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We studied the distribution of germline and somatic variants in epilepsy surgery patients with (suspected) malformations of cortical development (MCD) who underwent surgery between 2015 and 2020 at University Medical Center Utrecht (the Netherlands) and pooled our data with four previously published cohort studies. Tissue analysis yielded a pathogenic variant in 203 of 663 (31%) combined cases. In 126 of 379 (33%) focal cortical dysplasia (FCD) type II cases and 23 of 37 (62%) hemimegalencephaly cases, a pathogenic variant was identified, mostly involving the mTOR signaling pathway. Pathogenic variants in 10 focal epilepsy genes were found in 48 of 178 (27%) FCDI/mild MCD/mMCD with oligodendroglial hyperplasia and epilepsy cases; 36 of these (75%) were SLC35A2 variants. Six of 69 (9%) patients without a histopathological lesion had a pathogenic variant in SLC35A2 (n = 5) or DEPDC5 (n = 1). A germline variant in blood DNA was confirmed in all cases with a pathogenic variant in tissue, with a variant allele frequency (VAF) of ~50%. In seven of 114 patients (6%) with a somatic variant in tissue, mosaicism in blood was detected. More than half of pathogenic somatic variants had a VAF < 5%. Further analysis of the correlation between genetic variants and surgical outcomes will improve patient counseling and may guide postoperative treatment decisions. [ABSTRACT FROM AUTHOR]

The effects of Martian dust storms are not only limited to lower atmospheric regime, but the increased dust storm activity could also affect the vertical structure of the constituents in the thermosphere. To this end, this paper investigates the changes in the vertical mixing of neutral and ionic species densities in the thermosphere before and during a regional (2016) and a global (2018) dust storm event; using Neutral Gas and Ion Mass Spectrometer (NGIMS)/ Mars Atmosphere and Volatile Evolution (MAVEN) observations. Care has been taken to keep a restricted solar zenith angle variation (25º) to avoid the effects of changes in solar illumination on the distribution of thermospheric species densities. Contrasting differences in the vertical distribution of neutral (CO2, CO, O, N2, Ar, He) and ionic (CO2+, O+, O2+, N2+, CO+, Ar+) atmospheric species before and during the regional and global dust storm events are noticed. [ABSTRACT FROM AUTHOR]

Hypoglycemia is a rare complication of diffuse large B-cell lymphoma. We are presenting a case of 67-year-old woman presented to her primary care physician with fatigue and hyperhidrosis. Laboratory evaluation revealed a glucose level of 1.9 mmol/L. Computed tomographic scan of the abdomen and subsequent positron emission tomographic scan revealed extensive lymphadenopathy. The patient was then diagnosed with CD5-positive -diffuse large B-cell lymphoma and developed recurrent hypoglycemia despite continuous infusion of glucose. Following immunochemotherapy, hypoglycemia was resolved. Several explanations have been postulated but the exact pathophysiology is not well understood. Further investigation is warranted to more clearly define the pathophysiology of persistent hypoglycemia in patients with diffuse large B-cell lymphoma. [ABSTRACT FROM AUTHOR]

Background Glucocorticoids are the treatment of choice for proteinuric patients with minimal change disease (MCD) and primary focal segmental glomerulosclerosis (FSGS). Immunosuppressive as well as direct effects on podocytes are believed to mediate their actions. In this study, we analyzed the anti-proteinuric effects of inhibition of the glucocorticoid receptor (GR) in glomerular epithelial cells, including podocytes. Methods We employed genetic and pharmacological approaches to inhibit the GR. Genetically, we used Pax8-Cre/GRfl/fl mice to specifically inactivate the GR in kidney epithelial cells. Pharmacologically, we utilized a glucocorticoid antagonist called mifepristone. Results Genetic inactivation of GR, specifically in kidney epithelial cells, using Pax8-Cre/GRfl/fl mice, ameliorated proteinuria following protein overload. We further tested the effects of pharmacological GR inhibition in three models and species: the puromycin aminonucleoside–induced nephrosis model in rats, the protein overload model in mice and the inducible transgenic NTR/MTZ zebrafish larvae with specific and reversible podocyte injury. In all three models, both pharmacological GR activation and inhibition consistently and significantly ameliorated proteinuria. Additionally, we translated our findings to humans, where three nephrotic adult patients with MCD or primary FSGS with contraindications or insufficient responses to corticosteroids were treated with mifepristone. This treatment resulted in a clinically relevant reduction of proteinuria. Conclusions Thus, across multiple species and proteinuria models, both genetic and pharmacological GR inhibition was at least as effective as pronounced GR activation. While the mechanism remains perplexing, GR inhibition may be a novel and targeted therapeutic approach to treat glomerular proteinuria potentially bypassing adverse actions of steroids. [ABSTRACT FROM AUTHOR]

Balloon cells (BCs) are specific pathological marker of cortical malformations during brain development, often associated with epilepsy and development delay. Although a large number of studies have investigated the role of BCs in these diseases, the specific function of BCs as either epileptogenic or antiepileptic remains controversial. Therefore, we reviewed literatures on BCs, delved into the molecular mechanisms and signaling pathways, and updated their profile in several aspects. Firstly, BCs are heterogeneous and some of them show progenitor/stem cell characteristics. Secondly, BCs are relatively silent in electrophysiology but not completely isolated from their surroundings. Notably, abnormal mTOR signaling and aberrant immunogenic process have been observed within BCs-containing malformations of cortical development (MCDs). The question whether BCs function as the evildoer or the defender in BCs-containing MCDs is further discussed. Importantly, this review provides perspectives on future investigations of the potential role of BCs in epilepsy. [ABSTRACT FROM AUTHOR]

Human herpesvirus 8 (HHV8)-associated diseases include Kaposi sarcoma (KS), multicentric Castleman disease (MCD), germinotropic lymphoproliferative disorder (GLPD), Kaposi sarcoma inflammatory cytokine syndrome (KICS), HHV8-positive diffuse large B-cell lymphoma (HHV8+ DLBCL), primary effusion lymphoma (PEL), and extra-cavitary PEL (ECPEL). We report the case of a human immunodeficiency virus (HIV)-negative male treated for cutaneous KS, who developed generalized lymphadenopathy, hepatosplenomegaly, pleural and abdominal effusions, renal insufficiency, and pancytopenia. The excised lymph node showed features of concomitant involvement by micro-KS and MCD, with aggregates of HHV8+, Epstein Barr virus (EBV)-negative, IgM+, and lambda+ plasmablasts reminiscent of microlymphoma. Molecular investigations revealed a somatically hypermutated (SHM) monoclonal rearrangement of the immunoglobulin heavy chain (IGH), accounting for 4% of the B-cell population of the lymph node. Mutational analyses identified a pathogenic variant of KMT2D and variants of unknown significance in KMT2D, FOXO1, ARID1A, and KMT2A. The patient died shortly after surgery. The histological features (HHV8+, EBV−, IgM+, Lambda+, MCD+), integrated with the molecular findings (monoclonal IGH, SHM+, KMT2D mutated), supported the diagnosis of a monoclonal HHV8+ microlymphoma, with features intermediate between an incipient HHV8+ DLBCL and an EBV-negative ECPEL highlighting the challenges in the accurate classification of HHV8-driven lymphoid proliferations. [ABSTRACT FROM AUTHOR]

