate and high electrostatic coupling parameters is observed. For low coupling parameters, the effect is negligible. An increase of almost 500% in volumetric flow rate for moderate/high electrostatic coupling and surface separation is found when polarizable surfaces are considered. The most important result is that the increase in electrostatic coupling substantially increases the electroosmotic flow in all studied range of separations when the dielectric constant of electrolytes is much higher than the dielectric constant of confining walls. For the higher separation simulated, an increase of around 340% in volumetric flow rate when the electrostatic coupling is increased by a factor of two orders of magnitude is obtained.

Correction: Electroosmosis as a probe for electrostatic correlations.

Correction for 'Electroosmosis as a probe for electrostatic correlations' by Ivan Palaia et al., Soft Matter, 2020, 16, 10688-10696, DOI: 10.1039/D0SM01523G.

Clinical spectrum and risk factors for mortality among seawater and freshwater critically ill drowning patients: a French multicenter study.

BACKGROUND: Drowning is a global threat and one of the leading causes of injury around the world. The impact of drowning conditions including water salinity on patients' prognosis remains poorly explored in Intensive Care Units (ICUs) patients. METHODS: We conducted a retrospective multicenter study on patients admitted to 14 ICUs in the west of France from January 2013 to January 2020. We first compared demographic and clinical characteristics at admission as well as clinical courses of these patients according to the salinity of drowning water. Then, we aimed to identify variables associated with 28-day survival using a Cox proportional hazard model. RESULTS: Of the 270 consecutive included patients, drowning occurred in seawater in 199 patients (73.7%) and in freshwater in 71 patients (26.3%). Day-28 mortality was observed in 55 patients (20.4%). Freshwater was independently associated with 28-day mortality (Adjusted Hazard Ratio (aHR) 1.84 [95% Confidence Interval (CI) 1.03-3.29], p = 0.04). A higher proportion of freshwater patients presented psychiatric comorbidities (47.9 vs. 19.1%; p < 0.0001) and the etiology of drowning appeared more frequently to be a suicide attempt in this population (25.7 vs. 4.2%; p < 0.0001). The other factors independently associated with 28-day mortality were the occurrence of a drowning-related cardiac arrest (aHR 11.5 [95% CI 2.51-52.43], p = 0.0017), duration of cardiopulmonary resuscitation (aHR 1.05 [95% CI 1.03-1.07], p < 0.0001) and SOFA score at day 1 (aHR 1.2 [95% CI 1.11-1.3], p < 0.0001). CONCLUSIONS: In this large multicenter cohort, freshwater drowning patients had a poorer prognosis than saltwater drowning patients. Reasons for such discrepancies include differences in underlying psychiatric comorbidity, drowning circumstances and severities. Patients with initial cardiac arrest secondary to drowning remain with a very poor prognosis.

Etched fiber Bragg grating probe using a regular CNC machine and a 3D printer.

Etched fiber Bragg gratings (EFBGs) have been widely employed for refractive index (RI) measurements that can be used to monitor sugar consumption during the fermentation of alcoholic beverages. EFBGs are obtained by removing the cladding of a fiber Bragg grating, which is traditionally performed by a chemical attack with hydrogen fluoride, an extremely hazardous corrosive substance that causes severe wounds and even death. To overcome such drawbacks, this technical note presents a simple, practical, and low cost method for the diameter reduction of single mode optical fibers by mechanical polishing, employing a small scale computer numerical control device and an ad hoc 3D-printed rod. The sensor probe obtained was tested using sucrose aqueous solutions with RIs between 1.333 and 1.394, measured in an Abbe refractometer. The results show a linear shift of the Bragg wavelength with respect to RI with a correlation of 0.928.

SARS-CoV-2 variant N.9 identified in Rio de Janeiro, Brazil.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.33-derived lineage named N.9 was described recently in Brazil and it's considered a potential variant of interest (VOI) due to the presence of E484K substitution at the receptor-binding domain (RBD) of the Spike (S) protein. OBJECTIVE: To describe the first detection of variant N.9 in Rio de Janeiro State. METHODS: SARS-CoV-2 N.9 was confirmed by quantitative reverse transcription polymerase chain reaction (qRT-PCR), whole-genome sequencing and phylogenetic analysis. FINDINGS: Here, we report two SARS-CoV-2 N.9 lineage strains in Rio de Janeiro. One of them had only the E484K substitution of the six N.9 lineage-defining mutations. Other three strains pre-defined as N.9 have the same genomic profile. These four strains are grouped within the B.1.1.33 lineage and basal to the N.9 lineage in our phylogenetic analysis, and we call them "N.9-like/B.1.1.33 + E484K". MAIN CONCLUSIONS: The phylogenetic analysis shows four independent introductions of N.9 in the state of Rio de Janeiro in October and December 2020, January and March 2021. SARS-CoV-2 N.9 dissemination in the Rio de Janeiro could have been limited by the emergence and dominance of other variants, mainly by the lineage P.2 VOI Zeta that emerged in the same period and co-circulated with N.9, as observed in the neighboring State of São Paulo.