Miracle-dz/UniFAR-FTUs huggingface dataset:
The circadian clock is disrupted in pancreatic cancer

Disruption of the circadian clock is linked to cancer development and progression. Establishing this connection has proven beneficial for understanding cancer pathogenesis, determining prognosis, and uncovering novel therapeutic targets. However, barriers to characterizing the circadian clock in human pancreas and human pancreatic cancer – one of the deadliest malignancies – have hindered an appreciation of its role in this cancer. Here, we employed normalized coefficient of variation (nCV) and clock correlation analysis in human population-level data to determine the functioning of the circadian clock in pancreas cancer and adjacent normal tissue. We found a substantially attenuated clock in the pancreatic cancer tissue. Then we exploited our existing mouse pancreatic transcriptome data to perform an analysis of the human normal and pancreas cancer samples using a machine learning method, cyclic ordering by periodic structure (CYCLOPS). Through CYCLOPS ordering, we confirmed the nCV and clock correlation findings of an intact circadian clock in normal pancreas with robust cycling of several core clock genes. However, in pancreas cancer, there was a loss of rhythmicity of many core clock genes with an inability to effectively order the cancer samples, providing substantive evidence of a dysregulated clock. The implications of clock disruption were further assessed with a Bmal1 knockout pancreas cancer model, which revealed that an arrhythmic clock caused accelerated cancer growth and worse survival, accompanied by chemoresistance and enrichment of key cancer-related pathways. These findings provide strong evidence for clock disruption in human pancreas cancer and demonstrate a link between circadian disruption and pancreas cancer progression. Author Summary The circadian clock is a regulator of human homeostasis. Dysfunction of the clock can lead to the development of diseases, including cancer. Although several cancers have been shown to have a dysfunctional clock which may alter prognosis or change treatment, this has been suggested but not demonstrated in pancreatic cancer. Investigation of this link is important because pancreatic cancer is highly lethal with few effective treatment options. Here we use recently pioneered bioinformatics approaches to assess clock functionality in human pancreatic cancer specimens, where we demonstrate that the clock is dysfunctional relative to normal pancreatic tissue. We then knocked out the core clock gene, Bmal1, in pancreatic cancer cells, which led to faster tumor growth and worse survival in mice and enhanced chemotherapeutic resistance to standard chemotherapy agents used in the treatment of pancreatic cancer. Collectively, our findings establish human pancreatic cancer as having clock dysfunction and clock dysfunction causing a more aggressive cancer.
The Sources of intergalactic metals

We study the clustering properties of metals in the intergalactic medium (IGM) as traced by 619 Civ and 81 Siiv absorption components with N ≥ 10 12 cm -2 and 316 Mg II and 82 Fell absorption components with N ≥ 10 11.5 cm -2 in 19 high signal-to-noise ratio (60-100 pixel -1 ), high-resolution (R = 45 000) quasar spectra. C IV and Si iv trace each other closely and their line-of-sight correlation functions ξ(v) exhibit a steep decline at large separations and a flatter profile below 150 km s -1 , with a large overall bias. These features do not depend on absorber column densities, although there are hints that the overall amplitude of ξ CIV (v) increases with time over the redshift range detected (1.5-3). Carrying out a detailed smoothed particle hydrodynamic simulation (2 x 320 3 , 57 Mpc 3 comoving), we show that the C iv correlation function cannot be reproduced by models in which the IGM metallicity is constant or a local function of overdensity (Z Δ 2/3 ). However, the properties of ξ CIV (v) are generally consistent with a model in which metals are confined within bubbles with a typical radius R s about sources of mass ≥M s . We derive best-fitting values of R s 2 comoving Mpc and M s 10 12 M ○. at z = 3. Our lower-redshift (0.5-2) measurements of the Mg II and Fe II correlation functions also uncover a steep decline at large separations and a flatter profile at small separations, but the clustering is even higher than in the z = 1.5-3 measurements, and the turnover is shifted to somewhat smaller distances, 75 km s -1 . Again, these features do not change with column density, but there are hints that the amplitudes of ξ Mg II (v) and ξ Fe II (v) increase with time. We describe an analytic 'bubble' model for these species, which come from regions that are too compact to be accurately simulated numerically, deriving best-fitting values of R s 2.4 Mpc and M s 10 12 M ○. Equally good analytic fits to all four species are found in a similarly biased high-redshift enrichment model in which metals are placed within 2.4 comoving Mpc of M s 3 x 10 9 sources at z = 7.5.
Bacterial Microbiome and Host Inflammatory Gene Expression in Foreskin Tissue

