No pulsed radio emission during a bursting phase of a Galactic magnetar.

Fast radio bursts (FRBs) are millisecond-duration radio transients of unknown physical origin observed at extragalactic distances1-3. It has long been speculated that magnetars are the engine powering repeating bursts from FRB sources4-13, but no convincing evidence has been collected so far14. Recently, the Galactic magnetar SRG 1935+2154 entered an active phase by emitting intense soft γ-ray bursts15. One FRB-like event with two peaks (FRB 200428) and a luminosity slightly lower than the faintest extragalactic FRBs was detected from the source, in association with a soft γ-ray/hard-X-ray flare18-21. Here we report an eight-hour targeted radio observational campaign comprising four sessions and assisted by multi-wavelength (optical and hard-X-ray) data. During the third session, 29 soft-γ-ray repeater (SGR) bursts were detected in γ-ray energies. Throughout the observing period, we detected no single dispersed pulsed emission coincident with the arrivals of SGR bursts, but unfortunately we were not observing when the FRB was detected. The non-detection places a fluence upper limit that is eight orders of magnitude lower than the fluence of FRB 200428. Our results suggest that FRB-SGR burst associations are rare. FRBs may be highly relativistic and geometrically beamed, or FRB-like events associated with SGR bursts may have narrow spectra and characteristic frequencies outside the observed band. It is also possible that the physical conditions required to achieve coherent radiation in SGR bursts are difficult to satisfy, and that only under extreme conditions could an FRB be associated with an SGR burst.

Transcriptomic Analysis Under Drought and Salt Stress Provides Insight into Genes Putatively Involved in Ginsenoside Biosynthesis in Panax japonicus Meyer.

Panax japonicus Meyer, a perennial herb of the dicotyledonaceae family Araliaceae, is a rare folk traditional Chinese medicine, known as "the king of herbal medicine" in China. To understand the genes involved in secondary pathways under drought and salt stress, the transcriptomic analysis of P. japonicus is of vital importance. The transcriptome of underground rhizomes, stems, and leaves under drought and salt stress in P. japonicus were performed using the Illumina HiSeq platform. After de novo assembly of transcripts, expression profiling and identified differentially expressed genes (DEGs) were performed. Furthermore, putative functions of identified DEGs correlated with ginsenoside in P. japonicus were explored using Gene Ontology terms and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analysis. A total of 221,804 unigenes were obtained from the transcriptome of P. japonicus. The further analysis revealed that 10,839 unigenes were mapped to 91 KEGG pathways. Furthermore, a total of two metabolic pathways of P. japonicus in response to drought and salt stress related to triterpene saponin synthesis were screened. The sesquiterpene and triterpene metabolic pathways were annotated and finally putatively involved in ginsenoside content and correlation analysis of the expression of these genes were analyzed to identify four genes, ß-amyrin synthase, isoprene synthase, squalene epoxidase, and 1-deoxy-D-ketose-5-phosphate synthase, respectively. Our results paves the way for screening highly expressed genes and mining genes related to triterpenoid saponin synthesis. It also provides valuable references for the study of genes involved in ginsenoside biosynthesis and signal pathway of P. japonicus.

Altered hepatic and intestinal homeostasis in a neonatal murine model of short-term total parenteral nutrition and antibiotics.

