A Transcriptomic Classifier Model Identifies High-Risk Endotypes in a Prospective Study of Sepsis in Uganda.

OBJECTIVES: In high-income countries (HICs), sepsis endotypes defined by distinct pathobiological mechanisms, mortality risks, and responses to corticosteroid treatment have been identified using blood transcriptomics. The generalizability of these endotypes to low-income and middle-income countries (LMICs), where the global sepsis burden is concentrated, is unknown. We sought to determine the prevalence, prognostic relevance, and immunopathological features of HIC-derived transcriptomic sepsis endotypes in sub-Saharan Africa. DESIGN: Prospective cohort study. SETTING: Public referral hospital in Uganda. PATIENTS: Adults ( n = 128) hospitalized with suspected sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Using whole-blood RNA sequencing data, we applied 19-gene and 7-gene classifiers derived and validated in HICs (SepstratifieR) to assign patients to one of three sepsis response signatures (SRS). The 19-gene classifier assigned 30 (23.4%), 92 (71.9%), and 6 (4.7%) patients to SRS-1, SRS-2, and SRS-3, respectively, the latter of which is designed to capture individuals transcriptionally closest to health. SRS-1 was defined biologically by proinflammatory innate immune activation and suppressed natural killer-cell, T-cell, and B-cell immunity, whereas SRS-2 was characterized by dampened innate immune activation, preserved lymphocyte immunity, and suppressed transcriptional responses to corticosteroids. Patients assigned to SRS-1 were predominantly (80.0% [24/30]) persons living with HIV with advanced immunosuppression and frequent tuberculosis. Mortality at 30-days differed significantly by endotype and was highest (48.1%) in SRS-1. Agreement between 19-gene and 7-gene SRS assignments was poor (Cohen's kappa 0.11). Patient stratification was suboptimal using the 7-gene classifier with 15.1% (8/53) of individuals assigned to SRS-3 deceased at 30-days. CONCLUSIONS: Sepsis endotypes derived in HICs share biological and clinical features with those identified in sub-Saharan Africa, with major differences in host-pathogen profiles. Our findings highlight the importance of context-specific sepsis endotyping, the generalizability of conserved biological signatures of critical illness across disparate settings, and opportunities to develop more pathobiologically informed sepsis treatment strategies in LMICs.

Maternal Mediterranean-Style Diet Adherence during Pregnancy and Metabolomic Signature in Postpartum Plasma: Findings from the Boston Birth Cohort.

BACKGROUND: The health benefits of a Mediterranean-style diet (MSD) are well observed, but the underlying mechanisms are unclear. Metabolomic profiling offers a systematic approach for identifying which metabolic biomarkers and pathways might be affected by an MSD. OBJECTIVES: This study aimed to identify postpartum plasma metabolites that are associated with MSD adherence during pregnancy and to further test whether these identified metabolites may vary by maternal characteristics. METHODS: We analyzed data from 1410 mothers enrolled in the Boston Birth Cohort (BBC). A maternal food frequency questionnaire (FFQ) was administered and epidemiologic information was obtained via an in-person standard questionnaire interview within 24-72 h postpartum. Maternal clinical information was extracted from electronic medical records. A Mediterranean-style diet score (MSDS) was calculated using responses to the FFQ. Metabolomic profiling in postpartum plasma was conducted by liquid chromatography-MS. Linear regression models were used to assess the associations of each metabolite with an MSDS, adjusting for covariates. RESULTS: Among the 380 postpartum plasma metabolites analyzed, 24 were associated with MSDS during pregnancy (false discovery rate < 0.05). Of 24 MSDS-associated metabolites, 19 were lipids [for example, triacylglycerols, phosphatidylcholines (PCs), PC plasmalogen, phosphatidylserine, and phosphatidylethanolamine]; others were amino acids (methionine sulfoxide and threonine), tropane (nor-psi-tropine), vitamin (vitamin A), and nucleotide (adenosine). The association of adenosine and methionine sulfoxide with MSDS differed by race (P-interaction = 0.033) and maternal overweight or obesity status (P-interaction = 0.021), respectively. CONCLUSIONS: In the BBC, we identified 24 postpartum plasma metabolites associated with MSDS during pregnancy. The associations of the 2 metabolites varied by maternal race and BMI. This study provides a new insight into dietary effects on health under the skin. More studies are needed to better understand the metabolic pathways underlying the short- and long-term health benefits of an MSD during pregnancy.