The histopathological lesions, minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are entities without immune complex deposits which can cause podocyte injury, thus are frequently grouped under the umbrella of podocytopathies. Whether MCD and FSGS may represent a spectrum of the same disease remains a matter of conjecture. Both frequently require repeated high-dose glucocorticoid therapy with alternative immunosuppressive treatments reserved for relapsing or resistant cases and response rates are variable. There is an unmet need to identify patients who should receive immunosuppressive therapies as opposed to those who would benefit from supportive strategies. Therapeutic trials focusing on MCD are scarce, and the evidence used for the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) guideline for the management of glomerular diseases largely stems from observational and pediatric trials. In FSGS, the differentiation between primary forms and those with underlying genetic variants or secondary forms further complicates trial design. This article provides a perspective of the Immunonephrology Working Group (IWG) of the European Renal Association (ERA) and discusses the KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases focusing on the management of MCD and primary forms of FSGS in the context of recently published evidence, with a special emphasis on the role of rituximab, cyclophosphamide, supportive treatment options and ongoing clinical trials in the field. [ABSTRACT FROM AUTHOR]

Much of the variability in the Martian thermosphere can be attributed to vertically propagating atmospheric tides that are known to achieve significant amplitudes in this region. Concurrent observations from different altitudes have been used previously to discern the vertical propagation characteristics of tides but have primarily focused on low latitudes. The spectrum of tides and their vertical evolution are thereby less constrained at high latitudes. Few studies that have focused on high latitudes identified wavenumber‐3 structures which were interpreted to originate mainly from the non‐migrating tides SE1 and DE2. This paper presents the first analysis of MAVEN‐EUVM solar occultation observations to deduce atmospheric tides in the Martian thermosphere. These are compared to tides observed by MRO‐MCS in the middle atmosphere for six cases at high northern latitudes. To identify vertical propagation, wave signatures in the middle and upper atmosphere are compared and are found to be dominated by a mix of zonal wavenumbers‐2 and ‐3 in fixed local time. MCS observations show eastward propagating tides dominate, specifically highlighting SE1 near 76 km. Additionally, these observations indicate the presence of stationary planetary waves and terdiurnal tides. Mars Climate Database also indicates the presence of SE1, DE2, DE1, S0, TW1, and T0 tides. A change in the dominant wavenumber component with local time is seen, which is attributed to the presence of all three diurnal, semidiurnal and terdiurnal components at these latitudes. The significant decrease in the diurnal tide amplitude indicates the effect of zonal mean wind on vertical propagation. Plain Language Summary: Atmospheric tides are a kind of wave in the Martian atmosphere that can cause large oscillations in temperature, density, and pressure. Concurrent observations from different altitudes can determine how tides vary as they propagate into the upper atmosphere. Several previous studies have observed wave signatures from a range of heights but focused mainly on equatorial regions. Previous observations from near polar regions revealed strong tidal signatures, producing wave patterns with three peaks in the upper and middle atmosphere, attributed to a mix of waves with one and half a Mars day frequency. Here, using observations from two instruments that simultaneously measure the middle and upper atmosphere of Mars, dominant wave signatures at high latitudes are identified and how they change between these regions are examined. This study presents the first observations of atmospheric tides from new data derived from the extinction of solar radiation in the Martian upper atmosphere. Additionally, the observations are compared to a model, providing insight into how well the model captures the observations. A key finding is that the strongest wave component seen may vary with local time due to the presence of three different waves with one, half, and third of a Mars day frequency. Key Points: This study presents the first analysis of tides from solar occultation observations at MarsThe dominant wavenumber can change with local time due to the presence of tides with multiple periods at high latitudesDiurnal tides in the model diminish with altitude, suggesting the influence of mean winds on vertical propagation [ABSTRACT FROM AUTHOR]

Effective estimation of covariance matrices is crucial for statistical analyses and applications. In this paper, we focus on the robust estimation of covariance matrix for interval-valued data in low and moderately high dimensions. In the low-dimensional scenario, we extend the Minimum Covariance Determinant (MCD) estimator to interval-valued data. We derive an iterative algorithm for computing this estimator, demonstrate its convergence, and theoretically establish that it retains the high breakdown-point property of the MCD estimator. Further, we propose a projection-based estimator and a regularization-based estimator to extend the MCD estimator to moderately high-dimensional settings, respectively. We propose efficient iterative algorithms for solving these two estimators and demonstrate their convergence properties. We conduct extensive simulation studies and real data analysis to validate the finite sample properties of these proposed estimators. [ABSTRACT FROM AUTHOR]

This research proposes a novel framework that integrates intelligent clustering algorithms with “multi-criteria decision-making (MCDM)” techniques to enhance the longevity of WSNs in uncertain environment. Clustering techniques are crucial in WSNs for data aggregation and energy-efficient communication. To create energy efficient network, the proposed framework incorporates intelligent clustering algorithms that perform clustering dynamically in the presence of uncertain parameter and employed MCDM techniques to select of energy efficient CHs for clustering. The intelligent clustering algorithms employ data-driven approaches, machine learning and optimization algorithms to create optimal cluster formation, cluster head selection and energy efficiency. An intelligent clustering mechanism has been made using the Silhouette Index (SI) score. Utilizing the SI score as a benchmark, we conducted optimized clustering with the “Density-Based Spatial Clustering of Applications with Noise (DBSCAN)” algorithm. We employed the elbow method to validate the SI score in conjunction with the k-Means clustering algorithm. By considering uncertainty factors in the decision-making process, the proposed algorithms can effectively adapt the network’s operation to changing conditions, thus improving the overall lifetime of the WSN. Furthermore, the framework integrates MCDM approaches to prioritize cluster formation and cluster head selection criteria. Triangular Fuzzy Numbers are compatible with fuzzy logic systems, which are designed to handle uncertainty and imprecision. The triangular shape aligns well with the concept of fuzzy sets and fuzzy reasoning. Due to this reason TFNs have been considered to represent uncertain parameters. In the end, an experiment relating to WSNs has been studied and the results have been visually presented. It has been noticed that the suggested approach outperformed the “residual energy-aware clustering with isolated nodes (REAC-IN)” model, “Low-Energy Adaptive Clustering Hierarchy Fuzzy Clustering (LEACH-FC)” and “hybrid energy efficient distributed (HEED)” by 38%, 15% and 43%, respectively. The PSO and BFAO applied optimized clustering has been outperformed by 35% and 22%, respectively. To verify the simulation results, testing of hypotheses has been conducted.

