Miracle-dz/UniFAR-FTUs huggingface dataset:
A Global Approach to Estimating the Abundance and Duplication of Polyketide Synthase Domains in Dinoflagellates

Many dinoflagellate species make toxins in a myriad of different molecular configurations but the underlying chemistry in all cases is presumably via modular synthases, primarily polyketide synthases. In many organisms modular synthases occur as discrete synthetic genes or domains within a gene that act in coordination thus forming a module that produces a particular fragment of a natural product. The modules usually occur in tandem as gene clusters with a syntenic arrangement that is often predictive of the resultant structure. Dinoflagellate genomes however are notoriously complex with individual genes present in many tandem repeats and very few synthetic modules occurring as gene clusters, unlike what has been seen in bacteria and fungi. However, modular synthesis in all organisms requires a free thiol group that acts as a carrier for sequential synthesis called a thiolation domain. We scanned 47 dinoflagellate transcriptomes for 23 modular synthase domain models and compared their abundance among 10 orders of dinoflagellates as well as their co-occurrence with thiolation domains. The total count of domain types was quite large with over thirty-thousand identified, 29 000 of which were in the core dinoflagellates. Although there were no specific trends in domain abundance associated with types of toxins, there were readily observable lineage specific differences. The Gymnodiniales, makers of long polyketide toxins such as brevetoxin and karlotoxin had a high relative abundance of thiolation domains as well as multiple thiolation domains within a single transcript. Orders such as the Gonyaulacales, makers of small polyketides such as spirolides, had fewer thiolation domains but a relative increase in the number of acyl transferases. Unique to the core dinoflagellates, however, were thiolation domains occurring alongside tetratricopeptide repeats that facilitate protein-protein interactions, especially hexa and hepta-repeats, that may explain the scaffolding required for synthetic complexes capable of making large toxins. Clustering analysis for each type of domain was also used to discern possible origins of duplication for the multitude of single domain transcripts. Single domain transcripts frequently clustered with synonymous domains from multi-domain transcripts such as the BurA and ZmaK like genes as well as the multi-ketosynthase genes, sometimes with a large degree of apparent gene duplication, while fatty acid synthesis genes formed distinct clusters. Surprisingly the acyl-transferases and ketoreductases involved in fatty acid synthesis (FabD and FabG, respectively) were found in very large clusters indicating an unprecedented degree of gene duplication for these genes. These results demonstrate a complex evolutionary history of core dinoflagellate modular synthases with domain specific duplications throughout the lineage as well as clues to how large protein complexes can be assembled to synthesize the largest natural products known.
Penalized homophily latent space models for directed scale-free networks

Online social networks like Twitter and Facebook are among the most popular sites on the Internet. Most online social networks involve some specific features, including reciprocity, transitivity and degree heterogeneity. Such networks are so called scale-free networks and have drawn lots of attention in research. The aim of this paper is to develop a novel methodology for directed network embedding within the latent space model (LSM) framework. It is known, the link probability between two individuals may increase as the features of each become similar, which is referred to as homophily attributes. To this end, penalized pair-specific attributes, acting as a distance measure, are introduced to provide with more powerful interpretation and improve link prediction accuracy, named penalized homophily latent space models (PHLSM). The proposed models also involve in-degree heterogeneity of directed scale-free networks by embedding with the popularity scales. We also introduce LASSO-based PHLSM to produce an accurate and sparse model for high-dimensional covariates. We make Bayesian inference using MCMC algorithms. The finite sample performance of the proposed models is evaluated by three benchmark simulation datasets and two real data examples. Our methods are competitive and interpretable, they outperform existing approaches for fitting directed networks.
Quantum chaos and ensemble inequivalence of quantum long-range Ising chains

We use large-scale exact diagonalization to study the quantum Ising chain in a transverse field with long-range power-law interactions decaying with exponent $\alpha$. We numerically study various probes for quantum chaos and eigenstate thermalization {on} the level of eigenvalues and eigenstates. The level-spacing statistics yields a clear sign towards a Wigner-Dyson distribution and therefore towards quantum chaos across all values of $\alpha>0$. Yet, for $\alpha<1$ we find that the microcanonical entropy is nonconvex. This is due to the fact that the spectrum is organized in energetically separated multiplets for $\alpha<1$. While quantum chaotic behaviour develops within the individual multiplets, many multiplets don't overlap and don't mix with each other, as we analytically and numerically argue. Our findings suggest that a small fraction of the multiplets could persist at low energies for $\alpha\ll 1$ even for large $N$, giving rise to ensemble inequivalence.
On the Circular Polarization of Repeating Fast Radio Bursts

