Miracle-dz/UniFAR-FTUs huggingface dataset:
Structural hierarchy controlling dimerization and target DNA recognition in the AHR transcriptional complex

Significance The aryl hydrocarbon receptor (AHR) is unique among PAS family transcription factors in its diverse environmental and cellular ligands and broad array of biological endpoints. AHR dimerizes with AHR nuclear translocator (ARNT) and subsequently interacts with genomic enhancers, dioxin response elements (DREs). Our crystal structure of the AHR–ARNT heterodimer in complex with DRE provides structural insights into this transcriptional complex. Our studies reveal three-dimensional structural codes for specific engagement of DRE that discriminates it from the closely related hypoxia response elements; the highly intertwined dimerization and interdomain interfaces remotely control DRE-binding and ligand-induced exposure of nuclear localization signal. The structural similarity and ramifications of the AHR, HIF, and NPAS transcriptional complexes with ARNT provide general and unique insights into PAS family transcription factors and complex AHR signaling. The aryl hydrocarbon receptor (AHR) belongs to the PAS (PER-ARNT-SIM) family transcription factors and mediates broad responses to numerous environmental pollutants and cellular metabolites, modulating diverse biological processes from adaptive metabolism, acute toxicity, to normal physiology of vascular and immune systems. The AHR forms a transcriptionally active heterodimer with ARNT (AHR nuclear translocator), which recognizes the dioxin response element (DRE) in the promoter of downstream genes. We determined the crystal structure of the mammalian AHR–ARNT heterodimer in complex with the DRE, in which ARNT curls around AHR into a highly intertwined asymmetric architecture, with extensive heterodimerization interfaces and AHR interdomain interactions. Specific recognition of the DRE is determined locally by the DNA-binding residues, which discriminates it from the closely related hypoxia response element (HRE), and is globally affected by the dimerization interfaces and interdomain interactions. Changes at the interdomain interactions caused either AHR constitutive nuclear localization or failure to translocate to nucleus, underlying an allosteric structural pathway for mediating ligand-induced exposure of nuclear localization signal. These observations, together with the global higher flexibility of the AHR PAS-A and its loosely packed structural elements, suggest a dynamic structural hierarchy for complex scenarios of AHR activation induced by its diverse ligands.
d-Amino Acids Do Not Inhibit Biofilm Formation in Staphylococcus aureus

Bacteria can either exist in the planktonic (free floating) state or in the biofilm (encased within an organic framework) state. Bacteria biofilms cause industrial concerns and medical complications and there has been a great deal of interest in the discovery of small molecule agents that can inhibit the formation of biofilms or disperse existing structures. Herein we show that, contrary to previously published reports, d-amino acids do not inhibit biofilm formation of Bacillus subtilis (B. subtilis), Staphylococcus aureus (S. aureus), and Staphylococcus epidermis (S. epidermis) at millimolar concentrations. We evaluated a diverse set of natural and unnatural d-amino acids and observed no activity from these compounds in inhibiting biofilm formation.
P300 Event-Related Potential as an Indicator of Inattentional Deafness?

An analysis of airplane accidents reveals that pilots sometimes purely fail to react to critical auditory alerts. This inability of an auditory stimulus to reach consciousness has been coined under the term of inattentional deafness. Recent data from literature tends to show that tasks involving high cognitive load consume most of the attentional capacities, leaving little or none remaining for processing any unexpected information. In addition, there is a growing body of evidence for a shared attentional capacity between vision and hearing. In this context, the abundant information in modern cockpits is likely to produce inattentional deafness. We investigated this hypothesis by combining electroencephalographic (EEG) measurements with an ecological aviation task performed under contextual variation of the cognitive load (high or low), including an alarm detection task. Two different audio tones were played: standard tones and deviant tones. Participants were instructed to ignore standard tones and to report deviant tones using a response pad. More than 31% of the deviant tones were not detected in the high load condition. Analysis of the EEG measurements showed a drastic diminution of the auditory P300 amplitude concomitant with this behavioral effect, whereas the N100 component was not affected. We suggest that these behavioral and electrophysiological results provide new insights on explaining the trend of pilots’ failure to react to critical auditory information. Relevant applications concern prevention of alarms omission, mental workload measurements and enhanced warning designs.
Detection of cytomegalovirus by immunohistochemistry of colonic biopsies and quantitative blood polymerase chain reaction: evaluation of agreement in ulcerative colitis