Aim: Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are podocytopathies characterized by damage to the glomerular filtration barrier, leading to proteinuria and nephrotic syndrome. The production of anti‐podocyte antibodies has been proposed as potential circulating factors contributing to the development of these conditions. The aim of the study is to evaluate the levels of anti‐nephrin antibodies in patients with podocytopathies and healthy subjects. Methods: In this study, a total of 77 patients with active glomerulopathy and 11 healthy subjects were included. Forty one patients were diagnosed with FSGS, 11 with MCD, and 25 with MN. To measure the levels of anti‐nephrin antibodies, enzyme‐linked immunosorbent assay was used. Results: The levels of antibodies to nephrin were significantly higher in patients with MCD 61.2 [28.9–66.3] ng/mL and FSGS 32.5 [17.2–58.4] ng/mL compared to MN 20.3 [14.4–38.4] and healthy individuals 15.3 [12–18.9] ng/mL, p <.05. In patients with primary FSGS, the levels of antibodies to nephrin were significantly higher 45.2 [20–64.3] ng/mL compared to patients with secondary FSGS 26.7 [11.2–44.1] ng/mL, p <.05. There were no significant differences in the remission rate between the anti‐nephrin antibodies positive and negative groups (log‐rank test: p =.158). Conclusion: The level of anti‐nephrin antibodies was found to be significantly higher in patients with MCD and pFSGS compared to those with sFSGS, MN, and healthy subjects. Anti‐nephrin antibodies in MCD and primary FSGS may be associated with the severity of podocytopathies, however they did not have an impact on the response to therapy. [ABSTRACT FROM AUTHOR]

It is well known that trimmed estimators of multivariate scatter, such as the Minimum Covariance Determinant (MCD) estimator, are inconsistent unless an appropriate factor is applied to them in order to take the effect of trimming into account. This factor is widely recommended and applied when uncontaminated data are assumed to come from a multivariate normal model. We address the problem of computing a consistency factor for the MCD estimator in a heavy-tail scenario, when uncontaminated data come from a multivariate Student-t distribution. We derive a remarkably simple computational formula for the appropriate factor and show that it reduces to an even simpler analytic expression in the bivariate case. Exploiting our formula, we then develop a robust Monte Carlo procedure for estimating the usually unknown number of degrees of freedom of the assumed and possibly contaminated multivariate Student-t model, which is a necessary ingredient for obtaining the required consistency factor. Finally, we provide substantial simulation evidence about the proposed procedure and apply it to data from image processing and financial markets. [ABSTRACT FROM AUTHOR]

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Achiral purely organic molecules can show selectivity towards circularly polarized light in emission in the presence of a magnetic field. This phenomenon is called magnetic circularly polarized luminescence (MCPL). Recently a few examples of MCPL from organic molecules have appeared in the literature. Through this technique, interesting photophysical information can be inferred and, moreover, a few technological applications can be devised based on this principle. This short review has the purpose to give a general introduction to this recent field of research and some critical insights on the reported examples. [ABSTRACT FROM AUTHOR]

Factor analysis is a multivariate statistical analysis technique that has become very popular in recent years. In the factor analysis model, the error covariance matrix is assumed to be the multivariate normal distribution, and outliers are likely to be accounted for. Various estimation methods were compared with Monte Carlo simulation for the factor analysis model. The performances of the estimation methods were evaluated based on the ratio of the total variance explained and the criterion fit values. Considering the MLE, PCA, WLS, and GLS methods for classical factor analysis and the MCD, M, and S methods for robust factor analysis, the ratio of total variance explained, and fit values decreased as the sample size increased. When the number of variables increases, the ratio of total variance explained, and fit values increase at different sample sizes. It can be said that the WLS and GLS methods are better than others for classical factor analysis and the MCD and M methods are better than others for robust factor analysis. [ABSTRACT FROM AUTHOR]

Measurements of CO2, Ar and N2 densities from the Neutral Gas and Ion Mass Spectrometer on the Mars Atmosphere and Volatile Evolution Mission (MAVEN) between 150 and 200 km altitude during 2015–2022 are analyzed to reveal diurnal (DW1), semidiurnal (SW2) and terdiurnal (TW3) solar‐synchronous tides in Mars thermosphere. Multi‐year‐mean tidal perturbations on a diurnal‐ and zonal‐mean background, corrected for solar flux variations, are reported as a function of latitude (48°S–48°N), altitude and solar longitude (Ls). The DW1, SW2 and TW3 amplitudes at for example, 180 km altitude are of order 90%–120%, 15%–20%, and ≲10% for CO2 and Ar, and roughly 2/3 these values for N2, the latter presumably due to the difference in molecular weight from the other species. Through examination of vertical phase progressions, DW1 is concluded to be mainly excited in situ, but SW2 and TW3 contain significant contributions from tides propagating upward from lower altitudes. By analogy with studies for Earth's thermosphere, the DW1 amplitudes and phases are thought to reflect the combined influences of thermal expansion and vertical winds. Points of agreement and disagreement with DW1, SW2, and TW3 amplitudes and phases derived from the Mars Climate Database are noted and interpreted. Key Points: Global‐scale solar‐synchronous tides are derived from Mars Atmosphere and Volatile Evolution Mission/Neutral Gas and Ion Mass Spectrometer measurements of CO2, Ar, and N2 at Mars, 150–200 kmThe diurnal tide originates mainly in situ; semidiurnal and terdiurnal tides show evidence of upward propagation from belowPoints of agreement and disagreement with the Mars Climate Database are noted and interpreted [ABSTRACT FROM AUTHOR]

Key Clinical Message: There may be a connection between pemphigus vulgaris and nephrotic syndrome, as evidenced by the occurrence of focal segmental glomerulosclerosis in our pemphigus vulgaris patient and reviewing relevant literature. Therefore, if a patient with pemphigus vulgaris presents with bilateral lower extremity edema or proteinuria detected during urinalysis, it could indicate involvement of the kidneys. Pemphigus vulgaris is a type of autoimmune blistering disease characterized by the presence of IgG autoantibodies against desmogleins 3 and 1. It is important to evaluate potential autoimmune associations in patients with pemphigus vulgaris so that appropriate laboratory and physical examinations can be performed to monitor for any increased risk of other autoimmune disorders. This case report describes a 55‐year‐old woman who presented with oral and axillary erosions, which were diagnosed as pemphigus vulgaris based on skin histopathology and immunofluorescence. During follow‐up, the patient was found to have proteinuria, which led to referral to a nephrologist. The patient was diagnosed with nephrotic syndrome and minimal change disease after a biopsy. Despite treatment, the patient's proteinuria persisted and serum creatinine levels increased, leading to a second biopsy which confirmed the diagnosis of focal segmental glomerulosclerosis. This study reports on the first case of pemphigus vulgaris with focal segmental glomerulosclerosis and reviews the literature on the co‐occurrence of acquired immunobullous diseases and nephrotic syndrome of any kind. [ABSTRACT FROM AUTHOR]