As part of the CHAPS randomized clinical trial, we sequenced a segment of the bacterial 16S rRNA gene from foreskin tissue of 144 adolescents from South Africa and Uganda collected during surgical penile circumcision after receipt of 1 to 2 doses of placebo, emtricitabine with tenofovir disoproxil fumarate, or emtricitabine with tenofovir alafenamide. We found a large proportion of Corynebacterium in addition to other anaerobic species. Cutibacterium acnes was more abundant among participants from South Africa than Uganda, though this made no difference in surgical recovery. We did not find a difference in bacterial populations by treatment received nor bacterial taxa that were differentially abundant between participants who received placebo versus active drug. Using RNAseq libraries from foreskin tissue of the same participants, we found negative correlations between the relative abundance of bacterial taxa and the expression of genes downstream of the innate response to bacteria and regulation of the inflammatory response. When participants were divided into clusters based on bacterial community composition, two main clusters emerged which were distinguished by high and low bacterial diversity. Random forest classification showed higher expression of NFATC3 and SELENOS and lower expression of STAP1 and NLRP6 in the higher diversity group compared to the lower. Our results show no difference in the tissue microbiome of the foreskin with short-course PrEP but that bacterial taxa were largely inversely correlated with gene expression, consistent with non-inflammatory colonization. Author Summary We investigated the bacterial community of the foreskin of the penis. Previous studies found increased inflammation with certain anaerobic bacteria from swabs taken under the foreskin, but we found that higher relative abundances of the bacteria were correlated with lower expression of inflammatory genes. We did not find different bacteria in participants who received medicine to prevent HIV. Understanding the relationship between bacteria and inflammation in the penis will help us to understand how interventions like penile circumcision reduce the risk of acquiring sexually transmitted infections such as HIV.
inMTSCCA: An Integrated Multi-task Sparse Canonical Correlation Analysis for Multi-omic Brain Imaging Genetics

Identifying genetic risk factors for Alzheimer’s disease (AD) is an important research topic. To date, different endophenotypes such as imaging-derived endophenotypes and proteomic expression-derived endophenotypes have shown the great value in uncovering risk genes compared to case-control studies. Biologically, a co-varying pattern of these different omics derived endophenotypes could result from the shared genetic basis. However, existing methods mainly focus on the effect of endophenotypes, and that of cross-endophenotype associations remains largely unexploited. In this paper, we used both endophenotypes and their cross-associations of multi-omics to identify genetic risk factors, and proposed two integrated multi-task sparse canonical correlation analysis (MTSCCA) methods, i.e., pairwise endophenotype correlation guided MTSCCA (pcMTSCCA) and high-order endophenotype correlation guided MTSCCA (hocMTSCCA). pcMTSCCA employed pairwise correlations between MRI-derived, plasma-derived, and cerebrospinal fluid (CSF) derived endophenotypes as an additional penalty. hocMTSCCA used high-order correlations among these multi-omics for regularization. To figure out genetic risk factors at individual and group levels, as well as altered endophenotypic markers, we introduced sparsity-inducing penalties in both models. We compared pcMTSCCA and hocMTSCCA with three related methods on both simulation data and real neuroimaging, proteomic analytes, and genetic data. The results showed that our methods obtained better or comparable canonical correlation coefficients (CCCs) and feature subsets than benchmarks. Most importantly, the identified genetic loci and heterogeneous endophenotypic markers showed high relevance. Therefore, jointly using multi-omics endophenotypes and their cross-endophenotype associations are promising to reveal genetic risk factors, and both methods are qualified for this complicated task. The source code and manual of inMTSCCA is available at: https://ngdc.cncb. ac.cn/biocode/tools/BT007330.
Single cell CRISPR base editor engineering and transcriptional characterization of cancer mutations