Fast spinning (e.g., sub-second) neutron star with ultra-strong magnetic fields (or so-called magnetar) is one of the promising origins of repeating fast radio bursts (FRBs). Here we discuss circularly polarized emissions produced by propagation effects in the magnetosphere of fast spinning magnetars. We argue that the polarization-limiting region is well beyond the light cylinder, suggesting that wave mode coupling effects are unlikely to produce strong circular polarization for fast spinning magnetars. Cyclotron absorption could be significant if the secondary plasma density is high. However, high degrees of circular polarization can only be produced with large asymmetries in electrons and positrons. We draw attention to the non-detection of circular polarization in current observations of known repeating FRBs. We suggest that the circular polarization of FRBs could provide key information on their origins and help distinguish different radiation mechanisms.
5 Reasons to Expect an 8 MeV Line in the SN 1987A Neutrino Spectrum

Evidence was previously reported for an 8 MeV neutrino line associated with SN 1987A based on an analysis of 997 events recorded in the Kamiokande-II detector on the day of the supernova. That claimed line, however, occurred at the peak of the background spectrum, and both had a similar shape, making the claim tenuous at best. Here the claim is buttressed by providing five reasons to expect such an 8 MeV neutrino line. A final section of the paper concerns the ongoing KATRIN experiment to find the neutrino mass, which might provide additional support for the line, should it validate a controversial 3 + 3 model of the neutrino masses, including a tachyonic (m < 0) mass.
Goal-constrained Sparse Reinforcement Learning for End-to-End Driving

Deep reinforcement Learning for end-to-end driving is limited by the need of complex reward engineering. Sparse rewards can circumvent this challenge but suffers from long training time and leads to sub-optimal policy. In this work, we explore full-control driving with only goal-constrained sparse reward and propose a curriculum learning approach for end-to-end driving using only navigation view maps that benefit from small virtual-to-real domain gap. To address the complexity of multiple driving policies, we learn concurrent individual policies selected at inference by a navigation system. We demonstrate the ability of our proposal to generalize on unseen road layout, and to drive significantly longer than in the training.
Comment on acp-2021-147 Anonymous

This study examined the role of inner eyewall structure in the formation of a secondary eyewall by performing two WRF simulations of (realistic or idealized unknown) tropical cyclones (TCs) with different horizontal grid spacings. The simulation with secondary eyewall formation (SEF) has stronger and deeper eyewall updrafts that produce more hydrometers falling out of anvil clouds outside the eyewall. The associated diabatic cooling helps induce a descending inflow beneath the outflow layer that is argued to contribute to the formation of a moat. In contrast, the simulation without SEF does not show the descending inflow and moat. The authors then emphasized the importance of accurately simulating the structure of the eyewall in the SEF.
Hereditary thrombocytosis: the genetic landscape

tion of CHK1 sensitizes Ewing sarcoma cells to the ribonucleotide reductase inhibitor gemcitabine. Oncotarget. 2017;8(50):87016–32. 11. Man LM, Morris AL, Keng M. New therapeutic strategies in acute lymphocytic leukemia. Curr Hematol Malig Rep. 2017;12(3):197–206. 12. Wander P, Cheung LC, Pinhanҫos SS, Jones L, Kerstjens M, ArentsenPeters STCJM, et al. Preclinical efficacy of gemcitabine in MLL-rearranged infant acute lymphoblastic leukemia. Leukemia. 2020;34:2898–902. 13. Ianevski A, Giri AK, Aittokallio T. SynergyFinder 2.0: visual analytics of multi-drug combination synergies. Nucleic Acids Res. 2020;48(W1):W488– 93. 14. Chou T-C. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010;70(2):440–6. 15. Yadav B, Wennerberg K, Aittokallio T, Tang J. Searching for drug synergy in complex dose-response landscapes using an interaction potency model. Comput Struct Biotechnol J. 2015;25(13):504–13.
Effects and safety evaluation of Wuzhi Capsules combined with tacrolimus for the treatment of kidney transplantation recipients