Metabolomic analysis of maternal mid-gestation plasma and cord blood in autism spectrum disorders.

The discovery of prenatal and neonatal molecular biomarkers has the potential to yield insights into autism spectrum disorder (ASD) and facilitate early diagnosis. We characterized metabolomic profiles in ASD using plasma samples collected in the Norwegian Autism Birth Cohort from mothers at weeks 17-21 gestation (maternal mid-gestation, MMG, n = 408) and from children on the day of birth (cord blood, CB, n = 418). We analyzed associations using sex-stratified adjusted logistic regression models with Bayesian analyses. Chemical enrichment analyses (ChemRICH) were performed to determine altered chemical clusters. We also employed machine learning algorithms to assess the utility of metabolomics as ASD biomarkers. We identified ASD associations with a variety of chemical compounds including arachidonic acid, glutamate, and glutamine, and metabolite clusters including hydroxy eicospentaenoic acids, phosphatidylcholines, and ceramides in MMG and CB plasma that are consistent with inflammation, disruption of membrane integrity, and impaired neurotransmission and neurotoxicity. Girls with ASD have disruption of ether/non-ether phospholipid balance in the MMG plasma that is similar to that found in other neurodevelopmental disorders. ASD boys in the CB analyses had the highest number of dysregulated chemical clusters. Machine learning classifiers distinguished ASD cases from controls with area under the receiver operating characteristic (AUROC) values ranging from 0.710 to 0.853. Predictive performance was better in CB analyses than in MMG. These findings may provide new insights into the sex-specific differences in ASD and have implications for discovery of biomarkers that may enable early detection and intervention.

A multicenter virome analysis of blood, feces, and saliva in myalgic encephalomyelitis/chronic fatigue syndrome.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is estimated to affect 0.4%-2.5% of the global population. Most cases are unexplained; however, some patients describe an antecedent viral infection or response to antiviral medications. We report here a multicenter study for the presence of viral nucleic acid in blood, feces, and saliva of patients with ME/CFS using polymerase chain reaction and high-throughput sequencing. We found no consistent group-specific differences other than a lower prevalence of anelloviruses in cases compared to healthy controls. Our findings suggest that future investigations into viral infections in ME/CFS should focus on adaptive immune responses rather than surveillance for viral gene products.

Maternal mid-gestational and child cord blood immune signatures are strongly associated with offspring risk of ASD.

Epidemiological studies and work in animal models indicate that immune activation may be a risk factor for autism spectrum disorders (ASDs). We measured levels of 60 cytokines and growth factors in 869 maternal mid-gestational (MMG) and 807 child cord blood (CB) plasma samples from 457 ASD (385 boys, 72 girls) and 497 control children (418 boys, 79 girls) from the Norwegian Autism Birth Cohort. We analyzed associations first using sex-stratified unadjusted and adjusted logistic regression models, and then employed machine learning strategies (LASSO + interactions, Random Forests, XGBoost classifiers) with cross-validation and randomly sampled test set evaluation to assess the utility of immune signatures as ASD biomarkers. We found prominent case-control differences in both boys and girls with alterations in a wide range of analytes in MMG and CB plasma including but not limited to IL1RA, TNFα, Serpin E1, VCAM1, VEGFD, EGF, CSF1, and CSF2. MMG findings were most striking, with particularly strong effect sizes in girls. Models did not change appreciably upon adjustment for maternal conditions, medication use, or emotional distress ratings. Findings were corroborated using machine learning approaches, with area under the receiver operating characteristic curve values in the test sets ranging from 0.771 to 0.965. Our results are consistent with gestational immunopathology in ASD, may provide insights into sex-specific differences, and have the potential to lead to biomarkers for early diagnosis.

