Causal relationship of inflammatory cytokines and serum metabolites in cerebral small vessel disease: a two-step Mendelian randomization study.

BACKGROUND AND PURPOSE: The aim was to investigate the causal relationships of inflammatory cytokines and serum metabolites in cerebral small vessel disease (CSVD). METHODS: Bidirectional Mendelian randomization was first conducted to screen inflammatory cytokines and serum metabolites that were associated with imaging features of CSVD, including white matter hyperintensities, recent small subcortical infarcts, cortical cerebral microinfarcts, cerebral microbleeds, lacunes and enlarged perivascular spaces. Sensitivity analyses were performed to evaluate the robustness and pleiotropy of these results. Subsequently, inflammatory cytokines and serum metabolites that were associated with CSVD were subjected to functional enrichment. Finally, mediation analysis was employed to investigate whether inflammatory cytokines or serum metabolites acted as an intermediary for the other in their causal relationship with CSVD. RESULTS: Of the inflammatory cytokines, five were risk factors (e.g., tumour-necrosis-factor-related apoptosis-inducing ligand) and five (e.g., fibroblast growth factor 19) were protective factors for CSVD. Eleven serum metabolites that increased CSVD risk and 13 metabolites that decreased CSVD risk were also identified. The majority of these markers of CSVD susceptibility were lipid metabolites. Natural killer cell receptor sub-type 2B4 was determined to act as a mediating factor of an unidentified metabolite for the enlargement of perivascular spaces. CONCLUSION: Several inflammatory cytokines and serum metabolites had causal relationships with imaging features of CSVD. A natural killer cell receptor mediated in part the promotional effect of a metabolite on perivascular space enlargement.

Weighted gene coexpression network analysis and machine learning for the determination of tfh cell and B cell infiltrating biomarkers in thymoma-associated myasthenia gravis.

Patients with thymoma (THYM)-associated myasthenia gravis (MG) typically have a poor prognosis and recurring illness. This study aimed to discover important biomarkers associated with immune cell infiltration and THYM-associated MG (THYM-MG) development. Gene expression microarray data were downloaded from The Cancer Genome Atlas website (TCGA) and Gene Expression Omnibus (GEO). A total of 102 differentially expressed genes were investigated. According to the immune infiltration data, the distribution of Tfh cells, B cells, and CD4 T cells differed significantly between the THYM-MG and THYM-NMG groups. WGCNA derived 25 coexpression modules; one hub module (the blue module) strongly correlated with Tfh cells. Combining differential genes revealed 21 intersecting genes. LASSO analysis subsequently revealed 16 hub genes as potential THYM-MG biomarkers. ROC curve analysis of the predictive model revealed moderate diagnostic value. The association between the 16 hub genes and infiltrating immune cells was further evaluated in TIMER2.0 and the validation dataset. Draggability analysis identified the therapeutic target genes PTGS2 and ALB, along with significant drugs including Firocoxib, Alclofenac, Pyridostigmine, and Stavudine. This was validated through MD simulation, PCA, and MM-GBSA analyses. The interaction between numerous activated B cells and follicular helper T cells is closely associated with THYM-MG pathogenesis from a bioinformatics perspective. Hub genes (including SP6, SCUBE3, B3GNT7, and MAGEL2) may be downregulated in immune cells in THYM-MG and associated with progression.

Strategies to mitigate acute kidney injury risk during physical work in hot environments.

Prolonged physical work in the heat can reduce renal function and increase the risk of acute kidney injury (AKI). This is concerning given that the latest climate change projections forecast a rise in global temperature as well as the frequency, intensity, and duration of heatwaves. This means that outdoor and indoor workers in the agriculture or construction industries will be exposed to higher heat stress in the years ahead. Several studies indicate a higher incidence of chronic kidney disease from nontraditional origins (CKDnt) in individuals exposed to high temperatures, intense physical work, and/or recurrent dehydration. It has been proposed that prolonged physical work in the heat accompanied by dehydration results in recurrent episodes of AKI that ultimately lead to permanent kidney damage and the development of CKDnt. Thus, there is a need to identify and test strategies that can alleviate AKI risk during physical work in the heat. The purpose of this review is to present strategies that might prevent and mitigate the risk of AKI induced by physical work in the heat.