BackgroundRecent clinical and basic research implicated a strong correlation between NAFLD/NASH phenotypes with ectopic manifestations including neuroinflammation and neurodegeneration, but the mediators and critical pathways involved are not well understood. Lipocalin 2 (Lcn2) is one of the important mediators exclusively produced in the liver and circulation during NASH pathology.MethodsUsing murine model of NASH, we studied the role of Lcn2 as a potent mediator of neuroinflammation and neurodegeneration in NASH pathology via the liver-brain axis.ResultsResults showed that high circulatory Lcn2 activated 24p3R (Lipocalin2 receptor) in the brain and induced the release of high mobility group box 1 (HMGB1) preferably from brain cells. Released HMGB1 acted as a preferential ligand to toll-like receptor 4 (TLR4) and induced oxidative stress by activation of NOX-2 signaling involving activated p65 protein of the NF-κB complex. Further, the HMGB1-derived downstream signaling cascade activated NLRP3 inflammasome and release of proinflammatory cytokines IL-6 and IL-1β from brain cells. In addition, to advance our present understanding, in vitro studies were performed in primary brain endothelial cells where results showed high circulatory Lcn2 influenced HMGB1 secretion. Mechanistically, we also showed that elevated Lcn2 level in underlying NASH might be a likely cause for induction of blood-brain barrier dysfunction since the adipokine decreased the expression of tight junction protein Claudin 5 and caused subsequent elevation of pro-inflammatory cytokines IL-6 and IL-1β.ConclusionIn conclusion, the NASH-induced brain pathology might be because of increased Lcn2-induced release of HMGB1 and accompanying neuroinflammation.

Aiming at the local, global and temporal morphological characteristics of faults in seismic profiles, this paper proposes the MCD-ABiLSTM method for fault identification. The method uses multi-channel, convolution kernels of different sizes and convolution of different depths to extract multi-scale seismic profile features, and makes full use of the extracted features to enhance the model’s sensitivity to small faults. By combining Bi-directional Long Short-Term Memory (BiLSTM) with multi-scale dense convolution (MCD), the spatial and temporal characteristics of seismic signals are extracted successively, so that the seismic attribute features can be better represented in space and time. In order to solve the problem of extreme imbalance between label data and background data, an improved Weighted Cross Entropy is adopted as the loss function of MCD-ABiLSTM, which alleviates the imbalance between label data and background data. Then, the label data is expanded to establish a fault label data set suitable for deep learning, which further alleviates the problem of imbalance between fault label data and background data. The comparison results show that compared with FCN, U-net, U-net++ and Deeplap V3, the method proposed in this paper improves the precision by 6.27%, 3.65%, 2.94% and 4%.

The endogenous antioxidant defense plays a big part in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), a common metabolic disorder that can lead to serious complications such as cirrhosis and cancer. HuR, an RNA-binding protein of the ELAV family, controls, among others, the stability of MnSOD and HO-1 mRNA. These two enzymes protect the liver cells from oxidative damage caused by excessive fat accumulation. Our aim was to investigate the expression of HuR and its targets in a methionine-choline deficient (MCD) model of NAFLD. To this aim, we fed male Wistar rats with an MCD diet for 3 and 6 weeks to induce NAFLD; then, we evaluated the expression of HuR, MnSOD, and HO-1. The MCD diet induced fat accumulation, hepatic injury, oxidative stress, and mitochondrial dysfunction. A HuR downregulation was also observed in association with a reduced expression of MnSOD and HO-1. Moreover, the changes in the expression of HuR and its targets were significantly correlated with oxidative stress and mitochondrial injury. Since HuR plays a protective role against oxidative stress, targeting this protein could be a therapeutic strategy to both prevent and counteract NAFLD. [ABSTRACT FROM AUTHOR]

Objective: To describe neurosonographic findings diagnostic or highly suggestive of the presence of malformations of cortical development involving the cortex that may be identified before 24 weeks of gestation. Methods: This was a retrospective single‐center study of fetuses referred for neurosonography, during 2012–2019, with an abnormal cortical or sulcation pattern diagnosed early in the mid trimester. Stored files were analyzed for demographic data, abnormal brain findings, non‐central nervous system abnormalities, final diagnosis and postnatal outcome. Results: The study cohort included 20 fetuses, with a mean gestational age at diagnosis of 18.7 (range, 14.4–23.6) weeks, in 11 of which the diagnosis was made before 20 weeks of gestation. Reasons for referral were: midline anomaly (n = 7), ventriculomegaly (n = 4), infratentorial findings (n = 3), suspected malformation of cortical development (n = 3), 'abnormal brain' (n = 2) and skeletal dysplasia (n = 1). On neurosonography, both the sulcation pattern and the cortical layer were abnormal in four cases, only the sulcation pattern was considered abnormal in seven and only the cortical layer was abnormal in nine. Nineteen fetuses presented with associated central nervous system anomalies and six also had non‐central nervous system malformations. One case was recurrent. Eighteen parents opted for termination of pregnancy, including one selective termination in a twin pregnancy, and two fetuses were liveborn. Conclusions: Familiarity with fetal brain anatomy and its early sonographic landmarks allowed early diagnosis of malformations involving cortical development. These patients are likely to represent the most severe cases and all had associated malformations. The presence of an abnormal cortical layer and/or abnormal overdeveloped sulci appear to be early signs of malformation of cortical development. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

In this study, we propose the robust ratio-type estimator of finite population variance considering the minimum covariance determinant (MCD) and the minimum volume ellipsoid (MVE) robust covariance matrices in simple and stratified random sampling. The mean square errors (MSE) equations are obtained for the robust ratio-type estimator. The conditions for which the proposed robust ratio-type estimator is more efficient as compared to competing estimators have been discussed. The MCD and MVE are robust against outliers. Thus, when there is an outlier in the data, simulations and empirical results show that the proposed robust ratio-type estimators under simple and stratified random sampling have a lower mean square error than the traditional estimators. In addition, we support theoretical results with contaminated real examples and simulation studies. [ABSTRACT FROM AUTHOR]

BackgroundMinimal change disease (MCD) is a common pathological type of nephrotic syndrome (NS), and is one of the most common causes of NS in children, but is not common in adults. MCD is sensitive to corticosteroid therapy and has a good prognosis, but is prone to relapse. Venous thromboembolism (VTE) is less common in MCD.Case presentationWe report a case of acute pulmonary embolism (PE) with arrhythmia associated with MCD in adults. The hypercoagulable state caused by MCD through multiple systems may be one of the important causes of thrombosis in this patient. In addition to the conventional corticosteroid therapy, he was started on anticoagulation for VTE and PE. His hospital course was complicated by atrial tachyarrhythmias initially controlled by amiodarone but he required readmission due to recurrent atrial flutter. His clinical condition became more stable after radiofrequency ablation.ConclusionVTE associated with MCD in adults is rare. Treatment of MCD with corticosteroids may be associated with a higher risk of developing blood clots. This type of case is relatively rare and should be paid attention to. The mechanism of VTE in MCD is still a direction worthy of further research.