Formation of pre-metastatic niches induced by tumor extracellular vesicles in lung metastasis.

There are a number of malignant tumors that metastasize into the lung as one of their most common sites of dissemination. The successful infiltration of tumor cells into distant organs is the result of the cooperation between tumor cells and distant host cells. When tumor cells have not yet reached distant organs, in situ tumor cells secrete extracellular vesicles (EVs) carrying important biological information. In recent years, scholars have found that tumor cells-derived EVs act as the bridge between orthotopic tumors and secondary metastases by promoting the formation of a pre-metastatic niche (PMN), which plays a key role in awakening dormant circulating tumor cells and promoting tumor cell colonization. This review provides an overview of multiple routes and mechanisms underlying PMN formation induced by EVs and summaries study findings that underline a potential role of EVs in the intervention of lung PMN, both as a target or a carrier for drug design. In this review, the underlying mechanisms of EVs in lung PMN formation are highlighted as well as potential applications to lung metastasis diagnosis and treatment.

Metabolomic Evidence for Peroxisomal Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease characterized by unexplained physical fatigue, cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems. People with ME/CFS often report a prodrome consistent with infections. Using regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of plasma from 106 ME/CFS cases and 91 frequency-matched healthy controls. Subjects in the ME/CFS group had significantly decreased levels of plasmalogens and phospholipid ethers (p < 0.001), phosphatidylcholines (p < 0.001) and sphingomyelins (p < 0.001), and elevated levels of dicarboxylic acids (p = 0.013). Using machine learning algorithms, we were able to differentiate ME/CFS or subgroups of ME/CFS from controls with area under the receiver operating characteristic curve (AUC) values up to 0.873. Our findings provide the first metabolomic evidence of peroxisomal dysfunction, and are consistent with dysregulation of lipid remodeling and the tricarboxylic acid cycle. These findings, if validated in other cohorts, could provide new insights into the pathogenesis of ME/CFS and highlight the potential use of the plasma metabolome as a source of biomarkers for the disease.

Perinatal exposure to BDE-47 exacerbated autistic-like behaviors and impairments of dendritic development in a valproic acid-induced rat model of autism.

Perinatal exposure to polybrominated diphenyl ethers (PBDEs) may be a potential risk factor for autism spectrum disorders (ASD). BDE-47 is one of the most common PBDEs and poses serious health hazards on the central nervous system (CNS). However, effects of perinatal exposure to BDE-47 on social behaviors and the potential mechanisms are largely unexplored. Thus, we aimed to investigate whether BDE-47 exposure during gestation and lactation led to autistic-like behaviors in offspring rats in the present study. Valproic acid (VPA), which is widely used to establish animal model of ASD, was also adopted to induce autistic-like behaviors. A battery of tests was conducted to evaluate social and repetitive behaviors in offspring rats. We found that perinatal exposure to BDE-47 caused mild autistic-like behaviors in offspring, which were similar but less severe to those observed in pups maternally exposed to VPA. Moreover, perinatal exposure to BDE-47 aggravated the autistic-like behaviors in pups maternally exposed to VPA. Abnormal dendritic development is known to be deeply associated with autistic-like behaviors. Golgi-Cox staining was used to observe the morphological characteristics of dendrites in the prefrontal cortex of pups. We found perinatal exposure to BDE-47 reduced dendritic length and complexity of branching pattern, and spine density in the offspring prefrontal cortex, which may contribute to autistic-like behaviors observed in the present study. Perinatal exposure to BDE-47 also exacerbated the impairments of dendritic development in pups maternally exposed to VPA. Besides, our study also provided the evidence that the inhibition of BDNF-CREB signaling, a key regulator of dendritic development, may be involved in the dendritic impairments induced by perinatal exposure to BDE-47 and/or VPA, and the consequent autistic-like behaviors.

Unidirectional Magneto-Resistance in Modulation-Doped Magnetic Topological Insulators.