We developed a multiplexed single cell technology to genome engineer mutations, directly delineate their genotype among individual cells and determine each mutation’s transcriptional phenotype. This approach uses CRISPR base editors to introduce predesignated variants into a target gene. Long-read sequencing of the target gene’s transcript identifies the engineered mutations among individual cells. Simultaneously, we analyzed the transcriptome profile from the same set of cells by short-read sequencing. By integrating the two types of data, we determined the mutations’ genotype and expression phenotype at single cell resolution. Using cell lines, we engineered and evaluated the phenotype of more than 100 TP53 mutations. Based on the single cell gene expression, we classified the mutations as having a functionally significant phenotype versus the wild-type state. We validated these results on a subset of mutations using isolated clones analyzed with RNA-seq. Overall, we successfully demonstrated single cell mutation engineering and phenotypic assessment.
P bodies coat germ granules to promote transgenerational gene silencing in C. elegans

The formation of biomolecular condensates has emerged as a critical mechanism for compartmentation in living cells. Despite interactions between distinct condensates having been reported, the biological relevance of these interactions remains elusive. In germ cells, small RNA silencing factors are enriched in germ granule condensates, where distinct factors are organized into sub-compartments with specific functions linked to genome surveillance or transgenerational gene silencing. Here we showed that perinuclear germ granules are coated by P body condensates, which are known for housing translationally-inactive mRNAs and mRNA degradation factors. Disruption of P body factors, including CGH-1/DDX6 and CAR-1/LSM14, lead to dispersal of small RNA factors from perinuclear germ granules and disorganization of sub-compartments within germ granules. We further found that CAR-1 promotes the interaction between CGH-1 and germ granule factors, and these interactions are critical for the ability of CGH-1 to promote piRNA-mediated gene silencing. Importantly, we observed that cgh-1 mutants are competent in triggering gene silencing but exhibit defects in maintaining gene silencing in subsequent generations. Small RNA sequencing further showed that cgh-1 mutants exhibit defects in amplifying secondary small RNAs, known carriers of gene silencing memories. Together, our results uncover the function of P body factors in small RNA-mediated transgenerational gene silencing and highlight how the formation and function of one condensate can be regulated by an adjacent, interacting condensate in cells.
Structural basis of Irgb6 inactivation by Toxoplasma gondii through the phosphorylation of switch I

Irgb6 is a priming immune‐related GTPase (IRG) that counteracts Toxoplasma gondii. It is known to be recruited to the low virulent type II T. gondii parasitophorous vacuole (PV), initiating cell‐autonomous immunity. However, the molecular mechanism by which immunity‐related GTPases become inactivated after the parasite infection remains obscure. Here, we found that Thr95 of Irgb6 is prominently phosphorylated in response to low virulent type II T. gondii infection. We observed that a phosphomimetic T95D mutation in Irgb6 impaired its localization to the PV and exhibited reduced GTPase activity in vitro. Structural analysis unveiled an atypical conformation of nucleotide‐free Irgb6‐T95D, resulting from a conformational change in the G‐domain that allosterically modified the PV membrane‐binding interface. In silico docking corroborated the disruption of the physiological membrane binding site. These findings provide novel insights into a T. gondii‐induced allosteric inactivation mechanism of Irgb6.
In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma

Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed metabolism in patient-derived xenografts (tumorgrafts) from diverse forms of RCC. Tumorgrafts from VHL-mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engage in oxidative and reductive glutamine metabolism. We used several approaches to suppress glutamine metabolism and test the effect on tumor growth. Genetic silencing of isocitrate dehydrogenase-1 or -2 impaired reductive labeling of TCA cycle intermediates and suppressed tumor growth. Glutaminase inhibition resulted in modest growth suppression and variable effects on glutamine metabolism in vivo. Infusions with [amide-15N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities with the amidotransferase inhibitor JHU-083 also reduced tumor growth. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, perhaps explaining why it has been challenging to achieve therapeutic responses in patients by inhibiting glutaminase. Teaser Glutamine fuels the TCA cycle and amidotransferase pathways in clear cell renal cell carcinoma.
Schwann cells promote sensory neuron excitability during development