Key Clinical Message There may be a connection between pemphigus vulgaris and nephrotic syndrome, as evidenced by the occurrence of focal segmental glomerulosclerosis in our pemphigus vulgaris patient and reviewing relevant literature. Therefore, if a patient with pemphigus vulgaris presents with bilateral lower extremity edema or proteinuria detected during urinalysis, it could indicate involvement of the kidneys. Abstract Pemphigus vulgaris is a type of autoimmune blistering disease characterized by the presence of IgG autoantibodies against desmogleins 3 and 1. It is important to evaluate potential autoimmune associations in patients with pemphigus vulgaris so that appropriate laboratory and physical examinations can be performed to monitor for any increased risk of other autoimmune disorders. This case report describes a 55‐year‐old woman who presented with oral and axillary erosions, which were diagnosed as pemphigus vulgaris based on skin histopathology and immunofluorescence. During follow‐up, the patient was found to have proteinuria, which led to referral to a nephrologist. The patient was diagnosed with nephrotic syndrome and minimal change disease after a biopsy. Despite treatment, the patient's proteinuria persisted and serum creatinine levels increased, leading to a second biopsy which confirmed the diagnosis of focal segmental glomerulosclerosis. This study reports on the first case of pemphigus vulgaris with focal segmental glomerulosclerosis and reviews the literature on the co‐occurrence of acquired immunobullous diseases and nephrotic syndrome of any kind.

IntroductionMalonyl coenzyme A decarboxylase deficiency is caused by an abnormality in the MLYCD gene. The clinical manifestations of the disease involve multisystem and multiorgan.MethodsWe collected and analyzed a patient's clinical characteristics, genetic chain of evidence and RNA-seq. We use the search term “Malonyl-CoA Decarboxylase Deficiency” on Pubmed to collect cases reported.ResultsWe report a 3-year-old girl who is presented with developmental retardation, myocardial damage and elevated C3DC. High-throughput sequencing identified heterozygous mutation (c.798G>A, p.Q266?) in the patient inherited from her father. The other heterozygous mutation (c.641+5G>C) was found in the patient inherited from her mother. RNA-seq showed that there were 254 differential genes in this child, among which 153 genes were up-regulated and 101 genes were down-regulated. Exon jumping events occurred in exons encoding PRMT2 on the positive chain of chromosome 21, which led to abnormal splicing of PRMT2. (P

The elderly population is affected by a wide range of kidney diseases like young adult patients. However, their clinical course and morphological manifestations are affected by aging. Recognition, diagnosis, and management of glomerular disease in elderly persons have several unique challenges. We aimed to study the clinicopathologic spectrum of elderly patients with nephrotic syndrome (NS). In this retrospective study, we looked at 234 patients of adult NS who were biopsied during the last 5 years. Among them, 31 patients were above the age of 60 years (Elderly). Mean age in elderly patients was 67.48 ± 6.11 years, with age range from 60 to 86 years. Elderly NS patients constituted 13.2% of total adult NS patients. Nineteen patients (61.2%) were males and 12 (38.7%) were females. Hematuria was observed in 19% and hypertension in 48% patients. Mean serum albumin was 2.79 ± 0.39 g/dl and mean 24 h urinary protein was 3.77 ± 0.8 grams. Membranous nephropathy (MN) followed by minimal change disease (MCD) was the most common diagnosis. No major complication with biopsy was reported in our study as has been the case with most studies. [ABSTRACT FROM AUTHOR]

[Display omitted] • MCD and MCPL: the role of A, B and C terms. • Calculation of A and B terms via TD-DFT methods. • Porphyrinoid systems: highly symmetric and non-symmetric cases. • MCD of natural products extracted from plants: experiments and calculations. • MCD in the IR range: MVCD. A historical sketch of the MCD (magnetic circular dichroism) spectroscopy is reported in its experimental and theoretical aspects. MCPL (magnetic circularly polarized luminescence) is also considered. The main studies are presented encompassing porphyrinoid systems, aggregates and materials, as well as simple organic molecules useful for the advancement of the interpretation. The MCD of chiral systems is discussed with special attention to new studies of natural products with potential pharmaceutical valence, including Amaryllidaceae alkaloids and related isocarbostyrils. Finally, the vibrational form of MCD, called MVCD, which is recorded in the IR part of the spectrum is also discussed. A final brief note on perspectives is given. [ABSTRACT FROM AUTHOR]

IntroductionInflammation is a common unifying factor in experimental models of non-alcoholic fatty liver disease (NAFLD) progression. Recent evidence suggests that housing temperature-driven alterations in hepatic inflammation correlate with exacerbated hepatic steatosis, development of hepatic fibrosis, and hepatocellular damage in a model of high fat diet-driven NAFLD. However, the congruency of these findings across other, frequently employed, experimental mouse models of NAFLD has not been studied.MethodsHere, we examine the impact of housing temperature on steatosis, hepatocellular damage, hepatic inflammation, and fibrosis in NASH diet, methionine and choline deficient diet, and western diet + carbon tetrachloride experimental models of NAFLD in C57BL/6 mice.ResultsWe show that differences relevant to NAFLD pathology uncovered by thermoneutral housing include: (i) augmented NASH diet-driven hepatic immune cell accrual, exacerbated serum alanine transaminase levels and increased liver tissue damage as determined by NAFLD activity score; (ii) augmented methionine choline deficient diet-driven hepatic immune cell accrual and increased liver tissue damage as indicated by amplified hepatocellular ballooning, lobular inflammation, fibrosis and overall NAFLD activity score; and (iii) dampened western diet + carbon tetrachloride driven hepatic immune cell accrual and serum alanine aminotransferase levels but similar NAFLD activity score.DiscussionCollectively, our findings demonstrate that thermoneutral housing has broad but divergent effects on hepatic immune cell inflammation and hepatocellular damage across existing experimental NAFLD models in mice. These insights may serve as a foundation for future mechanistic interrogations focused on immune cell function in shaping NAFLD progression.