Abstract Objectives: Cytomegalovirus (CMV) often reactivates in ulcerative colitis (UC). In diagnostics, along with immunohistochemistry (IHC) of colonic biopsies, blood CMV polymerase chain reaction (PCR) is gaining increasing application. We aimed to assess agreement between the density of infected colonic cells by IHC and the viral load in the blood by PCR. Material and methods: We retrospectively identified patients with active UC or indeterminate colitis in whom blood CMV PCR had been performed while biopsies had been taken simultaneously. The latter were re-evaluated and the numbers of IHC–positive cells per square millimetre counted. Results: The analyses extended to 234 sample pairs, among which there were 184 cases (78.6% of the total) in which IHC was equal to 0. The median among the remaining 50 non-zero values for IHC was 1.7 cells/mm2. PCR was equal to 0 in 192 cases (82.1%), while the median among the remaining 42 non-zero values was 4995.3 IU/ml. The Spearman correlation coefficient was 0.43 (p < .001). The area under the curve (AUC) values did not differ significantly between different IHC cut-offs. The highest AUC of 0.753 was obtained while predicting if IHC would be above the 3rd quartile (>5.6 cells/mm2), where PCR > 0 had a sensitivity of 0.615 and a specificity of 0.846. Conclusions: In active CMV colitis, the specificity and negative predictive value of blood PCR are high, while the sensitivity grows with the intensity of colon infection. A highly positive result could justify the administration of antiviral treatment being brought forward in selected patients.
Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56bright NKG2A+++ Cells, and Yet Display Increased Degranulation and Higher Perforin Content

Mutations of the recombinase-activating genes 1 and 2 (RAG1 and RAG2) in humans are associated with a broad range of phenotypes. For patients with severe clinical presentation, hematopoietic stem cell transplantation (HSCT) represents the only curative treatment; however, high rates of graft failure and incomplete immune reconstitution have been observed, especially after unconditioned haploidentical transplantation. Studies in mice have shown that Rag−/− natural killer (NK) cells have a mature phenotype, reduced fitness, and increased cytotoxicity. We aimed to analyze NK cell phenotype and function in patients with mutations in RAG and in non-homologous end joining (NHEJ) genes. Here, we provide evidence that NK cells from these patients have an immature phenotype, with significant expansion of CD56bright CD16−/int CD57− cells, yet increased degranulation and high perforin content. Correlation was observed between in vitro recombinase activity of the mutant proteins, NK cell abnormalities, and in vivo clinical phenotype. Addition of serotherapy in the conditioning regimen, with the aim of depleting the autologous NK cell compartment, may be important to facilitate engraftment and immune reconstitution in patients with RAG and NHEJ defects treated by HSCT.
Meat, fish, and colorectal cancer risk: the European Prospective Investigation into cancer and nutrition.

BACKGROUND Current evidence suggests that high red meat intake is associated with increased colorectal cancer risk. High fish intake may be associated with a decreased risk, but the existing evidence is less convincing. METHODS We prospectively followed 478 040 men and women from 10 European countries who were free of cancer at enrollment between 1992 and 1998. Information on diet and lifestyle was collected at baseline. After a mean follow-up of 4.8 years, 1329 incident colorectal cancers were documented. We examined the relationship between intakes of red and processed meat, poultry, and fish and colorectal cancer risk using a proportional hazards model adjusted for age, sex, energy (nonfat and fat sources), height, weight, work-related physical activity, smoking status, dietary fiber and folate, and alcohol consumption, stratified by center. A calibration substudy based on 36 994 subjects was used to correct hazard ratios (HRs) and 95% confidence intervals (CIs) for diet measurement errors. All statistical tests were two-sided. RESULTS Colorectal cancer risk was positively associated with intake of red and processed meat (highest [>160 g/day] versus lowest [<20 g/day] intake, HR = 1.35, 95% CI = 0.96 to 1.88; Ptrend = .03) and inversely associated with intake of fish (>80 g/day versus <10 g/day, HR = 0.69, 95 % CI = 0.54 to 0.88; Ptrend<.001), but was not related to poultry intake. Correcting for measurement error strengthened the associations between colorectal cancer and red and processed meat intake (per 100-g increase HR = 1.25, 95% CI =1.09 to 1.41, Ptrend = .001 and HR = 1.55, 95% CI = 1.19 to 2.02, Ptrend = .001 before and after calibration, respectively) and for fish (per 100 g increase HR = 0.70, 95% CI = 0.57 to 0.87, Ptrend<.001 and HR = 0.46, 95% CI = 0.27 to 0.77, Ptrend = .003; before and after correction, respectively). In this study population, the absolute risk of development of colorectal cancer within 10 years for a study subject aged 50 years was 1.71% for the highest category of red and processed meat intake and 1.28% for the lowest category of intake and was 1.86% for subjects in the lowest category of fish intake and 1.28% for subjects in the highest category of fish intake. CONCLUSIONS Our data confirm that colorectal cancer risk is positively associated with high consumption of red and processed meat and support an inverse association with fish intake.
IFN‐γ knockout mice show Th2‐associated delayed‐type hypersensitivity and the inflammatory cells fail to localize and control chlamydial infection