Tacrolimus (FK506), an effective and potent calcineurin inhibitor, is the cornerstone of immunosuppression after kidney transplantation. Wuzhi capsule (WZC), a prescribed ethanol extract of Nan‐Wuweizi (Schisandra sphenanthera), is widely prescribed for kidney transplant recipients for the maintenance of tacrolimus concentration in clinical settings. Previous studies have demonstrated that WZC can increase the blood concentration of tacrolimus. However, it remains controversial whether to use WZC can be used to increase tacrolimus concentration in clinical practice. Our study aimed to evaluate the efficacy and safety of WZC combined with tacrolimus in the treatment of kidney transplant recipients.
Non‐invasive assessment of fibrosis regression and portal hypertension in patients with advanced chronic hepatitis C virus (HCV)‐associated liver disease and sustained virologic response (SVR): 3 years follow‐up of a prospective longitudinal study

Long‐term effects on cirrhosis and portal hypertension of direct antiviral agent (DAA)‐based eradication of hepatitis C virus (HCV) are still under debate. We analysed dynamics of liver and spleen elastography to assess potential regression of cirrhosis and portal hypertension 3 years post‐treatment. Fifty‐four patients with HCV‐associated cirrhosis and DAA‐induced SVR were included. Liver and spleen stiffness were measured at baseline (BL), end of treatment (EOT), 24 weeks after EOT (FU24) and 1, 2 and 3 (FU144) years post‐treatment by transient liver elastography (L‐TE) and point shear wave elastography (pSWE) using acoustic radiation force impulse (ARFI) of the liver (L‐ARFI) and spleen (S‐ARFI). Biochemical, virological and clinical data were also obtained. Liver stiffness assessed by L‐TE decreased between BL [median (range), 32.5(9.1–75) kPa] and EOT [21.3(6.7–73.5) kPa; p < . 0001] and EOT and FU144 [16(4.1–75) kPa; p = . 006]. L‐ARFI values improved between EOT [2.5(1.2–4.1) m/s] and FU144 [1.7(0.9–4.1) m/s; p = . 001], while spleen stiffness remained unchanged. Overall, L‐TE improved in 38 of 54 (70.4%) patients at EOT and 29 of 38 (76.3%) declined further until FU144, whereas L‐ARFI values decreased in 30/54 (55.6%) patients at EOT and continued to decrease in 28/30 (93.3%) patients at FU144. Low bilirubin and high albumin levels at BL were associated with improved L‐ARFI values (p = .048) at EOT or regression of cirrhosis (<12.5 kPa) by L‐TE at FU144 (p = .005), respectively. Liver stiffness, but not spleen stiffness, continued to decline in a considerable proportion of patients with advanced liver disease after HCV eradication.
Effect of the BCAT2 polymorphism (rs11548193) on plasma branched-chain amino acid concentrations after dietary intervention in subjects with obesity and insulin resistance

Abstract Branched-chain amino acids (BCAA) are considered markers of insulin resistance (IR) in subjects with obesity. In this study, we evaluated whether the presence of the SNP of the branched-chain aminotransferase 2 (BCAT2) gene can modify the effect of a dietary intervention (DI) on the plasma concentration of BCAA in subjects with obesity and IR. A prospective cohort study of adult subjects with obesity, BMI ≥ 30 kg/m2, homeostatic model assessment-insulin resistance (HOMA-IR ≥ 2·5) no diagnosed chronic disease, underwent a DI with an energy restriction of 3140 kJ/d and nutritional education for 1 month. Anthropometric measurements, body composition, blood pressure, resting energy expenditure, oral glucose tolerance test results, serum biochemical parameters and the plasma amino acid profile were evaluated before and after the DI. SNP were assessed by the TaqMan SNP genotyping assay. A total of eighty-two subjects were included, and fifteen subjects with a BCAT2 SNP had a greater reduction in leucine, isoleucine, valine and the sum of BCAA. Those subjects also had a greater reduction in skeletal muscle mass, fat-free mass, total body water, blood pressure, muscle strength and biochemical parameters after 1 month of the DI and adjusting for age and sex. This study demonstrated that the presence of the BCAT2 SNP promotes a greater reduction in plasma BCAA concentration after adjusting for age and sex, in subjects with obesity and IR after a 1-month energy-restricted DI.
The Meloidogyne javanica effector Mj2G02 interferes with jasmonic acid signalling to suppress cell death and promote parasitism in Arabidopsis