Primary focal segmental glomerulosclerosis (FSGS), along with minimal change disease (MCD), are diseases with primary podocyte damage that are clinically manifested by the nephrotic syndrome. The pathogenesis of these podocytopathies is still unknown, and therefore, the search for biomarkers of these diseases is ongoing. Our aim was to determine of the proteomic profile of urine from patients with FSGS and MCD. Patients with a confirmed diagnosis of FSGS (n = 30) and MCD (n = 9) were recruited for the study. For a comprehensive assessment of the severity of FSGS a special index was introduced, which was calculated as follows: the first score was assigned depending on the level of eGFR, the second score—depending on the proteinuria level, the third score—resistance to steroid therapy. Patients with the sum of these scores of less than 3 were included in group 1, with 3 or more—in group 2. The urinary proteome was analyzed using liquid chromatography/mass spectrometry. The proteome profiles of patients with severe progressive FSGS from group 2, mild FSGS from group 1 and MCD were compared. Results of the label free analysis were validated using targeted LC-MS based on multiple reaction monitoring (MRM) with stable isotope labelled peptide standards (SIS) available for 47 of the 76 proteins identified as differentiating between at least one pair of groups. Quantitative MRM SIS validation measurements for these 47 proteins revealed 22 proteins with significant differences between at least one of the two group pairs and 14 proteins were validated for both comparisons. In addition, all of the 22 proteins validated by MRM SIS analysis showed the same direction of change as at the discovery stage with label-free LC-MS analysis, i.e., up or down regulation in MCD and FSGS1 against FSGS2. Patients from the FSGS group 2 showed a significantly different profile from both FSGS group 1 and MCD. Among the 47 significantly differentiating proteins, the most significant were apolipoprotein A-IV, hemopexin, vitronectin, gelsolin, components of the complement system (C4b, factors B and I), retinol- and vitamin D-binding proteins. Patients with mild form of FSGS and MCD showed lower levels of Cystatin C, gelsolin and complement factor I. [ABSTRACT FROM AUTHOR]

Background: Metabolic associated fatty liver disease (MAFLD) is the most common chronic liver disease worldwide. The important role of urid acid (UA) in MAFLD has been widely investigated. Our previous studies unveiled the elevation of serum UA levels independently predicts an increased risk of incident MAFLD. However, the role of intrahepatic UA in MAFLD has not been investigated yet. Glucose transporter 9 (GLUT9) is a key transporter that mediates the uptake of UA in hepatocytes. Methods: In this study, we first explored the clinical association between GLUT9 polymorphism and MAFLD. Blood samples of 247 male Chinese (127 were MAFLD patients) were collected and tested for the blood UA levels and genotype of the single nucleotide polymorphism (SNP) of GLUT9 (rs1014290). Next, Glut9 hepatic-specific knockout mice (Glut9Hep−ko) were generated to investigate the role of hepatic GLUT9 in MAFLD in male mice. Results: We found that the GA/AA genotypes (rs1014290) were associated with elevated serum UA levels in MAFLD patients. Meanwhile, we found that Glut9Hep−ko mice displayed lower intrahepatic UA levels, down-regulated lipogenesis genes expressions, and attenuated MAFLD symptoms after 12 weeks of high-fat diet feeding, compared with Glut9Fl/Fl littermates. However, Glut9Hep−ko mice and wild-type littermates showed no significant difference on hepatic fatty acid oxidation or inflammation. Conclusions: Our results suggested that GLUT9 polymorphism was significantly associated with MAFLD, and hepatic-specific knockout of Glut9 significantly decreased intrahepatic contents and ameliorated diet-induced MAFLD in mice. [ABSTRACT FROM AUTHOR]

"When you can measure what you are speaking about, and express it in numbers, you know something about it." is a famous quote attributed to Lord Kelvin. This sentiment puts viral load measurements at the center of virology. Viral load, or more precisely, DNA copy number measurements, are also used to follow infections with human herpesviruses, such as Kaposi sarcoma herpesvirus (KSHV) and Epstein-Barr Virus (EBV). EBV and KSHV are associated with human cancers, and determining their DNA copy numbers in the context of cancer prediction and progression on therapy is of fundamental scientific and translational interest. Yet, there is no generally accepted assay for KSHV DNA quantitation, and KSHV viral load is not used in clinical decision-making. Here, we review the history of KSHV DNA detection assays, explore factors that affect sensitivity and specificity, and describe an automated, high-throughput, real-time quantitative polymerase chain reaction (PCR) assay for KSHV and EBV. In conjunction with a digital PCR assay using the same primer/probe combination, we describe how to determine the absolute KSHV genome copy numbers in plasma, peripheral blood mononuclear cells, saliva, and other easily accessible body fluids., (© 2024 Wiley Periodicals LLC.)

Reducing into a satisfiability (SAT) formulation has been proven effective in solving certain NP-hard problems. In this work, we extend this research by presenting a novel SAT formulation for computing the double-cut-and-join (DCJ) distance between two genomes with duplicate genes. The DCJ distance serves as a crucial metric in studying genome rearrangement. Previous work achieved an exact solution by transforming it into a maximum cycle decomposition (MCD) problem on the corresponding adjacency graph of two genomes, followed by reducing this problem into an integer linear programming (ILP) formulation. Using both simulated datasets and real genomic datasets, we firmly conclude that the SAT-based method scales much better and runs faster than using ILP, being able to solve a whole new range of instances which the ILP-based method cannot solve in a reasonable amount of time. This underscores the SAT-based approach as a versatile and more powerful alternative to ILP, with promising implications for broader applications in computational biology., Competing Interests: Disclosure of Interests. The authors declare that there is no conflict of interest.

Introduction: Steroid-resistant nephrotic syndrome (SRNS) is a rare condition that accounts for about 10% to 20% of all nephrotic syndromes in children. While calcineurin inhibitors induce remission in the majority, the data on long-term outcomes are limited. This retrospective study aimed to look at the clinical profile, biopsy findings, and long-term treatment outcomes in children with SRNS. Methods: The records of all children (1-18 years) with SRNS with biopsy findings of minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), or mesangioproliferative glomerulonephritis, who received treatment for a minimum period of 12 months and were in follow-up during the years 2007-2018 at a tertiary care teaching hospital were retrieved. The clinical, histopathological, and biochemical factors and treatment outcomes were recorded and analyzed. Results: Ninety-one (72 boys) children with a median (interquartile range [IQR]) age of onset of nephrotic syndrome as 48 (24-87) months were included. MCD and FSGS were the most common histopathological types (57.1% and 36.3%, respectively) and 62 (68.1%) patients had late steroid resistance. Calcineurin inhibitors (CNIs) were used in 86.8% of the children, and response rates with cyclosporine and tacrolimus for complete remission (CR) were 80% and 73.7%, respectively, with median (IQR) time to response being 3 (2-4) months. The presence of MCD on histology and the use of CNIs were significantly associated with CR (P < 0.01). At a median (IQR) follow-up of 5 (3-7) years, 76 (83.5%) children had either CR or partial remission, four (4.4%) developed chronic kidney disease and five (5.5%) died (three due to end-stage renal disease and two of infective complications). Conclusion: SRNS children with MCD on biopsy, late resistance, and response to CNIs have better long-term outcomes. Most patients respond to CNIs within the first 6 months of use and need therapy for at least 24 to 36 months. [ABSTRACT FROM AUTHOR]

In this work, we deal with a robust fitting of a wrapped normal model to multivariate circular data. Robust estimation is supposed to mitigate the adverse effects of outliers on inference. Furthermore, the use of a proper robust method leads to the definition of effective outlier detection rules. Robust fitting is achieved by a suitable modification of a classification-expectation-maximization algorithm that has been developed to perform a maximum likelihood estimation of the parameters of a multivariate wrapped normal distribution. The modification concerns the use of complete-data estimating equations that involve a set of data dependent weights aimed to downweight the effect of possible outliers. Several robust techniques are considered to define weights. The finite sample behavior of the resulting proposed methods is investigated by some numerical studies and real data examples.