Delayed‐type hypersensitivity (DTH) has been demonstrated to be a Th1 type immune response which is important in the host defense against infection with intracellular bacteria, including Chlamydia. In the present study, we surprisingly observed that C. trachomatis mouse pneumonitis MoPn‐infected IFN‐γ gene knockout (KO) mice mounted strong DTH responses following foopad challenge with inactivated organisms. The DTH responses in IFN‐γ KO mice were associated with Th2 cytokine production and partially blocked by anti‐IL‐4 monoclonal antibodies. In addition, the inflammatory cells in IFN‐γ KO mice failed to target the cellular sites of chlamydial inclusions in infected tissues and failed to clear the infection. The data, in conjunction with previous studies, suggest that different types (Th1 and Th2 associated) of DTH responses may function differently in host defense against chlamydial infection and that the functional differences in DTH responses may account for the dual role that DTH is speculated to play in chlamydial protective immunity and immunopathology. Moreover, the data suggest that the IFN‐γ KO mouse is a useful model system for studying chlamydial pathogenesis.
Novel Mitochondria-Targeted Heat-Soluble Proteins Identified in the Anhydrobiotic Tardigrade Improve Osmotic Tolerance of Human Cells

Tardigrades are able to tolerate almost complete dehydration through transition to a metabolically inactive state, called “anhydrobiosis”. Late Embryogenesis Abundant (LEA) proteins are heat-soluble proteins involved in the desiccation tolerance of many anhydrobiotic organisms. Tardigrades, Ramazzottius varieornatus, however, express predominantly tardigrade-unique heat-soluble proteins: CAHS (Cytoplasmic Abundant Heat Soluble) and SAHS (Secretory Abundant Heat Soluble) proteins, which are secreted or localized in most intracellular compartments, except the mitochondria. Although mitochondrial integrity is crucial to ensure cellular survival, protective molecules for mitochondria have remained elusive. Here, we identified two novel mitochondrial heat-soluble proteins, RvLEAM and MAHS (Mitochondrial Abundant Heat Soluble), as potent mitochondrial protectants from Ramazzottius varieornatus. RvLEAM is a group3 LEA protein and immunohistochemistry confirmed its mitochondrial localization in tardigrade cells. MAHS-green fluorescent protein fusion protein localized in human mitochondria and was heat-soluble in vitro, though no sequence similarity with other known proteins was found, and one region was conserved among tardigrades. Furthermore, we demonstrated that RvLEAM protein as well as MAHS protein improved the hyperosmotic tolerance of human cells. The findings of the present study revealed that tardigrade mitochondria contain at least two types of heat-soluble proteins that might have protective roles in water-deficient environments.
Neuroprotective Mechanism of Lycium barbarum Polysaccharides against Hippocampal-Dependent Spatial Memory Deficits in a Rat Model of Obstructive Sleep Apnea