Parenteral nutrition (PN) prevents starvation and supports metabolic requirements intravenously when patients are unable to be fed enterally. Clinically, infants are frequently provided PN in intensive care settings along with exposure to antibiotics (ABX) to minimize infection during care. Unfortunately, neonates experience extremely high rates of hepatic complications. Adult rodent and piglet models of PN are well-established but neonatal models capable of leveraging the considerable transgenic potential of the mouse remain underdeveloped. Utilizing our newly established neonatal murine PN mouse model, we administered ABX or controlled drinking water to timed pregnant dams to disrupt the maternal microbiome. We randomized mouse pups to PN or sham surgery controls +/- ABX exposure. ABX or short-term PN decreased liver and brain organ weights, intestinal length, and mucosal architecture (vs. controls). PN significantly elevated evidence of hepatic proinflammatory markers, neutrophils and macrophage counts, bacterial colony-forming units, and evidence of cholestasis risk, which was blocked by ABX. However, ABX uniquely elevated metabolic regulatory genes resulting in accumulation of hepatocyte lipids, triglycerides, and elevated tauro-chenoxycholic acid (TCDCA) in serum. Within the gut, PN elevated the relative abundance of Akkermansia, Enterococcus, and Suterella with decreased Anaerostipes and Lactobacillus compared with controls, whereas ABX enriched Proteobacteria. We conclude that short-term PN elevates hepatic inflammatory stress and risk of cholestasis in early life. Although concurrent ABX exposure protects against hepatic immune activation during PN, the dual exposure modulates metabolism and may contribute toward early steatosis phenotype, sometimes observed in infants unable to wean from PN.NEW & NOTEWORTHY This study successfully established a translationally relevant, murine neonatal parenteral nutrition (PN) model. Short-term PN is sufficient to induce hepatitis-associated cholestasis in a neonatal murine model that can be used to understand disease in early life. The administration of antibiotics during PN protects animals from bacterial translocation and proinflammatory responses but induces unique metabolic shifts that may predispose the liver toward early steatosis.

Experimental Verification of Dissipation-Time Uncertainty Relation.

Dissipation is vital to any cyclic process in realistic systems. Recent research focus on nonequilibrium processes in stochastic systems has revealed a fundamental trade-off, called dissipation-time uncertainty relation, that entropy production rate associated with dissipation bounds the evolution pace of physical processes [Phys. Rev. Lett. 125, 120604 (2020)PRLTAO0031-900710.1103/PhysRevLett.125.120604]. Following the dissipative two-level model exemplified in the same Letter, we experimentally verify this fundamental trade-off in a single trapped ultracold ^{40}Ca^{+} ion using elaborately designed dissipative channels, along with a postprocessing method developed in the data analysis, to build the effective nonequilibrium stochastic evolutions for the energy transfer between two heat baths mediated by a qubit. Since the dissipation-time uncertainty relation imposes a constraint on the quantum speed regarding entropy flux, our observation provides the first experimental evidence confirming such a speed restriction from thermodynamics on quantum operations due to dissipation, which helps us further understand the role of thermodynamical characteristics played in quantum information processing.

Global deficiency of stearoyl-CoA desaturase-2 protects against diet-induced adiposity.

In mouse, there are four stearoyl-CoA desaturase isoforms (SCD1-4) that catalyze the synthesis of monounsaturated fatty acids. Previously, we have shown that mice harboring a whole body deletion of the SCD1 isoform (SCD1KO) are protected from diet and genetically induced adiposity. Here, we report that global deletion of the SCD2 isoform (SCD2KO) provides a similar protective effect against the onset of both high-fat diet (HFD) and high-carbohydrate diet (HCD) induced adiposity. After 10 weeks of HFD feeding or 6 weeks of HCD feeding, SCD2KO mice failed to gain weight and had decreased fat mass. On HFD, SCD2KO mice remained glucose and insulin tolerant. Lastly, the markers for energy expenditure, UCP1 and PGC-1α, were increased in the brown adipose tissue of HFD fed SCD2KO mice.

Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, exhibits minimal immunogenicity in patients with moderate-to-severe plaque psoriasis.

BACKGROUND: The proinflammatory cytokine interleukin (IL)-17A plays a pivotal role in psoriasis pathogenesis. Secukinumab, a fully human monoclonal antibody (mAb) that selectively targets IL-17A, has been demonstrated to be highly efficacious for the treatment of moderate-to-severe psoriasis, starting at early time points, with a sustained effect and a favourable safety profile. mAb therapies may be associated with production of antidrug antibodies (ADAs) that can affect drug pharmacokinetics, diminish response or cause hypersensitivity reactions. OBJECTIVES: To investigate the immunogenicity of secukinumab across six phase III clinical trials in which patients with plaque psoriasis were treated with secukinumab for up to 52 weeks and additionally followed up at week 60. METHODS: Immunogenicity in patients with plaque psoriasis exposed to secukinumab was evaluated at baseline and at weeks 12, 24, 52 and 60. Treatment-emergent (TE)-ADAs were defined as a positive ADA signal detected in post-treatment samples from patients with a negative baseline signal. Confirmed positive samples were further analysed for their drug-neutralizing potential. RESULTS: Among 2842 patients receiving secukinumab and evaluated for ADAs, 11 (0·4%) developed TE-ADAs. Associations between TE-ADAs and secukinumab dose, frequency or mode of administration were not observed. Neutralizing antibodies were detected in three of nine evaluable patients with TE-ADAs. CONCLUSIONS: Secukinumab immunogenicity was low, as shown by TE-ADA detection in only 11 of 2842 (0·4%) patients with moderate-to-severe plaque psoriasis treated with secukinumab. All but one of the patients with TE-ADAs were biologic naive. Neither TE-ADAs nor neutralizing antibodies were associated with loss of secukinumab efficacy or issues of clinical concern.