Objective Neurological Testing Methods Used to Follow Up Vestibular Neuritis Depending on Different Factors.

Purpose: We analyze the impact of different factors on clinical performance and prognosis in vestibular neuritis (VN) and explore indicators that could accurately reflect changes in patients' symptoms at different stages. Methods: We observed patients with VN during the acute and recovery phases. Clinical symptoms, vertigo-related scales, neurological examination, vestibular function tests (caloric test, video head impulse test (vHIT), vestibular evoked myogenic potential (VEMP)), and the history of disease (underlying diseases, glucocorticoid therapy) were recorded at onset and at 4 and 12 weeks after onset in VN patients. Multiple linear regression analysis was used to identify vestibular function tests that had a linear regression relationship with the subjective quantitative results. Results: At 4 weeks after onset, the group without underlying disease had better improvement in EEV, gain, and UW than the group with underlying disease (P < 0.05). There was a significant difference in the change in DHI, EEV, gain of the affected horizontal semicircular canal in the vHIT and unilateral weakness (UW) between the glucocorticoid treatment group and the no glucocorticoid treatment group (P < 0.05), and glucocorticoid treatment group was better. The change value in the gain of horizontal canals in the vHIT was mainly positively and linearly correlated with the EEV scores (P<0.001). Possible dynamic correlation between vHIT results and vestibular symptoms. Conclusion: The absence of underlying disease and the receipt of glucocorticoid therapy significantly contributed to the improvement of objective vestibular function tests in the short term, while the improvement of subjective vertigo may correlate with the different objective measures and questionnaire. We believe that the improvement of the affected horizontal semicircular canal gain value in the vHIT can be used as a reference indicator of the degree of improvement of vestibular symptoms with superior vestibular neuritis.

Enhanced Exciton Drift Transport through Suppressed Diffusion in One-Dimensional Guides.

Drift-diffusion dynamics is investigated in a one-dimensional (1D) exciton guide at room temperature. Spatial engineering of the exciton energy in a WSe2 monolayer is achieved using local strain to confine and direct exciton transport. An unexpected and massive deviation from the Einstein relation is observed and correlated to exciton capture by defects. We find that the capture reduces exciton temperature and diffusion so much that drift transport visibility improves to 38% as excitons traverse asymmetrically over regions with occupied defect states. Based on measurements over multiple potential gradients, we estimate the exciton mobility to be 169 ± 39 cm2/(eV s) at room temperature. Experiments at elevated exciton densities reveal that the exciton drift velocity monotonically increases with exciton density, unlike exciton mobility, due to contributions from nonequilibrium many-body effects.

Autophagy in peripheral blood mononuclear cells is associated with body fat percentage.

CONTEXT: Numerous chronic conditions including obesity exhibit autophagic dysfunction. Association of immune cell autophagic marker regulation by body fat percentage (%BF) is unknown. OBJECTIVE: Investigate autophagy activity in peripheral blood mononuclear cells (PBMCs) of adults with distinct %BFs and obesity-related circulating inflammatory markers. MATERIALS AND METHODS: Sixteen individuals (eight males) with %BF above (n = 8, 36.9 ± 3.6 years, 27.1 ± 8.1%BF) and below (n = 8, 37.1 ± 3.7 years, 13.3 ± 3.7%BF) their age- and sex-specific 50th percentile value based on the American College Sports Medicine guidelines participated. Body fat percentage was calculated from hydrostatic weighing. PBMCs were isolated from venous blood, and PBMC autophagic flux markers (LC3-I, LC3-II, and p62) were measured via Western blot. CRP, resistin, leptin, and adiponectin were measured via ELISA. RESULTS: LC3-II/LC3-I ratio correlated with %BF (r=-0.56, p=.023). Insulin (p=.05) and CRP (p=.018) were higher in high %BF participants. DISCUSSION AND CONCLUSIONS: Autophagic activity markers in PBMCs correlate with %BF, but are not different between %BF groups.

EP400NL is involved in PD-L1 gene activation by forming a transcriptional coactivator complex.