Abstract Plant‐parasitic nematodes can cause devastating damage to crops. These nematodes secrete effectors that suppress the host immune responses to enhance their survival. In this study, Mj2G02, an effector from Meloidogyne javanica, is described. In situ hybridization and transcriptional analysis showed that Mj2G02 was highly expressed in the early infection stages and exclusively expressed in the nematode subventral oesophageal gland cells. In planta RNA interference targeting Mj2G02 impaired M. javanica parasitism, and Mj2G02‐transgenic Arabidopsis lines displayed more susceptibility to M. javanica. Using an Agrobacterium‐mediated transient expression system and plant immune response assays, we demonstrated that Mj2G02 localized in the plant cell nuclei and could suppress Gpa2/RBP‐1‐induced cell death. Moreover, by RNA‐Seq and quantitative reverse transcription PCR analyses, we showed that Mj2G02 was capable of interfering with the host jasmonic acid (JA) signalling pathway. Multiple jasmonate ZIM‐domain (JAZ) genes were significantly upregulated, whereas the JAR1 gene and four JA‐responsive genes, MYC3, UPI, THI2.1, and WRKY75, were significantly downregulated. In addition, HPLC analysis showed that the endogenous jasmonoyl‐isoleucine (JA‐Ile) level in Mj2G02‐transgenic Arabidopsis lines was significantly decreased compared to that in wildtype plants. Our results indicate that the M. javanica effector Mj2G02 suppresses the plant immune response, therefore facilitating nematode parasitism. This process is probably mediated by a JA‐Ile reduction and JAZ enhancement to repress JA‐responsive genes.
High-Precision Quantitative Analysis Reveals Carcinoembryonic Protein Expression Differs Among Colorectal Cancer Primary Foci and Metastases to Different Sites

The expression of carcinoembryonic protein (CEA) is an important biological marker and therapeutic target in colorectal cancer (CRC). CEA expression heterogeneity confers resistance to CEA-targeting immunotherapy antibodies. Thus, quantification of the CEA-positive cell ratio among all tumor cells would be important in identifying patients that would benefit from CEA-targeted therapies. However, the proportion of tumor cells that express CEA within primary and metastasized tumors at different sites has not been studied. Therefore, the present study aimed to determine CEA positive cell proportion in paired CRC primary foci, liver metastases, and lymph node (LN) metastases, and whether proportion of CEA positive cell differs among colorectal cancer primary foci, liver metastases, and LN metastases from 26 patients. The CEA expression was detected by immunohistochemical assay. Then we set up a quantification approach to quantify the proportion of CEA-positive cells based on the TissueGnostics (TG) system. Then the proportion of CEA positive cells were measured and compared among primary foci, liver metastases, and LN metastases. As a result, the proportion of CEA positive tumor cells was slightly higher in liver metastases than in primary foci (89.8% ± 2.71% vs 82.1% ± 5.05%, P < 0.001). The proportion of CEA-positive cells was significantly lower in LN metastases than in primary foci (82.3% ± 4.32% vs 70.28% ± 5.04%, P < 0.001). In 8 cases with matched CRC primary foci, liver metastases, and LN metastases, the proportions of CEA proportion in liver metastasis was the highest, followed by primary foci and LNs metastasis. In conclusion, this study provided an new approach for quantification of CEA positive cell in tumors and proved the percentage of CEA-positive cells varied in different metastases.
S-methyl cysteine sulfoxide mitigates histopathological damage, alleviate oxidative stress and promotes immunomodulation in diabetic rats