Fluorine Pseudocontact Shifts Used for Characterizing the Protein-Ligand Interaction Mode in the Limit of NMR Intermediate Exchange.

The characterization of protein-ligand interaction modes becomes recalcitrant in the NMR intermediate exchange regime as the interface resonances are broadened beyond detection. Here, we determined the 19 F low-populated bound-state pseudocontact shifts (PCSs) of mono- and di-fluorinated inhibitors of the BRM bromodomain using a highly skewed protein/ligand ratio. The bound-state 19 F PCSs were retrieved from 19 F chemical exchange saturation transfer (CEST) in the presence of the lanthanide-labeled protein, which was termed the 19 F PCS-CEST approach. These PCSs enriched in spatial information enabled the identification of best-fitting poses, which agree well with the crystal structure of a more soluble analog in complex with the BRM bromodomain. This approach fills the gap of the NMR structural characterization of lead-like inhibitors with moderate affinities to target proteins, which are essential for structure-guided hit-to-lead evolution.

Delayed refractory hyperventilation following endoscopic third ventriculostomy in a 5-year-old boy.

We present the case of a 5-year-old boy who developed a delayed onset intractable hyperventilation following endoscopic third ventriculostomy. The proposed aetiology of this exceptionally rare phenomenon is discussed. To our knowledge, previous cases have only been reported in the adult population.

Topography and age mediate the growth responses of Smith fir to climate warming in the southeastern Tibetan Plateau.

The Tibetan Plateau holds some of the world's highest undisturbed natural treelines and timberlines. Such extreme environments constitute potentially valuable monitoring sites of the effects of climate warming on high-elevation forests. Here, we analyze a network of 21 Smith fir forests situated in the Sygera Mountains, southeastern Tibetan Plateau, using tree-ring width (TRW) and basal area increment (BAI) chronologies. Sampled sites encompassed a wide elevation gradient, from 3600 to 4400 m, including some treeline sites and diverse aspects and tree ages. In comparison with TRW series, BAI series better capture the long-term warming signal. Previous November and current April and summer temperatures are the dominant climatic factors controlling Smith fir radial growth. The mean inter-series correlations of TRW increased upwards, but the forest limit presented the highest potential to reconstruct past temperature variability. Moreover, the growth responses of young trees were less stable than those of trees older than 100 years. Climate warming is accelerating radial growth of Smith fir forest subjected to mesic conditions. Collectively, these findings confirm that the effects of site elevation and tree age should be considered when quantifying climate-growth relationships. The type of tree-ring data (BAI vs. TRW) is also relevant since BAI indices seem to be a better climatic proxy of low-frequency temperature signals than TRW indices. Therefore, site (e.g., elevation) and tree (e.g., age) features should be considered to properly evaluate the effects of climate warming on growth of high-elevation forests.

[Impact of long-term continuous positive airway pressure treatment for patients with obstructive sleep apnea syndrome].

OBJECTIVE: To investigate the long-term efficacy of continuous positive airway pressure (CPAP) treatment for patients with obstructive sleep apnea syndrome (OSAS). METHODS: This case control study was performed among 154 patients with moderate or severe OSAS between September 2009 and September 2014. Patients were divided into treatment group (n=66, 53 patients with hypertension) and control group (n=88, 67 patients with hypertension). The long-term efficacy of CPAP treatment on clinical events and blood pressure was evaluated. RESULTS: The combined incidence of death, myocardial infarction, coronary revascularization and stroke events was 1.5% (1/66) in treatment group and 11.4% (10/88) in control group (P<0.05). CPAP treatment also led to more significant reduction in systolic blood pressure ((12.24±18.06) mmHg(1 mmHg=0.133 kPa) to (4.24±16.63) mmHg, P<0.05) in the patients with hypertension in these two groups. CONCLUSIONS: CPAP treatment could reduce the risk of cardiovascular and neurovascular events for patients with moderate or severe OSAS.