EP400 is an ATP-dependent chromatin remodelling enzyme that regulates DNA double-strand break repair and transcription, including cMyc-dependent gene expression. We previously showed that the N-terminal domain of EP400 increases the efficacy of chemotherapeutic drugs against cancer cells. As the EP400 N-terminal-Like (EP400NL) gene resides next to the EP400 gene locus, this prompted us to investigate whether EP400NL plays a similar role in transcriptional regulation to the full-length EP400 protein. We found that EP400NL forms a human NuA4-like chromatin remodelling complex that lacks both the TIP60 histone acetyltransferase and EP400 ATPase. However, this EP400NL complex displays H2A.Z deposition activity on a chromatin template comparable to the human NuA4 complex, suggesting another associated ATPase such as BRG1 or RuvBL1/RuvBL2 catalyses the reaction. We demonstrated that the transcriptional coactivator function of EP400NL is required for serum and IFNγ-induced PD-L1 gene activation. Furthermore, transcriptome analysis indicates that EP400NL contributes to cMyc-responsive mitochondrial biogenesis. Taken together, our studies show that EP400NL plays a role as a transcription coactivator of PD-L1 gene regulation and provides a potential target to modulate cMyc functions in cancer therapy.

Torsional periodic lattice distortions and diffraction of twisted 2D materials.

Twisted 2D materials form complex moiré structures that spontaneously reduce symmetry through picoscale deformation within a mesoscale lattice. We show twisted 2D materials contain a torsional displacement field comprised of three transverse periodic lattice distortions (PLD). The torsional PLD amplitude provides a single order parameter that concisely describes the structural complexity of twisted bilayer moirés. Moreover, the structure and amplitude of a torsional periodic lattice distortion is quantifiable using rudimentary electron diffraction methods sensitive to reciprocal space. In twisted bilayer graphene, the torsional PLD begins to form at angles below 3.89° and the amplitude reaches 8 pm around the magic angle of 1. 1°. At extremely low twist angles (e.g. below 0.25°) the amplitude increases and additional PLD harmonics arise to expand Bernal stacked domains separated by well defined solitonic boundaries. The torsional distortion field in twisted bilayer graphene is analytically described and has an upper bound of 22.6 pm. Similar torsional distortions are observed in twisted WS2, CrI3, and WSe2/MoSe2.

The effect of prolonged interval and continuous exercise in the heat on circulatory markers of intestinal barrier integrity.

PURPOSE: The purpose of this study was to determine the effect of prolonged high-intensity interval (INT) and moderate-intensity continuous (CONT) treadmill exercise in the heat on markers of enterocyte injury and bacterial endotoxin translocation. METHODS: Nine males completed 2 h of work-matched exercise in the heat (40 °C and 15% RH) as either INT (2 min at 80% VO2max and 3 min at 30% VO2max) or CONT (~ 50% of VO2max). Blood samples collected pre- and post-exercise were assayed for intestinal fatty acid-binding protein (I-FABP), claudin-3 (CLDN-3), and lipopolysaccharide-binding protein (LBP). RESULTS: I-FABP was significantly increased from pre- to post-exercise in CONT (913.96 ± 625.13 to 1477.26 ± 760.99 pg•mL-1; p = 0.014, d = 0.766) and INT (714.59 ± 470.27 to 1547.93 ± 760.99 pg•mL-1; p = 0.001, d = 1.160). Pre- to post-exercise changes in I-FABP were not different between CONT and INT (p = 0.088, d = 0.414). LBP was significantly increased from pre- to post-exercise in INT (15.94 ± 2.90 to 17.35 ± 3.26 µg•mL-1; p = 0.028, d = 0.459) but not CONT (18.11 ± 5.35 to 16.93 ± 5.39 µg•mL-1; p = 0.070, d = 0.226), and pre- to post-exercise changes in LBP were higher in the INT compared to CONT (p < 0.001, d = 1.160). No significant changes were detected from pre- to post-exercise for CLDN-3 in CONT (14.90 ± 2.21 to 15.30 ± 3.07 µg•mL-1) or INT (15.55 ± 1.63 to 16.41 ± 2.11 µg•mL-1) (p > 0.05). CONCLUSIONS: We conclude that prolonged exercise in the heat induces enterocyte injury, but interval (or intermittent) exercise may cause greater bacterial endotoxin translocation which may increase the risk for local and systemic inflammation.

