Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases.

Visceral leishmaniasis is responsible for up to 30,000 deaths every year. Current treatments have shortcomings that include toxicity and variable efficacy across endemic regions. Previously, we reported the discovery of GNF6702, a selective inhibitor of the kinetoplastid proteasome, which cleared parasites in murine models of leishmaniasis, Chagas disease, and human African trypanosomiasis.

Pancreatic circulating tumor cell profiling identifies LIN28B as a metastasis driver and drug target.

Pancreatic ductal adenocarcinoma (PDAC) lethality is due to metastatic dissemination. Characterization of rare, heterogeneous circulating tumor cells (CTCs) can provide insight into metastasis and guide development of novel therapies. Using the CTC-iChip to purify CTCs from PDAC patients for RNA-seq characterization, we identify three major correlated gene sets, with stemness genes LIN28B/KLF4, WNT5A, and LGALS3 enriched in each correlated gene set; only LIN28B CTC expression was prognostic.

[Correlations of Methylenetetrahydrofolate Reductase Gene Polymorphism and Genomic DNA Hypomethylation Level with Ankylosing Spondylitis].

To investigate the relationship of both DNA methylation level and methylenetrahydrofolate reductase(MTHFR)gene polymorphism with ankylosing spondylitis(AS). Totally 200 Chinese AS patients with HLA-B27(+)and 120 healthy controls were included from Hunan Province.All the cases were diagnosed according to the 1984 modified New York criteria for AS.

SNP rs2043211 (p.C10X) in CARD8 Is Associated with Large-Artery Atherosclerosis Stroke in a Chinese Population.

SNP rs2043211 in CARD8 was found to have significant association with ischemic stroke. This study aimed to explore the possible association between rs2043211 and large-artery atherosclerosis stroke in Chinese and explain the possible mechanism. In total, 716 large-artery atherosclerosis stroke patients and 1088 controls were included in the study.

Molecular Stressors Engender Protein Connectivity Dysfunction through Aberrant N-Glycosylation of a Chaperone.

Stresses associated with disease may pathologically remodel the proteome by both increasing interaction strength and altering interaction partners, resulting in proteome-wide connectivity dysfunctions. Chaperones play an important role in these alterations, but how these changes are executed remains largely unknown. Our study unveils a specific N-glycosylation pattern used by a chaperone, Glucose-regulated protein 94 (GRP94), to alter its conformational fitness and stabilize a state most permissive for stable interactions with proteins at the plasma membrane.

The association of inflammasome and TLR2 gene polymorphisms with susceptibility to tuberculosis in the Han Taiwanese population.

Pulmonary tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a global public health concern. Although inflammasome and the toll-like receptor 2 (TLR2) genes play an important role in host defense against Mtb, the associations of polymorphisms in these genes with TB risk are incompletely understood. A total of 230 TB patients and 213 individuals without TB were enrolled in this study.

Critical Role of Intestinal Microbiota in ATF3-Mediated Gut Immune Homeostasis.

Secretory Ig A (sIgA) plays an important role in the maintenance of intestinal homeostasis via cross-talk with gut microbiota. The defects in sIgA production could elicit dysbiosis of commensal microbiota and subsequently facilitate the development of inflammatory bowel disease. Our previous study revealed activating transcription factor 3 (ATF3) as an important regulator of follicular helper T (T) cells in gut.

Whole Blood DNA Methylation Signatures of Diet Are Associated With Cardiovascular Disease Risk Factors and All-Cause Mortality.

Background: DNA methylation patterns associated with habitual diet have not been well studied.

Methods: Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides) in 5 population-based cohorts including 6662 European ancestry, 2702 African ancestry, and 360 Hispanic ancestry participants.

RNA binding protein PCBP1 is an intracellular immune checkpoint for shaping T cell responses in cancer immunity.

Distinct lineages of T cells can act in response to various environmental cues to either drive or restrict immune-mediated pathology. Here, we identify the RNA binding protein, poly(C)-binding protein 1 (PCBP1) as an intracellular immune checkpoint that is up-regulated in activated T cells to prevent conversion of effector T (T) cells into regulatory T (T) cells, by restricting the expression of T cell-intrinsic T commitment programs. This was critical for stabilizing T cell functions and subverting immune-suppressive signals.

The polymorphism of rs11614913 T/T in pri- alters the miRNA expression and associates with recurrent spontaneous abortion in a Han-Chinese population.