Adult-onset deficiency of acyl CoA:monoacylglycerol acyltransferase 2 protects mice from diet-induced obesity and glucose intolerance.

Acyl-CoA:monoacylglycerol acyltransferase (MGAT) 2 catalyzes triacylglycerol (TAG) synthesis, required in intestinal fat absorption. We previously demonstrated that mice without a functional MGAT2-coding gene (Mogat2(-/-)) exhibit increased energy expenditure and resistance to obesity induced by excess calories. One critical question raised is whether lacking MGAT2 during early development is required for the metabolic phenotypes in adult mice. In this study, we found that Mogat2(-/-) pups grew slower than wild-type littermates during the suckling period. To determine whether inactivating MGAT2 in adult mice is sufficient to confer resistance to diet-induced obesity, we generated mice with an inducible Mogat2-inactivating mutation. Mice with adult-onset MGAT2 deficiency (Mogat2(AKO)) exhibited a transient decrease in food intake like Mogat2(-/-) mice when fed a high-fat diet and a moderate increase in energy expenditure after acclimatization. They gained less weight than littermate controls, but the difference was smaller than that between wild-type and Mogat2(-/-) mice. The moderate reduction in weight gain was associated with reduced hepatic TAG and improved glucose tolerance. Similar protective effects were also observed in mice that had gained weight on a high-fat diet before inactivating MGAT2. These findings suggest that adult-onset MGAT2 deficiency mitigates metabolic disorders induced by high-fat feeding and that MGAT2 modulates early postnatal nutrition and may program metabolism later in life.

In situ investigation of the surface morphology evolution of the bulk ceramic Y2Mo3O12 during crystal water release.

The surface morphology evolution of the bulk ceramic Y2Mo3O12 during the release of crystal water is followed in situ for the first time using atomic force microscopy. It is found that both the shape and size of individual grains and the integration morphology of the sample exhibit dynamic changes with increasing temperature. We believe that the surface morphology evolution of the sample with increasing temperature is closely correlated with the forces induced by the contraction and expansion of the lattice during crystal water release in two different stages.

Pan-cancer analysis of 60S Ribosomal Protein L7-Like 1 (RPL7L1) and validation in liver hepatocellular carcinoma.

BACKGROUND AND AIMS: There is an association between cancer and increased ribosome biogenesis. At present, the RPL7L1 (60S Ribosomal Protein L7-Like 1) were less reported by literature search. Study reports that RPL7L1 is associated with mouse embryonic and skeletal muscle. The study of RPL7L1 on tumors has not been reported. METHODS: Our team downloaded the pan-cancer dataset that is uniformly normalized from the UCSC database (N=19131). Our study examined the relationship between RPL7L1 expression level and clinical prognosis with methylation, anti-tumour immunity, functional states, MSI, TMB, DNSss, LOH and chemotherapeutic responses in 43 cancer types and subtypes. RESULTS AND CONCLUSIONS: RPL7L1 was overexpressed in nine tumor types. Gene mutation, tumor microenvironment and methylation modification of RPL7L1 plays a key role in patient prognosis. And the high expression of RPL7L1 was associated with TMB, MSI, LOH especially LIHC and HNSC. We experimentally verified that genes can promote the proliferation and migration of tumor cells. Our study suggested that RPL7L1 biomarker can be used for treating cancer, detecting it, and predicting its prognosis.

A first-in-human phase I study of a novel MDM2/p53 inhibitor alrizomadlin in advanced solid tumors.