The combined effects of exercise-induced muscle damage and heat stress on acute kidney stress and heat strain during subsequent endurance exercise.

PURPOSE: The purpose of the study was to investigate the combined effect of downhill running and heat stress on muscle damage, as well as on heat strain and kidney stress during subsequent running in the heat. METHODS: In a randomized cross-over study, ten non-heat-acclimated, physically active males completed downhill running in temperate (EIMD in Temp) and hot (EIMD in Hot) conditions followed by an exercise-heat stress (HS) test after 3-h seated rest. Blood and urine samples were collected immediately pre- and post-EIMD and HS, and 24 h post-EIMD (post-24 h). Core temperature and thermal sensation were measured to evaluate heat strain. Serum creatine kinase (CK), maximal voluntary isometric contraction of the quadriceps (MVC) and perceived muscle soreness were measured to evaluate muscle damage. Urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) levels were measured to indicate acute kidney stress. RESULTS: CK, MVC and perceived soreness were not different between conditions at any timepoints. In the EIMD in Hot condition, urinary NGAL was significantly elevated from pre- to post-HS (pre-HS: 6.56 {1.53-12.24} ng/min, post-HS: 13.72 {7.67-21.46} ng/min, p = 0.034). Such elevation of NGAL or KIM-1 was not found in the EIMD in Temp condition. CONCLUSIONS: As compared with downhill running in a temperate environment, downhill running in a hot environment does not appear to aggravate muscle damage. However, elevated NGAL levels following EIMD in a hot environment suggest such exercise may increase risk of mild acute kidney injury during subsequent endurance exercise in the heat.

Two-dimensional charge order stabilized in clean polytype heterostructures.

Compelling evidence suggests distinct correlated electron behavior may exist only in clean 2D materials such as 1T-TaS2. Unfortunately, experiment and theory suggest that extrinsic disorder in free standing 2D layers disrupts correlation-driven quantum behavior. Here we demonstrate a route to realizing fragile 2D quantum states through endotaxial polytype engineering of van der Waals materials. The true isolation of 2D charge density waves (CDWs) between metallic layers stabilizes commensurate long-range order and lifts the coupling between neighboring CDW layers to restore mirror symmetries via interlayer CDW twinning. The twinned-commensurate charge density wave (tC-CDW) reported herein has a single metal-insulator phase transition at ~350 K as measured structurally and electronically. Fast in-situ transmission electron microscopy and scanned nanobeam diffraction map the formation of tC-CDWs. This work introduces endotaxial polytype engineering of van der Waals materials to access latent 2D ground states distinct from conventional 2D fabrication.

Dielectric Engineering for Manipulating Exciton Transport in Semiconductor Monolayers.

The dielectric screening from the disordered media surrounding atomically thin transition metal dichalcogenides (TMDs) monolayers modifies the effective defect energy levels and thereby the transport and energy dynamics of excitons. In this work, we study this effect in WSe2 monolayers for different combinations of surrounding dielectric media. Specifically, we study the source of the anomalous diffusion of excitons in the WSe2 monolayer and attribute the anomaly to the modification of the energy distribution of defect states in different disordered dielectric environments. We use this insight to manipulate exciton transport by engineering the dielectric environment using a graphene/hexagonal boron nitride (h-BN) moiré superlattice. Finally, we observe that the effect of dielectric disorder is even more significant at high excitation fluences, contributing to the nonequilibrium phonon drag effect. These results provide an important step toward achieving control over the exciton energy transport for next-generation opto-excitonic devices.

Neutralizing Defect States in MoS2 Monolayers.

We report a method to neutralize the mid-gap defect states in MoS2 monolayers using laser soaking of an organic/transition metal oxide (TMO) blend thin film. The treated MoS2 monolayer shows negligible emission from defect states as compared to the as-exfoliated MoS2, accompanied by a photoluminescence quantum yield improvement from 0.018 to 4.5% at excitation power densities of 10 W/cm2. The effectiveness of the method toward defect neutralization is governed by the polaron pair generated at the organic/TMO interface, the diffusion of free electrons, and the subsequent formation of TMO radicals at the MoS2 monolayer. The treated monolayers are stable in air, vacuum, and acetone environments, potentially enabling the fabrication of defect-free optoelectronic devices based on 2D materials and 2D/organic heterojunctions.