Chronic intermittent hypoxia (CIH) is a hallmark of obstructive sleep apnea (OSA), which induces hippocampal injuries mediated by oxidative stress. This study aims to examine the neuroprotective mechanism of Lycium barbarum polysaccharides (LBP) against CIH-induced spatial memory deficits. Adult Sprague–Dawley rats were exposed to hypoxic treatment resembling a severe OSA condition for a week. The animals were orally fed with LBP solution (1mg/kg) daily 2 hours prior to hypoxia or in air for the control. The effect of LBP on the spatial memory and levels of oxidative stress, inflammation, endoplasmic reticulum (ER) stress, apoptosis and neurogenesis in the hippocampus was examined. There was a significant deficit in the spatial memory and an elevated level of malondialdehyde with a decreased expression of antioxidant enzymes (SOD, GPx-1) in the hypoxic group when compared with the normoxic control. In addition, redox-sensitive nuclear factor kappa B (NFКB) canonical pathway was activated with a translocation of NFКB members (p65, p50) and increased expression levels of NFКB-dependent inflammatory cytokines and mediator (TNFα, IL-1β, COX-2); also, a significantly elevated level of ER stress (GRP78/Bip, PERK, CHOP) and autophagic flux in the hypoxic group, leading to neuronal apoptosis in hippocampal subfields (DG, CA1, CA3). Remarkably, LBP administration normalized the elevated level of oxidative stress, neuroinflammation, ER stress, autophagic flux and apoptosis induced by hypoxia. Moreover, LBP significantly mitigated both the caspase-dependent intrinsic (Bax, Bcl2, cytochrome C, cleaved caspase-3) and extrinsic (FADD, cleaved caspase-8, Bid) signaling apoptotic cascades. Furthermore, LBP administration prevented the spatial memory deficit and enhanced the hippocampal neurogenesis induced by hypoxia. Our results suggest that LBP is neuroprotective against CIH-induced hippocampal-dependent spatial memory deficits by promoting hippocampal neurogenesis and negatively modulating the apoptotic signaling cascades activated by oxidative stress and inflammation.
Epithelium Lining Rat Renal Papilla: Nomenclature and Association with Chronic Progressive Nephropathy (CPN)

Chronic progressive nephropathy (CPN) occurs commonly in rats, more frequently and severely in males than females. High-grade CPN is characterized by increased layers of the renal papilla lining, designated as urothelial hyperplasia in the International Harmonization of Nomenclature and Diagnostic Criteria classification. However, urothelium lining the pelvis is not equivalent to the epithelium lining the papilla. To evaluate whether the epithelium lining the renal papilla is actually urothelial in nature and whether CPN-associated multicellularity represents proliferation, kidney tissues from aged rats with CPN, from rats with multicellularity of the renal papilla epithelium of either low-grade or marked severity, and from young rats with normal kidneys were analyzed and compared. Immunohistochemical staining for uroplakins (urothelial specific proteins) was negative in the papilla epithelium in all rats with multicellularity or not, indicating these cells are not urothelial. Mitotic figures were rarely observed in this epithelium, even with multicellularity. Immunohistochemical staining for Ki-67 was negative. Papilla lining cells and true urothelium differed by scanning electron microscopy. Based on these findings, we recommend that the epithelium lining the papilla not be classified as urothelial, and the CPN-associated lesion be designated as vesicular alteration of renal papilla instead of hyperplasia and distinguished in diagnostic systems from kidney pelvis urothelial hyperplasia.
High-Density Genetic Linkage Map Construction and QTL Mapping of Grain Shape and Size in the Wheat Population Yanda1817 × Beinong6