Our aim was to investigate the usefulness of 18fluorine-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in the diagnosis, treatment response evaluation, and follow-up of human herpesvirus-8 (HHV-8)-associated multicentric Castleman’s disease (MCD). Fifteen patients with histologically diagnosis of HHV-8-associated MCD were retrospectively included. For all patients, a 18F-FDG PET/CT scan was performed before any treatment for diagnosis and PET/CT scans after Rituximab (4 cycles) for the evaluation of treatment response; moreover, 22 PET/CT were performed during the follow-up to check disease status. To evaluate treatment response, we applied Deauville criteria. PET/CT findings were compared with other conventional imaging (CI) findings. At diagnosis, 18F-FDG PET/CT showed an increased FDG-uptake in all cases corresponding to lymph nodes and confirming the MCD. The average SUVmax of the FDG avid lesions were 8.75, average lesion-to-liver SUVmax ratio was 3.6, and average lesion-to-blood pool SUVmax ratio was 3.9. After first-line therapy, 18F-FDG PET/CT resulted negative (Deauville score < 4) in seven patients and positive in the remaining eight (Deauville score 4–5). A negative restaging PET/CT was associated with a lower risk of relapse. During follow-up, PET/CT detected the presence of relapse or progression in 5 (23%) cases with an accuracy higher than CI. 18F-FDG PET/CT seems to be an useful tool in studying HHV-8-associated MCD both at diagnosis and during follow-up.

Li Lin,1 Weiming Wang,1 YiFan Wu,2 JingYuan Xie,1 Xiao Li,1 XiaoXia Pan,1 Wen Zhang,1 Jing Xu,1 YiKai Cai,1 Hong Ren,1 Nan Chen1 1Department of Nephrology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, People’s Republic of China; 2Biomedical and Health Informatics, University of Washington, Seattle, WA, USACorrespondence: Hong Ren; Nan ChenDepartment of Nephrology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, No. 197, Ruijin Er Road, Shanghai, People’s Republic of ChinaTel +86 21 64370045, extension 665233Fax +86 21 64456419Email renhong66@126.com; cnrj100@126.comPurpose: There is currently a lack of studies investigating long-term prognosis and the necessity of further rituximab (RTX) consolidation treatment for minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). The aim of this study was to evaluate the efficacy of RTX for these diseases and to investigate whether a consolidation treatment can lower risks of relapse and reinforce long-term remission.Patients and Methods: A retrospective study was conducted. The relapse and remission of 70 patients treated with 1 course of RTX treatment (4 infusions of 375 mg/m2) over a median follow-up time of 27 months (12– 60 months) were analyzed. The rates of patients that were able to achieve non-relapse for a duration of 24 months between RTX consolidation therapy and non-consolidation therapy were compared.Results: There were 67 cases (95.71%) of remission and 3 cases (4.29%) of non-remission. The average number of relapses decreased from 3.7± 2.5 times before the treatment to 0.8± 1.8 times after treatment (P < 0.001). The average avannual number of relapses decreased from 1.3± 1.2 times/year to 0.2± 0.3 times/year (P < 0.001). The results from the Cox proportional-hazards model showed that the risk of relapse in patients who received RTX non-consolidation treatment was significantly higher than those with consolidation treatment (odds ratios (OR) 20.9, 95% confidence intervals (CI) OR 5.7– 75.7, p< 0.001). The 24-month relapse-free rate was also significantly higher in patients with consolidation therapy compared with non-consolidation therapy (86.36% vs 25%, p< 0.001). No adverse events were recorded.Conclusion: RTX is highly effective in treating MCD and FSGS, and RTX consolidation therapy may be recommended to reinforce long-term remissions.Keywords: RTX, MCD, FSGS, consolidation, therapeutic effect

Shugan Xiaozhi (SGXZ) decoction is a traditional Chinese medicine used for treating nonalcoholic steatohepatitis (NASH). It has been used clinically for over 20 years and proved to be effective; however, the molecular mechanism underlying the effects of SGXZ decoction remains unclear. We analyzed the chemical components, core targets, and molecular mechanisms of SGXZ decoction to improve NASH through network pharmacology and in vivo experiments. The chemical components, core targets, and related signaling pathways of SGXZ decoction intervention in NASH were predicted using network pharmacology. Molecular docking was performed to verify chemical components and their core targets. The results were validated in the NASH model treated with SGXZ decoction. Mouse liver function was assessed by measuring ALT and AST levels. TC and TG levels were determined to evaluate lipid metabolism, and lipid deposition was assessed via oil red O staining. Mouse liver damage was determined via microscopy following hematoxylin and eosin staining. Liver fibrosis was assessed via Masson staining. Western blot (WB) and immunohistochemical (IHC) analyses were performed to detect inflammation and the expression of apoptosis-related proteins, including IL-1β, IL-6, IL-18, TNF-α, MCP1, p53, FAS, Caspase-8, Caspase-3, Caspase-9, Bax, Bid, Cytochrome c, Bcl-2, and Bcl-XL. In addition, WB and IHC were used to assess protein expression associated with the TLR4/MyD88/NF-κB pathway. Quercetin, luteolin, kaempferol, naringenin, and nobiletin in SGXZ decoction were effective chemical components in improving NASH, and TNF-α, IL-6, and IL-1β were the major core targets. Molecular docking indicated that these chemical components and major core targets might interact. KEGG pathway analysis showed that the pathways affected by SGXZ decoction, primarily including apoptosis and TLR4/NF-κB signaling pathways, interfere with NASH. In vivo experiments indicated that SGXZ decoction considerably ameliorated liver damage, fibrosis, and lipid metabolism disorder in MCD-induced NASH mouse models. In addition, WB and IHC verified the underlying molecular mechanisms of SGXZ decoction as predicted via network pharmacology. SGXZ decoction inhibited the activation of apoptosis-related pathways in MCD-induced NASH mice. Moreover, SGXZ decoction suppressed the activation of TLR4/MyD88/NF-κB pathway in MCD-induced NASH mice. SGXZ decoction can treat NASH through multiple targets and pathways. These findings provide new insights into the effective treatment of NASH using SGXZ decoction. [Display omitted] • Non-alcoholic steatohepatitis (NASH) is a kind of fatty liver disease. • Shugan Xiaozhi (SGXZ) decoction has the effect of protecting liver function. • SGXZ decoction could improve NASH by inhibiting apoptosis signalling pathways. • SGXZ decoction might alleviate NASH though suppressing TLR4/MyD88/NF-κB pathway. [ABSTRACT FROM AUTHOR]