BACKGROUND: The mouse double minute 2 homolog (MDM2) oncogene exerts oncogenic activities in many cancers and represents a potential therapeutic target. This trial evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of alrizomadlin (APG-115), a novel MDM2/p53 inhibitor, in patients with advanced solid tumors. PATIENTS AND METHODS: Patients with histologically confirmed advanced solid tumors who had progressed to standard treatment or lacked effective therapies were recruited. Alrizomadlin was administered once daily every other day for 21 days of a 28-day cycle until disease progression or intolerable toxicity. RESULTS: A total of 21 patients were enrolled and treated with alrizomadlin; 57.1% were male and the median age was 47 (25-60) years. The maximum tolerated dose of alrizomadlin was 150 mg and the recommended phase II dose was 100 mg. One patient in the 200-mg cohort experienced dose-limiting toxicity of thrombocytopenia and febrile neutropenia. The most common grade 3/4 treatment-related adverse events were thrombocytopenia (33.3%), lymphocytopenia (33.3%), neutropenia (23.8%), and anemia (23.8%). Alrizomadlin demonstrated approximately linear pharmacokinetics (dose range 100-200 mg) and was associated with increased plasma macrophage inhibitory cytokine-1, indicative of p53 pathway activation. Of the 20 assessable patients, 2 [10%, 95% confidence interval (CI) 1.2% to 31.7%] patients achieved partial response and 10 (50%, 95% CI 27.2% to 72.8%) showed stable disease. The median progression-free survival was 6.1 (95% CI 1.7-10.4) months, which was significantly longer in patients with wild-type versus mutant TP53 (7.9 versus 2.2 months, respectively; P < 0.001). Among patients with MDM2 amplification and wild-type TP53, the overall response rate was 25% (2/8) and the disease control rate was 100% (8/8). CONCLUSIONS: Alrizomadlin had an acceptable safety profile and demonstrated promising antitumor activity in MDM2-amplified and TP53 wild-type tumors. This study supports further exploration of alrizomadlin with recommended doses of 100 mg q.o.d. in 21 days on and 7 days off regimen.

A novel cancer-germline gene DAZL promotes progression and cisplatin resistance of non-small cell lung cancer by upregulating JAK2 and MCM8.

Germline-specific genes are usually activated in cancer cells and drive cancer progression; such genes are called cancer-germline or cancer-testis genes. The RNA-binding protein DAZL is predominantly expressed in germ cells and plays a role in gametogenesis as a translational activator or repressor. However, its expression and role in non-small cell lung cancer (NSCLC) are unknown. Here, mining of RNA-sequencing data from public resources and immunohistochemical analysis of tissue microarrays showed that DAZL was expressed exclusively in testis among normal human tissues but ectopically expressed in NSCLC tissues. Testis and NSCLC cells expressed the shorter and longer transcript variants of the DAZL gene, respectively. Overexpression of the longer DAZL transcript promoted tumor growth in a mouse xenograft model. Silencing of DAZL suppressed cell proliferation, colony formation, migration, invasion, and cisplatin resistance in vitro and tumor growth in vivo. Quantitative proteomic analysis based on tandem mass tag and Western blot analysis showed that DAZL upregulated the expression of JAK2 and MCM8. RNA-binding protein immunoprecipitation assays showed that DAZL bound to the mRNA of JAK2 and MCM8. The JAK2 inhibitor fedratinib attenuated the oncogenic outcomes induced by DAZL overexpression, whereas silencing MCM8 counteracted the effects of DAZL overexpression on cisplatin-damaged DNA synthesis and half-maximal inhibitory concentration of cisplatin. In conclusion, DAZL was identified as a novel cancer-germline gene that enhances the translation of JAK2 and MCM8 to promote NSCLC progression and resistance to cisplatin, respectively. These findings suggest that DAZL is a potential therapeutic target in NSCLC.

Dietary lipid is largely deposited in skin and rapidly affects insulating properties.

Skin has been shown to be a regulatory hub for energy expenditure and metabolism: mutations of skin lipid metabolism enzymes can change the rate of thermogenesis and susceptibility to diet-induced obesity. However, little is known about the physiological basis for this function. Here we show that the thermal properties of skin are highly reactive to diet: within three days, a high fat diet reduces heat transfer through skin. In contrast, a dietary manipulation that prevents obesity accelerates energy loss through skins. We found that skin was the largest target in a mouse body for dietary fat delivery, and that fat was assimilated both by epidermis and by dermal white adipose tissue. Dietary triglyceride acyl groups persist in skin for weeks after feeding. Using multi-modal lipid profiling, we have implicated both keratinocytes and sebocytes in the altered lipids which correlate with thermal function. In response to high fat feeding, wax diesters and ceramides accumulate, and triglycerides become more saturated. In contrast, in response to the dramatic loss of adipose tissue that accompanies restriction of the branched chain amino acid isoleucine, skin becomes highly heat-permeable: skins shows limited uptake of dietary lipids and editing of wax esters, and acquires a signature of depleted signaling lipids, which include the acyl carnitines and lipid ethers. We propose that skin should be routinely included in physiological studies of lipid metabolism, given the size of the skin lipid reservoir and its adaptable functionality.