High-density genetic linkage maps are necessary for precisely mapping quantitative trait loci (QTLs) controlling grain shape and size in wheat. By applying the Infinium iSelect 9K SNP assay, we have constructed a high-density genetic linkage map with 269 F 8 recombinant inbred lines (RILs) developed between a Chinese cornerstone wheat breeding parental line Yanda1817 and a high-yielding line Beinong6. The map contains 2431 SNPs and 128 SSR & EST-SSR markers in a total coverage of 3213.2 cM with an average interval of 1.26 cM per marker. Eighty-eight QTLs for thousand-grain weight (TGW), grain length (GL), grain width (GW) and grain thickness (GT) were detected in nine ecological environments (Beijing, Shijiazhuang and Kaifeng) during five years between 2010–2014 by inclusive composite interval mapping (ICIM) (LOD≥2.5). Among which, 17 QTLs for TGW were mapped on chromosomes 1A, 1B, 2A, 2B, 3A, 3B, 3D, 4A, 4D, 5A, 5B and 6B with phenotypic variations ranging from 2.62% to 12.08%. Four stable QTLs for TGW could be detected in five and seven environments, respectively. Thirty-two QTLs for GL were mapped on chromosomes 1B, 1D, 2A, 2B, 2D, 3B, 3D, 4A, 4B, 4D, 5A, 5B, 6B, 7A and 7B, with phenotypic variations ranging from 2.62% to 44.39%. QGl.cau-2A.2 can be detected in all the environments with the largest phenotypic variations, indicating that it is a major and stable QTL. For GW, 12 QTLs were identified with phenotypic variations range from 3.69% to 12.30%. We found 27 QTLs for GT with phenotypic variations ranged from 2.55% to 36.42%. In particular, QTL QGt.cau-5A.1 with phenotypic variations of 6.82–23.59% was detected in all the nine environments. Moreover, pleiotropic effects were detected for several QTL loci responsible for grain shape and size that could serve as target regions for fine mapping and marker assisted selection in wheat breeding programs.
Voxel-Based Texture Analysis of the Brain

This paper presents a novel voxel-based method for texture analysis of brain images. Texture analysis is a powerful quantitative approach for analyzing voxel intensities and their interrelationships, but has been thus far limited to analyzing regions of interest. The proposed method provides a 3D statistical map comparing texture features on a voxel-by-voxel basis. The validity of the method was examined on artificially generated effects as well as on real MRI data in Alzheimer's Disease (AD). The artificially generated effects included hyperintense and hypointense signals added to T1-weighted brain MRIs from 30 healthy subjects. The AD dataset included 30 patients with AD and 30 age/sex matched healthy control subjects. The proposed method detected artificial effects with high accuracy and revealed statistically significant differences between the AD and control groups. This paper extends the usage of texture analysis beyond the current region of interest analysis to voxel-by-voxel 3D statistical mapping and provides a hypothesis-free analysis tool to study cerebral pathology in neurological diseases.
Linking Human Health and Livestock Health: A “One-Health” Platform for Integrated Analysis of Human Health, Livestock Health, and Economic Welfare in Livestock Dependent Communities

Background For most rural households in sub-Saharan Africa, healthy livestock play a key role in averting the burden associated with zoonotic diseases, and in meeting household nutritional and socio-economic needs. However, there is limited understanding of the complex nutritional, socio-economic, and zoonotic pathways that link livestock health to human health and welfare. Here we describe a platform for integrated human health, animal health and economic welfare analysis designed to address this challenge. We provide baseline epidemiological data on disease syndromes in humans and the animals they keep, and provide examples of relationships between human health, animal health and household socio-economic status. Method We designed a study to obtain syndromic disease data in animals along with economic and behavioral information for 1500 rural households in Western Kenya already participating in a human syndromic disease surveillance study. Data collection started in February 2013, and each household is visited bi-weekly and data on four human syndromes (fever, jaundice, diarrhea and respiratory illness) and nine animal syndromes (death, respiratory, reproductive, musculoskeletal, nervous, urogenital, digestive, udder disorders, and skin disorders in cattle, sheep, goats and chickens) are collected. Additionally, data from a comprehensive socio-economic survey is collected every 3 months in each of the study households. Findings Data from the first year of study showed 93% of the households owned at least one form of livestock (55%, 19%, 41% and 88% own cattle, sheep, goats and chickens respectively). Digestive disorders, mainly diarrhea episodes, were the most common syndromes observed in cattle, goats and sheep, accounting for 56% of all livestock syndromes, followed by respiratory illnesses (18%). In humans, respiratory illnesses accounted for 54% of all illnesses reported, followed by acute febrile illnesses (40%) and diarrhea illnesses (5%). While controlling for household size, the incidence of human illness increased 1.31-fold for every 10 cases of animal illness or death observed (95% CI 1.16–1.49). Access and utilization of animal source foods such as milk and eggs were positively associated with the number of cattle and chickens owned by the household. Additionally, health care seeking was correlated with household incomes and wealth, which were in turn correlated with livestock herd size. Conclusion This study platform provides a unique longitudinal dataset that allows for the determination and quantification of linkages between human and animal health, including the impact of healthy animals on human disease averted, malnutrition, household educational attainment, and income levels.