Nonlinear unidirectional spin Hall magnetoresistance (USMR) has been reported in heavy metal/ferromagnet bilayers, which could be employed as an effective method in detecting the magnetization orientation in spintronic devices with two-terminal geometry. Recently, another unidirectional magnetoresistance (UMR) was reported in magnetic topological insulator (TI)-based heterostructures at cryogenic temperature, whose amplitude is orders of magnitude larger than the USMR measured in heavy metal-based magnetic heterostructures at room temperature. Here, we report the UMR effect in the modulation-doped magnetic TI structures. This UMR arises due to the interplay between the magnetic dopant's magnetization and the current-induced surface spin polarization, when they are parallel or antiparallel to each other in the TI material. By varying the dopant's position in the structure, we reveal that the UMR is mainly originating from the interaction between the magnetization and the surface spin-polarized carriers (not bulk carriers). Furthermore, from the magnetic field-, the angular rotation-, and the temperature-dependence, we highlight the correlation between the UMR effect and the magnetism in the structures. The large UMR versus current ratio in TI-based magnetic bilayers promises the easy readout in TI-based spintronic devices with two-terminal geometry.

Interfacial States and Fano-Feshbach Resonance in Graphene-Silicon Vertical Junction.

Interfacial quantum states are drawing tremendous attention recently because of their importance in design of low-dimensional quantum heterostructures with desired charge, spin, or topological properties. Although most studies of the interfacial exchange interactions were mainly performed across the interface vertically, the lateral transport nowadays is still a major experimental method to probe these interactions indirectly. In this Letter, we fabricated a graphene and hydrogen passivated silicon interface to study the interfacial exchange processes. For the first time we found and confirmed a novel interfacial quantum state, which is specific to the 2D-3D interface. The vertically propagating electrons from silicon to graphene result in electron oscillation states at the 2D-3D interface. A harmonic oscillator model is used to explain this interfacial state. In addition, the interaction between this interfacial state (discrete energy spectrum) and the lateral band structure of graphene (continuous energy spectrum) results in Fano-Feshbach resonance. Our results show that the conventional description of the interfacial interaction in low-dimensional systems is valid only in considering the lateral band structure and its density-of-states and is incomplete for the ease of vertical transport. Our experimental observation and theoretical explanation provide more insightful understanding of various interfacial effects in low-dimensional materials, such as proximity effect, quantum tunneling, etc. More important, the Fano-Feshbach resonance may be used to realize all solid-state and scalable quantum interferometers.

Discovery of two highly divergent negative-sense RNA viruses associated with the parasitic nematode, Capillaria hepatica, in wild Mus musculus from New York City.

Recent advances in high-throughput sequencing technology have led to a rapid expansion in the number of viral sequences associated with samples from vertebrates, invertebrates and environmental samples. Accurate host identification can be difficult in assays of complex samples that contain more than one potential host. Using unbiased metagenomic sequencing, we investigated wild house mice (Mus musculus) and brown rats (Rattus norvegicus) from New York City to determine the aetiology of liver disease. Light microscopy was used to characterize liver disease, and fluorescent microscopy with in situ hybridization was employed to identify viral cell tropism. Sequences representing two novel negative-sense RNA viruses were identified in homogenates of wild house mouse liver tissue: Amsterdam virus and Fulton virus. In situ hybridization localized viral RNA to Capillaria hepatica, a parasitic nematode that had infected the mouse liver. RNA from either virus was found within nematode adults and unembryonated eggs. Expanded PCR screening identified brown rats as a second rodent host for C. hepatica as well as both nematode-associated viruses. Our findings indicate that the current diversity of nematode-associated viruses may be underappreciated and that anatomical imaging offers an alternative to computational host assignment approaches.

Room-Temperature Spin-Orbit Torque from Topological Surface States.