Piezoelectric Modulation of Excitonic Properties in Monolayer WSe2 under Strong Dielectric Screening.

We investigate the interaction of excitons in monolayer WSe2 with the piezoelectric field of surface acoustic wave (SAW) at room temperature using photoluminescence (PL) spectroscopy and report a large in-plane exciton polarizability of 8.43 ± 0.18 × 10-6 Dm/V. Such large polarizability arises due to the strong dielectric screening from the piezoelectric substrate. In addition, we show that the exciton-piezoelectric field interaction and population distribution between neutral excitons and trions can be optically manipulated by controlling the field screening using photogenerated free carriers. Finally, we model the broadening of the exciton PL line width and report that the interaction is dominated by type-II band edge modulation, because of the in-plane electric field in the system. The results help understand the interaction of excitons in monolayer transition-metal dichalcogenides that will aid in controlled manipulation of excitonic properties for applications in sensing, detection, and on-chip communication.

Waveguiding properties of perylene microcrystals synthesized by retarding the growth along the π-stack direction.

Selective, hard to realize growth retardation of the π-stacking direction over the edge-packing direction has been achieved in perylene microcrystals using an aryl amphiphile. The perylene microcrystals grow predominantly along the edge-packing direction resulting in novel and hitherto unknown perylene square rods. The rods show exciton-polariton waveguiding along the rod axis even though it corresponds to pure edge-packing of the molecules, which is unprecedented in organic microcrystals.

The Potential Role of Exercise-Induced Muscle Damage in Exertional Heat Stroke.

Exertional heat stroke (EHS) is a life-threatening condition that affects mainly athletes, military personnel, firefighters, and occupational workers. EHS is frequently observed in non-compensable conditions (where the body is unable to maintain a steady thermal balance) as a result of heavy heat stress and muscle contraction associated with prolonged and strenuous physical and occupational activities, resulting in central nervous system dysfunction followed by multi-organ damage and failure. Since the pathophysiology of EHS is complex and involves multiple organs and systems, any condition that changes the interrelated systems may increase the risk for EHS. It has been suggested that exercise-induced muscle damage (EIMD) can lead to thermoregulatory impairment and systemic inflammation, which could be a potential predisposing factor for EHS. In this review article, we aim to (1) address the evidence of EIMD as a predisposing factor for EHS and (2) propose a possible mechanism of how performing muscle-damaging exercise in the heat may aggravate muscle damage and subsequent risk of EHS and acute kidney injury (AKI). Such an understanding could be meaningful to minimize the risks of EHS and AKI for individuals with muscle damage due to engaging in physical work in hot environments.

Interlayer Exciton Transport in MoSe2/WSe2 Heterostructures.

A moiré superlattice formed by stacking two lattice mismatched transition metal dichalcogenide monolayers, functions as a diffusion barrier that affects the energy transport and dynamics of interlayer excitons (electron and hole spatially concentrated in different monolayers). In this work, we experimentally quantify the diffusion barrier experienced by interlayer excitons in hexagonal boron nitride-encapsulated molybdenum diselenide/tungsten diselenide (MoSe2/WSe2) heterostructures with different twist angles. We observe the localization of interlayer excitons at low temperature and the temperature-activated diffusivity as a function of twist angle and hence attribute it to the deep periodic potentials arising from the moiré superlattice. We further support the observations with theoretical calculations, Monte Carlo simulations, and a three-level model that represents the exciton dynamics at various temperatures.

Energy Transport of Hybrid Charge-Transfer Excitons.