Abstract Objectives S-methyl cysteine sulfoxide (SMCS) is a hydrophilic cysteine-containing natural compound found in plants and is known to possess antidiabetic and antioxidant properties. We investigated the antioxidant and immunomodulatory properties of SMCS, as well as histopathological changes in the liver and pancreas in streptozotocin (STZ)-induced diabetic rats. Methods The rats were divided into the following groups: control (CG), comprising non-diabetic rats; STZ-DB, comprising STZ-induced diabetic rats; and STZ-SMCS, comprising STZ-induced diabetic rats treated with SMCS. SMCS (200 mg/kg) was administered by gavage daily for 30 days. Biochemical and cytokine analyses, catalase (CAT) and superoxide dismutase (SOD) activities assays and histopathological analysis of liver and pancreas tissues were performed. Results SMCS treatment reduced glycemia (p<0.05), decreased triglyceride (p<0.01) and very-low-density lipoprotein (VLDL) levels (p<0.01), and increased SOD and CAT activity in the liver (both p<0.01) compared with STZ-DB group. Higher activity values of IL-10 were observed in the STZ-SMCS group than in the other groups (p<0.001). Liver glycogen was significantly improved in the STZ-SMCS group compared with the STZ-DB group. SMCS also ameliorated damage to pancreatic islets, which resulted in restoration of their morphology. Conclusions Oral treatment of SMCS showed improvement of the morphological alterations in liver and pancreatic islet in diabetic rats. These beneficial morphological effects of SMCS can be partially explained by IL-10 modulation associated with antioxidant action.
A filamentous archaeal virus is enveloped inside the cell and released through pyramidal portals

Significance Egress of most eukaryotic enveloped viruses, including such human pathogens as HIV-1, Ebola, and coronaviruses, occurs via budding through cellular membranes, a process concomitant with virion assembly. Archaea are also infected by enveloped viruses, but how their virions are assembled and released from the cells remained largely unknown. We show that virions of Sulfolobus islandicus filamentous virus (SIFV) are assembled and enveloped in the cell cytoplasm. Instead of budding, SIFV induces the formation of pyramidal structures, which penetrate the cell envelope and serve as portals for virion release. Comparison of the infection cycles of evolutionarily related enveloped and nonenveloped filamentous archaeal viruses suggests that the primary role of the lipothrixvirus membrane is to protect the genome against extreme environmental conditions. The majority of viruses infecting hyperthermophilic archaea display unique virion architectures and are evolutionarily unrelated to viruses of bacteria and eukaryotes. The lack of relationships to other known viruses suggests that the mechanisms of virus–host interaction in Archaea are also likely to be distinct. To gain insights into archaeal virus–host interactions, we studied the life cycle of the enveloped, ∼2-μm-long Sulfolobus islandicus filamentous virus (SIFV), a member of the family Lipothrixviridae infecting a hyperthermophilic and acidophilic archaeon Saccharolobus islandicus LAL14/1. Using dual-axis electron tomography and convolutional neural network analysis, we characterize the life cycle of SIFV and show that the virions, which are nearly two times longer than the host cell diameter, are assembled in the cell cytoplasm, forming twisted virion bundles organized on a nonperfect hexagonal lattice. Remarkably, our results indicate that envelopment of the helical nucleocapsids takes place inside the cell rather than by budding as in the case of most other known enveloped viruses. The mature virions are released from the cell through large (up to 220 nm in diameter), six-sided pyramidal portals, which are built from multiple copies of a single 89-amino-acid-long viral protein gp43. The overexpression of this protein in Escherichia coli leads to pyramid formation in the bacterial membrane. Collectively, our results provide insights into the assembly and release of enveloped filamentous viruses and illuminate the evolution of virus–host interactions in Archaea.
Effect of high altitude on human postprandial 13C‐octanoate metabolism, intermediary metabolites, gastrointestinal peptides, and visceral perception

At high altitude (HA), acute mountain sickness (AMS) is accompanied by neurologic and upper gastrointestinal symptoms (UGS). The primary aim of this study was to test the hypothesis that delayed gastric emptying (GE), assessed by 13C‐octanoate breath testing (OBT), causes UGS in AMS. The secondary aim was to assess post‐gastric mechanisms of OBT, which could confound results under these conditions, by determination of intermediary metabolites, gastrointestinal peptides, and basal metabolic rate.