Spin-momentum locked surface states in topological insulators (TIs) provide a promising route for achieving high spin-orbit torque (SOT) efficiency beyond the bulk spin-orbit coupling in heavy metals (HMs). However, in previous works, there is a huge discrepancy among the quantitative SOTs from TIs in various systems determined by different methods. Here, we systematically study the SOT in the TI(HM)/Ti/CoFeB/MgO systems by the same method, and make a conclusive assessment of SOT efficiency for TIs and HMs. Our results demonstrate that TIs show more than one order of magnitude higher SOT efficiency than HMs even at room temperature, at the same time the switching current density as low as 5.2×10^{5} A cm^{-2} is achieved with (Bi_{1-x}Sb_{x})_{2}Te_{3}. Furthermore, we investigate the relationship between SOT efficiency and the position of Fermi level in (Bi_{1-x}Sb_{x})_{2}Te_{3}, where the SOT efficiency is significantly enhanced near the Dirac point, with the most insulating bulk and conducting surface states, indicating the dominating SOT contribution from topological surface states. This work unambiguously demonstrates the ultrahigh SOT efficiency from topological surface states.

Tailoring exchange couplings in magnetic topological-insulator/antiferromagnet heterostructures.

Magnetic topological insulators such as Cr-doped (Bi,Sb)2Te3 provide a platform for the realization of versatile time-reversal symmetry-breaking physics. By constructing heterostructures exhibiting Néel order in an antiferromagnetic CrSb and ferromagnetic order in Cr-doped (Bi,Sb)2Te3, we realize emergent interfacial magnetic phenomena which can be tailored through artificial structural engineering. Through deliberate geometrical design of heterostructures and superlattices, we demonstrate the use of antiferromagnetic exchange coupling in manipulating the magnetic properties of magnetic topological insulators. Proximity effects are shown to induce an interfacial spin texture modulation and establish an effective long-range exchange coupling mediated by antiferromagnetism, which significantly enhances the magnetic ordering temperature in the superlattice. This work provides a new framework on integrating topological insulators with antiferromagnetic materials and unveils new avenues towards dissipationless topological antiferromagnetic spintronics.

Topological Transitions Induced by Antiferromagnetism in a Thin-Film Topological Insulator.

Magnetism in topological insulators (TIs) opens a topologically nontrivial exchange band gap, providing an exciting platform for manipulating the topological order through an external magnetic field. Here, we show that the surface of an antiferromagnetic thin film can magnetize the top and the bottom TI surface states through interfacial couplings. During the magnetization reversal, intermediate spin configurations are ascribed from unsynchronized magnetic switchings. This unsynchronized switching develops antisymmetric magnetoresistance spikes during magnetization reversals, which might originate from a series of topological transitions. With the high Néel ordering temperature provided by the antiferromagnetic layers, the signature of the induced topological transition persists up to ∼90 K.

Effects of Cd vacancies and unconventional spin dynamics in the Dirac semimetal Cd3As2.

Cd3As2 is a Dirac semimetal that is a 3D analog of graphene. We investigated the local structure and nuclear-spin dynamics in Cd3As2 via 113Cd NMR. The wideline spectrum of the static sample at 295 K is asymmetric and its features are well described by a two-site model with the shielding parameters extracted via Herzfeld-Berger analysis of the magic-angle spinning spectrum. Surprisingly, the 113Cd spin-lattice relaxation time (T1) is extremely long (T1 = 95 s at 295 K), in stark contrast to conductors and the effects of native defects upon semiconductors; but it is similar to that of 13C in graphene (T1 = 110 s). The temperature dependence of 1/T1 revealed a complex bipartite mechanism that included a T2 power-law behavior below 330 K and a thermally activated process above 330 K. In the high-temperature regime, the Arrhenius behavior is consistent with a field-dependent Cd atomic hopping relaxation process. At low temperatures, a T2 behavior consistent with a spin-1/2 Raman-like process provides evidence of a time-dependent spin-rotation magnetic field caused by angular oscillations of internuclear vectors due to lattice vibrations. The observed mechanism does not conform to the conventional two-band model of semimetals, but is instead closer to a mechanism observed in high-Z element ionic solids with large magnetorotation constant [A. J. Vega et al., Phys. Rev. B 74, 214420 (2006)].

Vitamin D and lung cancer risk: a comprehensive review and meta-analysis.