We investigate the energy transport in an organic-inorganic hybrid platform formed between semiconductors that support stable room-temperature excitons. We find that following photoexcitation, fast-moving hot hybrid charge-transfer excitons (HCTEs) are formed in about 36 ps via scattering with optical phonons at the interface between j-aggregates of organic dye and inorganic monolayer MoS2. Once the energy falls below the optical phonon energy, the excess kinetic energy is relaxed slowly via acoustic phonon scattering, resulting in energy transport that is dominated by fast-moving hot HCTEs that transition into cold HCTEs in about 110 ps. We model the exciton-phonon interactions using Fröhlich and deformation potential theory and attribute the prolonged transport of hot HCTEs to phonon bottleneck. We find that the measured diffusivity of HCTEs in both hot and cold regions of transport was higher than the diffusivity of MoS2 A exciton and verify these results by conducting the experiments with different excitation energies. This work not only provides significant insight into the initial energy transport of HCTEs at organic-inorganic hybrid interfaces but also contributes to the formulation of a complete physical picture of the energy dynamics in hybrid materials, which are poised to advance applications in energy conversion and optoelectronic devices.

Comparison of transperitoneal laparoscopic versus open adrenalectomy for large pheochromocytoma: A retrospective propensity score-matched cohort study.

BACKGROUND: Surgical resection is the main treatment strategy for pheochromocytoma. Whether laparoscopic techniques are feasible for large pheochromocytoma treatments is controversial. The aim of this study was to evaluate the feasibility and safety of transperitoneal laparoscopic adrenalectomy (LA) compared with open adrenalectomy (OA). METHODS: We retrospectively studied 182 patients with radiographic tumor sizes ≥ 6 cm who underwent adrenalectomy at our center between 1 January 2007 and 31 December 2017. After propensity score-matching to balance baseline variables, 82 patients treated with LA and 100 patients treated with OA were grouped into 64 pairs. Patient demographics, and extensive peri-operative and oncologic data were recorded and compared. RESULTS: In the matched group, the incidence of intra-operative hemodynamic instability, transfusion rate, prolonged hypotension, and cardiovascular morbidity in the LA group were lower than the OA group (25.0% vs. 48.4%, 29.7% vs. 46.9%, 4.7% vs. 23.4%, and 14.1% vs. 37.5%, respectively). The estimated blood loss was less (100 ml vs. 300 ml) and bowel recovery was quicker (1.9 d vs. 2.3 d) in the LA group. The proportion of patients in whom blood pressure returned to normal (P = 0.184), had recurrences (P = 0.197), and survived (P = 0.763) were equivalent. The surgical approach (OA vs. LA) was an independent risk factor for IHD, prolonged hypotension, cardiovascular morbidity, and longer bowel recovery. CONCLUSIONS: This propensity score-matched cohort study showed that LA was feasible, safe, and superior to OA for patients with large pheochromocytoma, meanwhile LA had comparable oncological outcomes compared with OA after a lengthy follow-up.

Risk factors for postoperative cardiovascular morbidity after pheochromocytoma surgery: a large single center retrospective analysis.

Surgical resection is the primary treatment strategy for pheochromocytoma; however, it carries a high risk of morbidity and mortality, especially with respect to cardiovascular complications, which is the most common kinds of morbidity. The risk factors for morbidity remain unclear and require further exploration, moreover no studies focus on risk factors for cardiovascular morbidity. Herein we identified the risk factors for cardiovascular morbidity after pheochromocytoma surgery in Chinese patients. We retrospectively reviewed 262 patients who underwent unilateral surgical resection of pheochromocytoma at our center between 1 January 2007 and 31 December 2016. Patient demographics and extensive perioperative data were recorded and evaluated. Adjusted odds ratios and 95% confidence intervals were determined by multivariate logistic regression. Cut-off values and the area under the curve for continuous risk factors were calculated based on receiver operating characteristic curve analysis. A p-value <0.05 was considered statistically significant. Of the 262 patients, 63 (24.0%) had cardiovascular morbidity. The independent risk factors for cardiovascular morbidity were low body mass index, large radiographic tumor size, coronary heart disease, no preoperative crystal/colloid administration, and intraoperative hemodynamic instability; the corresponding odds ratio were 0.762 (p < 0.001), 1.208 (p = 0.010), 2.378 (p = 0.012), 2.720 (p = 0.011), and 4.764 (p = 0.001), respectively. The optimal cut-off values for body mass index and radiographic tumor size were 24.59 kg/m2 and 6.05 cm. We found that cardiovascular morbidity is common in patients after pheochromocytoma surgery. We identified five independent risk factors for cardiovascular morbidity. Identification of these risk factors may help to improve treatment strategies.