Rs11614913 in pri- is involved in the occurrence of many diseases, especially in cancers. However, it remains unknown whether is associated with human recurrent spontaneous abortion (RSA) in Chinese Han population. Our study found that rs11614913 T/T in pri- was associated with the increase risk of human unexplained RSA (URSA) in recessive mode in Chinese Han population.

Pharmacological inhibition of P2RX7 ameliorates liver injury by reducing inflammation and fibrosis.

Extracellular adenosine triphosphate (eATP) released by damaged cells, and its purinergic receptors, comprise a crucial signaling network after injury. Purinergic receptor P2X7 (P2RX7), a major driver of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and IL-1β processing, has been shown to play a role in liver injury in murine diet- and chemically-induced liver injury models. It is unclear, however, whether P2RX7 plays a role in non-alcoholic steatohepatitis (NASH) and which cell type is the main target of P2RX7 pharmacological inhibition.

Validation and Disease Risk Assessment of Previously Reported Genome-Wide Genetic Variants Associated With Brugada Syndrome: SADS-TW BrS Registry.

Background: Brugada syndrome (BrS) is an oligogenic arrhythmic disease with increased risk of sudden cardiac arrest. Several BrS or ECG traits-related single-nucleotide polymorphisms (SNPs) were identified through previous genome-wide association studies in white patients. We aimed to validate these SNPs in BrS patients in the Taiwanese population, assessing the cumulative effect of risk alleles and the BrS-polygenic risk score in predicting cardiac events.

The p53 effector Perp mediates the persistence of CD4 effector memory T-cell undergoing lymphopenia-induced proliferation.

Under lymphopenic conditions, the rapid spontaneous proliferation produces cells that robustly differentiate into effector memory T (T) cells, and the aberrant expansion is preferentially driven by self-antigens. The pool size of effector memory T-cell is governed by a complex homeostatic balance between proliferation and death. Perp is a critical effector involved in the p53-dependent apoptotic pathway and widely expressed in mammalian tissues.

Extracellular Vesicle-Mediated Delivery of Circular RNA SCMH1 Promotes Functional Recovery in Rodent and Nonhuman Primate Ischemic Stroke Models.

Background: Stroke is a leading cause of adult disability that can severely compromise the quality of life of patients, yet no effective medication currently exists to accelerate rehabilitation. A variety of circular RNA (circRNA) molecules are known to function in ischemic brain injury. Lentivirus-based expression systems have been widely used in basic studies of circRNAs, but safety issues with such delivery systems have limited exploration of the potential therapeutic roles for circRNAs.

Photodecomposition of ibuprofen over g-CN/BiWO/rGO heterostructured composites under visible/solar light.

A microwave-assisted hydrothermal preparation of heterostructured graphitic carbon nitride/bismuth tungsten oxide/reduced graphene oxide nanocomposites (denoted as GBR-T, T = microwave irradiation time) is performed. The prepared GBR-T photocatalysts are identified by employing X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), time-resolved photoluminescence (TRPL) and nitrogen adsorption-desorption isotherms. The photocatalytic performance of these GBR-T is evaluated by the photocatalytic degradation of ibuprofen (IBP) under the visible light (λ > 420 nm) and solar light irradiation.

Perivascular Lymphocyte Clusters Induced by Gastric Subserous Layer Vaccination Mediate Optimal Immunity against Helicobacter through Facilitating Immune Cell Infiltration and Local Antibody Response.

Background: vaccination-induced local inflammatory response resulted in the establishment of a pool of tissue-resident memory T (T) cells and new vessels after the resolution of inflammation. T cells have received increasing attention; however, the role of new vessels in protective response is still unknown.

Materials And Methods: We performed the laparotomy to access the stomach and injected alum-based vaccine into the gastric subserous layer (GSL).

The Effects of Glaucoma on the Pressure-Induced Strain Response of the Human Lamina Cribrosa.

Purpose: To measure the ex vivo pressure-induced strain response of the human optic nerve head and analyze for variations with glaucoma diagnosis and optic nerve axon damage.

Methods: The posterior sclera of 16 eyes from 8 diagnosed glaucoma donors and 10 eyes from 6 donors with no history of glaucoma were inflation tested between 5 and 45 mm Hg. The optic nerve from each donor was examined for degree of axon loss.

Tissue-resident CD8 T memory cells with unique properties are present in human decidua during early pregnancy.

Problem: Resident memory T (T ) cells reside in the uterus during pregnancy may play an important role in balancing maternal-fetal tolerance with anti-infectious immunity. Although CD8 T and decidual CD8 T cells have been extensively characterized, the properties of decidual CD8 T (dT ) cells remain poorly defined.