Clinical manifestations of malformations of cortical development (MCD) are variable and can range from mild to severe intellectual disability, cerebral palsy and drug-resistant epilepsy. Besides common clinical features, non-specific or more subtle clinical symptoms may be present in association with different types of MCD. Especially in severely affected individuals, subtle but specific underlying clinical symptoms can be overlooked or overshadowed by the global clinical presentation. To facilitate the interpretation of genetic variants detailed clinical information is indispensable. Detailed (neurological) examination can be helpful in assisting with the diagnostic trajectory, both when referring for genetic work-up as well as when interpreting data from molecular genetic testing. This systematic literature review focusses on different clues derived from the neurological examination and potential further work-up triggered by these signs and symptoms in genetically defined MCDs. A concise overview of specific neurological findings and their associations with MCD subtype and genotype are presented, easily applicable in daily clinical practice. The following pathologies will be discussed: neuropathy, myopathy, muscular dystrophies and spastic paraplegia. In the discussion section, tips and pitfalls are illustrated to improve clinical outcome in the future. [ABSTRACT FROM AUTHOR]

Abstract Background Recent clinical and basic research implicated a strong correlation between NAFLD/NASH phenotypes with ectopic manifestations including neuroinflammation and neurodegeneration, but the mediators and critical pathways involved are not well understood. Lipocalin 2 (Lcn2) is one of the important mediators exclusively produced in the liver and circulation during NASH pathology. Methods Using murine model of NASH, we studied the role of Lcn2 as a potent mediator of neuroinflammation and neurodegeneration in NASH pathology via the liver-brain axis. Results Results showed that high circulatory Lcn2 activated 24p3R (Lipocalin2 receptor) in the brain and induced the release of high mobility group box 1 (HMGB1) preferably from brain cells. Released HMGB1 acted as a preferential ligand to toll-like receptor 4 (TLR4) and induced oxidative stress by activation of NOX-2 signaling involving activated p65 protein of the NF-κB complex. Further, the HMGB1-derived downstream signaling cascade activated NLRP3 inflammasome and release of proinflammatory cytokines IL-6 and IL-1β from brain cells. In addition, to advance our present understanding, in vitro studies were performed in primary brain endothelial cells where results showed high circulatory Lcn2 influenced HMGB1 secretion. Mechanistically, we also showed that elevated Lcn2 level in underlying NASH might be a likely cause for induction of blood-brain barrier dysfunction since the adipokine decreased the expression of tight junction protein Claudin 5 and caused subsequent elevation of pro-inflammatory cytokines IL-6 and IL-1β. Conclusion In conclusion, the NASH-induced brain pathology might be because of increased Lcn2-induced release of HMGB1 and accompanying neuroinflammation.

Abstract Background Use of rituximab (RTX) for focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) is widely described in children. Clinical evidence in adults is limited. The objective of this study was to determine the treatment outcomes of RTX in adults with FSGS and MCD. Methods Ovid MEDLINE, SCOPUS, and Cochrane Database of Systematic Reviews were searched up to September 2019. Out of 699 studies, we included 16 studies describing the treatment outcomes of rituximab in adult patients with FSGS or MCD. Results were reported in remission rate and relapse rate. Serious adverse events were also reported. Results A total of 16 studies were included in our review and analysis. All studies were observational studies and included a total of 221 patients (23.1% FSGS, 76.9% MCD). Mean follow-up duration was 26.3 ± 12.8 months. From the analysis of five studies with FSGS patients (n = 51), the overall remission rate and relapse rate of RTX therapy was 53.6% (95% CI, 15.8–87.6%) and 47.3% (95% CI, 25.4–70.2%), respectively. Complete remission occurred in 42.9%. In contrast, from the analysis of 11 studies with MCD patients (n = 170), the overall remission rate and relapse rate of RTX therapy was 80.3% (95% CI, 68.5–88.5%) and 35.9% (95% CI, 25.1–48.4), respectively. Complete remission occurred in 74.7%. Subgroup analyses showed that overall remission and relapse were not different after adjusted for study year and RTX dose for both FSGS and MCD. Incidence of serious adverse events was 0.092 events/year. Conclusions Rituximab may be considered as an additional treatment to the standard therapy for adult patients with FSGS and MCD. Remissions and relapses are similar between FSGS and MCD. Serious adverse effects of rituximab were uncommon. We encourage further randomized controlled trials to confirm the efficacy of rituximab therapy in these patients.

We propose a hybrid network-based learning framework for speaker-adaptive vocal emotion conversion, tested on three different datasets (languages), namely, EmoDB (German), IITKGP (Telugu), and SAVEE (English). The optimized learning model introduced is unique because of its ability to synthesize emotional speech with an acceptable perceptive quality while preserving speaker characteristics. The multilingual model is extremely beneficial in scenarios wherein emotional training data from a specific target speaker are sparsely available. The proposed model uses speaker-normalized mel-generalized cepstral coefficients for spectral training with data adaptation using the seed data from the target speaker. The fundamental frequency (F0) is transformed using a wavelet synchrosqueezed transform prior to mapping to obtain a sharpened time-frequency representation. Moreover, a feedforward artificial neural network, together with particle swarm optimization, was used for F0 training. Additionally, static-intensity modification was also performed for each test utterance. Using the framework, we were able to capture the spectral and pitch contour variabilities of emotional expression better than with other state-of-the-art methods used in this study. Considering the overall performance scores across datasets, an average melcepstral distortion (MCD) of 4.98 and root mean square error (RMSE-F0) of 10.67 were obtained in objective evaluations, and an average comparative mean opinion score (CMOS) of 3.57 and speaker similarity score of 3.70 were obtained for the proposed framework. Particularly, the best MCD of 4.09 (EmoDB-happiness) and RMSE-F0 of 9.00 (EmoDB-anger) were obtained, along with the maximum CMOS of 3.7 and speaker similarity of 4.6, thereby highlighting the effectiveness of the hybrid network model.

In order to solve the problems of poor security and small application scope of speech content authentication, and to improve the robustness, discrimination and real-time performance of speech authentication, a multi-format speech BioHashing algorithm based on energy to zero ratio and improved linear prediction minimum mean square error (LP-MMSE) parameter fusion is proposed. Firstly, the algorithm extracts the short-term logarithmic energy, zero-crossing rate and the covariance method's LP-MMSE of speech signal to be processed. Then, the time-frequency parameters are fused, and the fused feature vector and the orthogonal normalized random matrix of the key control are generated into BioHashing sequences through the inner product form. Finally, the BioHashing is encrypted by equal-length scrambling using henon chaotic map. The experimental results show that the proposed algorithm not only has the characteristics of good discrimination, strong robustness, good security, high real-time performance and wide application range, but also realizes the detection and localization of small-scale tampering of speech through minimum code distance (MCD) algorithm. At the same time, the algorithm also validates the unidirectionality of BioHashing with trapdoor by comparative difference method. [ABSTRACT FROM AUTHOR]