Excitability—the ability to fire action potentials—is a signature feature of neurons. How neurons become excitable during development, and whether excitability is an intrinsic property of neurons or requires signaling from glial cells, remain unclear. Here we demonstrate that Schwann cells, the most abundant glia in the peripheral nervous system, promote somatosensory neuron excitability during development. We find that Schwann cells secrete prostaglandin E2, which is necessary and sufficient to induce developing somatosensory neurons to express normal levels of voltage-gated sodium channels and fire action potential trains. Inactivating this signaling pathway specifically in Schwann cells selectively impairs the maturation of nociceptor and proprioceptor somatosensory neuron subtypes, leading to corresponding sensory defects in thermoception, inflammatory pain, and proprioception. Our studies thus reveal a cell non-autonomous mechanism by which glia regulate neuronal excitability to enable the development of normal sensory functions.
Plant protoplast-based assay to screen for salicylic acid response-modulating bacteria

Leaves host remarkably diverse microbes, collectively referred to as the leaf microbiota. While many beneficial functions have been attributed to the plant microbiota, the individual contributions of leaf-colonising bacteria range from pathogenic to mutualistic interactions. Omics approaches demonstrated that some leaf-colonising bacteria evoke substantial changes in gene expression and metabolic profiles in the plant host, including plant immunity. While omic approaches provide a system level view on cellular functions, they are costly and laborious, thereby severely limiting the throughput of the number of bacterial strains that can be tested in planta. To enable cost-effective high-throughput screens, we have developed a plant protoplast-based assay to measure real-time target gene expression changes following bacterial inoculation. Here, protoplasts were isolated from leaves of stable transgenic plants containing a pPR1:eYFP-nls construct. Changes in yellow fluorescence were captured for up to 96 treatments using a plate reader. This allowed the monitoring of changes in the salicylic acid-dependent plant immune response over time. Protoplast isolation per se evoked mild fluorescence responses, likely linked to endogenous salicylic acid production. This is advantageous in a bacterial assay, as bidirectional changes in PR1 expression can be measured. Plate reader-generated data were validated via fluorescence microscopy and RT-qPCR. Fluorescence microscopy further demonstrated heterogeneity in the response of individual protoplasts, which is potentially linked to differences in cell-type. In summary, the protoplast assay is an affordable and easily up-scalable way of measuring changes in target gene expression to bacterial colonisation.
Programmed death-ligand 1 expression in human cancer three-dimensional cell culture models

Programmed death-ligand 1 (PD-L1) expression is a survival mechanism employed by tumours to mediate immune evasion and tumour progression. PD-1/PD-L1-targeted therapies have revolutionised the cancer therapy landscape due to their ability to promote durable anti-tumour immune responses in select patients with advanced cancers. However, some patients are unresponsive, hyper-progressive or develop resistance. Better characterisation of the 3D architecture of solid tumours by utilising 3D cell culture could provide an environment that more closely recapitulates in vivo human tumours for investigating tumour-intrinsic PD-L1 signalling and immunotherapy responses. Here we investigated whether PD-L1 expression by human breast, prostate and colorectal cancer cell lines altered in 3D cell culture models compared to their 2D monolayer counterparts. We found that PD-L1 expression changed in 3D-cultured cancer cells when compared to 2D-cultured cells. Additionally, the expression of immunological markers, PD-1, PD-L2, CD44, DR4, DR5, Fas, and HLA-ABC were assessed in 3D cell culture and compared to their expression in 2D. These markers were also altered in 3D compared to 2D-cultured cells, highlighting the importance of utilising 3D models which may better able the investigation of tumour-intrinsic PD-L1 signalling, responses to PD-1/PD-L1-targeted therapy, and combination therapies.
Probiotics for the improvement of metabolic profiles in patients with metabolic-associated fatty liver disease: A systematic review and meta-analysis of randomized controlled trials