Method Of Study: We investigated the heterogeneity, phenotypes, and functions of dT cells, and compared the proportion of dT cells between normal pregnancy and recurrent spontaneous abortion (RSA) using flow cytometry.

IFITM3 affects the level of antibody response after influenza vaccination.

Interferon-induced transmembrane protein 3 (IFITM3) as an antiviral factor can inhibit replication of several viruses including influenza virus. A single-nucleotide polymorphism rs12252-C of results in a truncated IFITM3 protein lacking its first 21 amino acids, which is much higher in the Han Chinese population and associated with severe illness in adults infected with pandemic influenza H1N1/09 virus. To investigate if IFITM3 or rs12252-C could affect the antibody response after influenza vaccination, we detected the haemagglutination inhibition (HI) of 171 healthy young adult volunteers ( rs12252-C/C, C/T, T/T carriers) and in an IFITM3-deletion mouse model () after trivalent inactivated vaccine (TIV) immunization.

Construction of collagen gel with high viscoelasticity and thermal stability via combining cross-linking and dehydration.

Collagen gel is widely used in tissue engineering due to excellent biological properties and swollen three-dimensional network structure. To improve viscoelasticity and thermal stability, collagen gels consisting of fibrils were cross-linked with glutaraldehyde and sequentially dehydrated via ethanol or heating (named as EGC or HGC, respectively). For EGC, ethanol replaced free and loosely bound water and then combined with tightly bound water, inducing the increase in hydrogen bonds and molecular interactions.

Artificial Intelligence to Detect Papilledema from Ocular Fundus Photographs.

Background: Nonophthalmologist physicians do not confidently perform direct ophthalmoscopy. The use of artificial intelligence to detect papilledema and other optic-disk abnormalities from fundus photographs has not been well studied.

Methods: We trained, validated, and externally tested a deep-learning system to classify optic disks as being normal or having papilledema or other abnormalities from 15,846 retrospectively collected ocular fundus photographs that had been obtained with pharmacologic pupillary dilation and various digital cameras in persons from multiple ethnic populations.

Genotypes and Haplotypes in the Cholesterol-Related Pathway Genes Predict Non-Small Cell Lung Cancer Survival.

Background: Several oncogenic signals are involved in the synthesis, metabolism, transportation, and modulation of cholesterol. However, the roles of genetic variants of the cholesterol pathway genes in cancer survival remain unclear.

Methods: We investigated associations between 26,781 common SNPs in 209 genes of the cholesterol pathway and non-small cell lung cancer (NSCLC) survival by utilizing genotyping data from two published genome-wide association studies.

SNP rs17079281 decreases lung cancer risk through creating an YY1-binding site to suppress DCBLD1 expression.

Genome-wide association studies (GWAS) have identified numerous genetic variants that are associated with lung cancer risk, but the biological mechanisms underlying these associations remain largely unknown. Here we investigated the functional relevance of a genetic region in 6q22.2 which was identified to be associated with lung cancer risk in our previous GWAS.

Mutational and transcriptomic landscapes of a rare human prostate basal cell carcinoma.

Background: As a rare subtype of prostate carcinoma, basal cell carcinoma (BCC) has not been studied extensively and thus lacks systematic molecular characterization.

Methods: Here, we applied single-cell genomic amplification and RNA-Seq to a specimen of human prostate BCC (CK34βE12 /P63 /PAP /PSA ). The mutational landscape was obtained via whole exome sequencing of the amplification mixture of 49 single cells, and the transcriptomes of 69 single cells were also obtained.

Vectorial effect on the evolution of fractional-order vector vortex beams in a strongly nonlocal nonlinear medium.

Propagation of a vector vortex optical field (VVOF) with both fractional order of polarization topological charge $m$m and fractional order of vortex topological charge $n$n with spatially variant states of polarization (SoP) in a strongly nonlocal nonlinear medium (SNNM) is studied. The optical field always evolves reciprocally with a cycle of stretch and shrink in a SNNM with dark stripes forming at $z=t\pi {z_p}$z=tπz ($t$t denotes an integer number, and ${{z}_p}$z is a parameter that depends on the initial power of the VVOF and the material constant associated with the response function), as a result from the coherent superposition of the vortices with different order of topological charges and weighting coefficients. In particular, the conversions between linear and circular polarization components occur during propagation, and the converted SoP distributions in different propagation distances depend closely on the topological charges and the initial powers.