Coronaviruses in bats from Mexico.

Bats are reservoirs for a wide range of human pathogens including Nipah, Hendra, rabies, Ebola, Marburg and severe acute respiratory syndrome coronavirus (CoV). The recent implication of a novel beta (ß)-CoV as the cause of fatal respiratory disease in the Middle East emphasizes the importance of surveillance for CoVs that have potential to move from bats into the human population. In a screen of 606 bats from 42 different species in Campeche, Chiapas and Mexico City we identified 13 distinct CoVs. Nine were alpha (α)-CoVs; four were ß-CoVs. Twelve were novel. Analyses of these viruses in the context of their hosts and ecological habitat indicated that host species is a strong selective driver in CoV evolution, even in allopatric populations separated by significant geographical distance; and that a single species/genus of bat can contain multiple CoVs. A ß-CoV with 96.5 % amino acid identity to the ß-CoV associated with human disease in the Middle East was found in a Nyctinomops laticaudatus bat, suggesting that efforts to identify the viral reservoir should include surveillance of the bat families Molossidae/Vespertilionidae, or the closely related Nycteridae/Emballonuridae. While it is important to investigate unknown viral diversity in bats, it is also important to remember that the majority of viruses they carry will not pose any clinical risk, and bats should not be stigmatized ubiquitously as significant threats to public health.

LMNB1 targets FOXD1 to promote progression of prostate cancer.

Forkhead box D1 (FOXD1) expression is upregulated in various types of human cancer. To the best of our knowledge, the roles of FOXD1 in prostate cancer (PC) remain largely unknown. The Cancer Genome Atlas dataset was used for the bioinformatics analysis of FOXD1 in PC. FOXD1 expression levels in normal immortalized human prostate epithelial cells (RWPE-1) and prostate cancer cells were detected by reverse transcription-quantitative PCR. PC cell viability was detected using Cell Counting Kit-8 assay. Transwell assays were performed to assess the migration and invasion of PC cells. Luciferase reporter gene assay was used to validate the association between FOXD1 and lamin (LMN)B1. LMNB1 is an important part of the cytoskeleton, which serves an important role in the process of tumor occurrence and development, regulating apoptosis and DNA repair. FOXD1 expression was upregulated in PC tissues, with its high expression being associated with clinical stage and survival in PC. Knockdown of FOXD1 inhibited viability, migration and invasion of PC cells. FOXD1 positively regulated LMNB1 expression. The effect of FOXD1 knockdown on PC cells was reversed by LMNB1 overexpression. In conclusion, FOXD1, positively regulated by LMNB1, served as an oncogene in PC and may be a potential biomarker and treatment target for PC.

Defining blood gas analysis stability limits across five sample types.

Accurate reporting of blood gas samples is dependent upon following proper preanalytical sample handling requirements though there is variation for sample acceptability criteria across institutions. We examined five common sample types (arterial, venous, umbilical arterial, umbilical venous and capillary) stored at either room temperature or on crushed ice in a time series (0, 15, 30, 45, 60, 90, 180, 240 min) and applied local regulatory and/or institutional allowable performance limits to determine the need for cold preservation and/or maximum stability time for pH, pO2, pCO2, glucose, lactate, sodium, potassium, chloride, and ionized calcium where applicable in each sample type. Although changes in sample pO2 and/or lactate values were responsible, in part or in whole, for surpassing the allowable limits in nearly all sample types analyzed, this was not uniformly observed across sample types within the typical time limits that are referenced in literature. Furthermore, we demonstrated that cold preservation may not ubiquitously provide longer stability for blood gas specimens and this is dependent on the sample type and analyte in question. Nevertheless, these results demonstrate the known instability of pO2 and lactate and suggest that it may be possible to simplify the monitoring of preanalytical conditions by first evaluating pO2 and lactate in patient blood gas samples if applicable.