BACKGROUND/AIM: Vitamin D has been suggested to have important roles against cancer development. There were several published studies on the association between vitamin D and lung cancer risk, but not conclusive results were available. METHODS: To clarify the role of vitamin D in lung carcinogenesis, we performed a comprehensive review of the literature and a meta-analysis to evaluate the association of serum vitamin D levels and dietary vitamin D intake with lung cancer risk. Twelve studies (9 prospective cohort and 3 nested case-control studies) with a total of 288,778 individuals were included. The summary relative risk (RR) with 95% confidence interval (CI) was used to assess lung cancer risk. RESULTS: Meta-analysis of total 12 studies showed that RR for the association of high vitamin D status with lung cancer was 0.84 (95%CI 0.78-0.90, P < 0.001). The RR of lung cancer for the highest versus lowest quintile of serum vitamin D levels was 0.83 (95%CI 0.77-0.90, P < 0.001). The RR of lung cancer for the highest versus lowest quintile of vitamin D intake was 0.89 (95%CI 0.74-1.06, P = 0.184). CONCLUSION: Current data suggest an inverse association between serum vitamin D and lung cancer risk. Further studies are needed to investigate the effect of vitamin D intake on lung cancer risk and to evaluate whether vitamin D supplementation can prevent lung cancer.

MiR-183 promotes growth of non-small cell lung cancer cells through FoxO1 inhibition.

Non-small cell lung cancer (NSCLC) is a prevalent cancer in lung of high incidence. NSCLCs often appear to be fast growing, which renders comprehension of the mechanisms underlying the growth of NSCLC extremely critical. Previous study has addressed a role of microRNA (miR) family member, miR-183, in the regulation of the invasiveness of NSCLC, whereas the role of miR-183 in the growth control of NSCLC is not clear. Here, we analyzed the regulation of FoxO1 by miR-183 in vitro using luciferase-reporter assay. We also analyzed the effects of miR-183 on NSCLC cell growth in vitro using a microculture tetrazolium (MTT) assay and in vivo by visualizing tumor growth using bioluminescence assay. We found that overexpression of miR-183 in NSCLC cells decreased FoxO1 protein levels, whereas inhibition of miR-183 increased FoxO1 protein levels without affecting FoxO1 transcripts. Moreover, miR-183 bound to FoxO1 mRNA to prevent its translation through its 3'untranslated region (UTR). Furthermore, administration of miR-183 suppressed FoxO1 levels in NSCLC, resulting in a significant increase in NSCLC growth in vitro and in vivo, while administration of antisense of miR-183 significantly increased FoxO1 levels in NSCLC resulting in a significant decrease in NSCLC growth. Taken together, our data demonstrate that miR-183/FoxO1 axis may be a novel therapeutic target for regulating the growth of NSCLC.

Distribution and correlates of plasma folate, vitamin B12, and homocysteine in a sample of low-income minority children aged 6 months to 9 years in the U.S.

Background: Precision nutrition emphasizes tailoring dietary requirements across populations and life stages. Optimal folate and vitamin B12 levels are important for normal growth and development, but data are lacking for low-income minority U.S. children during early life periods. This study aimed to describe folate, vitamin B12, homocysteine (Hcy) levels, and influencing factors to address the gaps. Methods: Blood samples from children aged 6 months to 9 years and mothers 48-72 hours postpartum in the Boston Birth Cohort (BBC) were tested for folate, vitamin B12, and Hcy. Maternal and child characteristics, sociodemographic factors, and feeding status were obtained from a standard maternal questionnaire interview at the enrollment and follow-up, and medical records. The distribution of children's folate, vitamin B12, and Hcy were described and factors influencing these biomarkers were analyzed. Results: A wide distribution of folate, vitamin B12, and Hcy levels was observed in this sample, with longitudinal trends consistent with National Health and Nutrition Examination Survey (NHANES) data. Multivariate analysis showed that very preterm birth correlated with higher folate levels (adjusted ß 4.236; 95% CI: 1.218, 7.253; p=0.006). Children aged 1-2 years and 3-8 years had lower folate levels compared to those <1 year (adjusted ß -10.191 and -7.499 respectively; p<0.001). Vitamin B12 levels were higher in Black children (adjusted fold change 1.139; 95% CI: 1.052, 1.233; p=0.001) and those children whose mothers' B12 levels were at the highest quartile (Q4) (adjusted fold change 1.229; 95% CI: 1.094, 1.380; p=0.001). Delayed solid food introduction (> 6 months) correlated with lower children's B12 levels (adjusted fold change 0.888; 95% CI: 0.809, 0.975; p=0.013). Hcy levels were lower in Black children (adjusted fold change 0.962; 95% CI: 0.932, 0.993; p=0.018), higher in children with maternal Hcy levels in Q4 (adjusted fold change 1.081; 95% CI: 1.03, 1.135; p=0.002) and in children aged 3-8 years (adjusted fold change 1.084; 95% CI: 1.040, 1.131; p< 0.001). Conclusions: This study revealed wide variations in plasma folate, vitamin B12, and Hcy levels among low-income minority U.S. children and identified race, maternal levels, child's age, prematurity, and timing of solid food introduction as significant correlates.