Objective This meta-analysis of randomized controlled trials (RCTs) was conducted to assess the efficacy of probiotics in the treatment of metabolic-associated fatty liver disease (MAFLD) mainly in terms of liver function, glucose and lipid metabolism, and inflammation. Methods RCTs were searched on PubMed, Web of Science, Embase, and the Cochrane Library until June 2022. A meta-analysis was performed on the therapeutic efficacy of probiotics on liver function, glucose and lipid metabolism, and inflammatory biomarkers by using RevMan 5.4 software. Results A total of 772 patients from 15 studies were included in the analysis. The methodological quality varied across studies. We found that adding probiotic therapies could reduce the levels of alanine aminotransferase [mean difference (MD): −11.76 (−16.06, −7.46), p < 0.00001], aspartate aminotransferase (MD: −9.08 (−13.60, −4.56), p < 0.0001], γ-glutamyltransferase [MD: −5.67 (−6.80, −4.54), p < 0.00001] and homeostasis model assessment–insulin resistance [MD: −0.62 (−1.08, −0.15), p = 0.01], in patients with MAFLD compared with those in control individuals. However, there was no statistically significant improvement in the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, C-reactive protein and tumor necrosis factor α among patients with MAFLD. Subgroup analyses showed that other key factors, such as age, participants’ baseline body mass index, and the duration of intervention, may influence probiotic therapy outcomes. Conclusion There is promising evidence that probiotic supplementation can reduce liver enzyme levels and regulate glycometabolism in patients with MAFLD. Further rigorous and long-term trials exploring these novel therapeutic perspectives are warranted to confirm these results.
Association between the reactivity of local cerebral oxygen saturation after hypo-to-hypercapnic tests and delirium after abdominal surgery in older adults: A prospective study

Objective This study aimed to investigate the correlation between changes in regional cerebral oxygen saturation (rSO2) and postoperative delirium in older adults undergoing major abdominal surgery. Materials and methods This prospective study enrolled older adults scheduled for elective major abdominal surgery at the Second Affiliated Hospital of Anhui Medical University from August 2021 to January 2022. The change in rSO2 from baseline was determined using the hypo-to-hypercapnic test. The main study outcome was the occurrence of postoperative delirium. Results A total of 101 participants were included for analysis, of whom 16 (15.8%) developed postoperative delirium. Compared with non-delirium participants, the mean arterial pressure and heart rate were not significantly different in the postoperative delirium group at T0, T1, T2, T3, T4, and T6 (all Pinteraction > 0.05), but the delirium group had lower pH, lower PaO2, and higher lactate levels at T4, T5, and T6 (all Pinteraction < 0.05). rSO2 at T0, T1, T2, T3, T4, and T6 was 69.0 (63.2–75.2), 70.7 ± 7.3, 68.2 ± 7.5, 72.1 ± 8.0, 69.9 ± 7.8, 67.4 ± 7.2, and 71.7 ± 8.1, respectively. The postoperative change in rSO2 during the hypercapnia test (TΔrSO2%) was 6.62 (5.31–9.36). Multivariable analysis showed that the Cumulative Illness Rating Scale (odd ratio, OR = 1.89, 95% confidence interval, CI: 1.10–3.25, P = 0.021), preoperative albumin levels (OR = 0.67, 95% CI: 0.48–0.94, P = 0.022), rSO2 at T4 (OR = 0.61, 95% CI: 0.41–0.89, P = 0.010), and postoperative TΔrSO2% (OR = 0.80, 95% CI: 0.66–0.98, P = 0.028) were independently associated with postoperative delirium in older adults undergoing elective abdominal surgery. Conclusion The rSO2 measured at T4 and postoperative TΔrSO2% were independently associated with postoperative delirium in older adults undergoing elective abdominal surgery.