The effect of floating spline parameter on the dynamic characteristic of encased differential planetary gear train.

The load sharing performance of encased differential planetary system has a great impact on the operating performance and service life of the transmission system of the coaxial high speed helicopter. In order to improve the load-sharing performance of the gear pair, the influence of different floating spline structural parameters on the load sharing characteristics of the system was studied. Considering the manufacturing error, installation error, time varying meshing stiffness and other factors, the Lagrange equation is used to construct the dynamic model of encased differential planetary gear train with floating spline structure. The effects of input torque, spline clearance, spline shaft stiffness and spline friction coefficient on the load sharing performance of gear pairs were analyzed. The results show that the differential stage system has a better load sharing performance than the encased stage system. The increase of input torque helps to improve the load sharing performance of the system, and the improvement of the encased stage system is more obvious. The floating spline of sun gear of the encased stage has a greater impact on the load sharing performance of the system. Furthermore, increasing the floating spline clearance, reducing spline shaft stiffness or increasing the friction coefficient of the spline can improve the load sharing performance of the system overall.

Tanshinone IIA normalized hepatocellular carcinoma vessels and enhanced PD-1 inhibitor efficacy by inhibiting ELTD1.

BACKGROUND: Hepatocellular carcinoma responds poorly to immune checkpoint inhibitors, such as PD-1 inhibitors, primarily due to the low infiltration capacity of TILs in the TME. Abnormal vasculature is an important factor which limiting the infiltration of TILs. According to recent research, targeting ELTD1 expression may improve TILs delivery to reverse immunosuppression and boost tumor responses to immunotherapy. Research has demonstrated that Tanshinone IIA (TSA) improves blood vessel normalization, but the precise mechanism is yet unknown. PURPOSE: The purpose of this study is to investigate the molecular processes for TSA's pro-vascular normalization of HCC in vitro and in vivo. METHODS: We established a mouse H22-luc in situ liver tumor model to evaluate the role of TSA vascular normalization and the immunosuppressive microenvironment. The role of ELTD1 in vascular and immune crosstalk was evaluated by bioinformatic analysis of the TCGA database. By creating a transwell co-culture cell model, the effects of TSA on enhancing tumor endothelial cell activities and ELTD1 intervention were evaluated. RESULTS: We investigated the effect of Tanshinone IIA (TSA), a major component of Salvia miltiorrhiza Bge., on the normalization of vasculature in situ HCC models. Our results demonstrated that TSA elicited vascular normalization in a hepatocellular carcinoma model in situ. In addition, the combination of TSA with anti-PD-1 significantly inhibited tumor development due to increased infiltration of immune cells in the tumor. Mechanistically, we demonstrated that TSA improved the immunosuppressive microenvironment by inhibiting tumor growth by suppressing ELTD1 expression, inhibiting downstream JAK1 and JAK2, promoting the expression of ZO-1, occlaudin, Claudin 5, and Col IV, and promoting vascular integrity and perfusion in situ. CONCLUSIONS: This study reveals a new mechanism between TSA and ELTD1 for vascular normalization, suggesting that therapeutic or pharmacological intervention with ELTD1 may enhance the efficacy of PD-1 inhibitors in HCC.