Aneuploidy Causes Non-genetic Individuality.

Phenotypic variability is a hallmark of diseases involving chromosome gains and losses, such as Down syndrome and cancer. Allelic variances have been thought to be the sole cause of this heterogeneity. Here, we systematically examine the consequences of gaining and losing single or multiple chromosomes to show that the aneuploid state causes non-genetic phenotypic variability. Yeast cell populations harboring the same defined aneuploidy exhibit heterogeneity in cell-cycle progression and response to environmental perturbations. Variability increases with degree of aneuploidy and is partly due to gene copy number imbalances, suggesting that subtle changes in gene expression impact the robustness of biological networks and cause alternate behaviors when they occur across many genes. As inbred trisomic mice also exhibit variable phenotypes, we further propose that non-genetic individuality is a universal characteristic of the aneuploid state that may contribute to variability in presentation and treatment responses of diseases caused by aneuploidy.

Enantioselective synthesis of 4-aryl-3,4-dihydrocoumarins via N-heterocyclic carbene catalyzed ß-arylation/cyclization of α-bromoenals.

4-Aryl-3,4-dihydrocoumarins are one of the most important structural motifs. Herein, we disclose an enantioselective N-heterocyclic carbene catalyzed ß-arylation/cyclization of α-bromoenals with 3-aminophenols under mild conditions. The protocol allows for the rapid preparation of 4-aryl-3,4-dihydrocoumarins in acceptable yields with good enantioselectivities. The products of this reaction could be converted into chiral diarylpropanoic acid derivatives without erosion of the enantioselectivity.

Safety, tolerability, pharmacokinetics, and antiviral activity of the novel core protein allosteric modulator ZM-H1505R (Canocapavir) in chronic hepatitis B patients: a randomized multiple-dose escalation trial.

BACKGROUND: Hepatitis B virus (HBV) core protein-targeting antivirals (CpTAs) are promising therapeutic agents for treating chronic hepatitis B (CHB). In this study, the antiviral activity, pharmacokinetics (PK), and tolerability of ZM-H1505R (Canocapavir), a chemically unique HBV CpTA, were evaluated in patients with CHB. METHODS: This study was a double-blind, randomized, placebo-controlled phase 1b trial in Chinese CHB patients. Noncirrhotic and treatment-naive CHB patients were divided into three cohorts (10 patients per cohort) and randomized within each cohort in a ratio of 4:1 to receive a single dose of 50, 100, or 200 mg of Canocapavir or placebo once a day for 28 consecutive days. RESULTS: Canocapavir was well tolerated, with the majority of adverse reactions being grade I or II in severity. There were no serious adverse events, and no patients withdrew from the study. Corresponding to 50, 100, and 200 mg doses of Canocapavir, the mean plasma trough concentrations of the drug were 2.7-, 7.0-, and 14.6-fold of its protein-binding adjusted HBV DNA EC50 (135 ng/mL), respectively, with linear PK and a low-to-mild accumulation rate (1.26-1.99). After 28 days of treatment, the mean maximum HBV DNA declines from baseline were -1.54, -2.50, -2.75, and -0.47 log10 IU/mL for the 50, 100, and 200 mg of Canocapavir or placebo groups, respectively; and the mean maximum pregenomic RNA declines from baseline were -1.53, -2.35, -2.34, and -0.17 log10 copies/mL, respectively. CONCLUSIONS: Canocapavir treatment is tolerated with efficacious antiviral activity in CHB patients, supporting its further development in treating HBV infection. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT05470829).

In Situ Microreaction Platform Based on Acoustic Droplet Manipulation for Ultra-High-Precision Multiplex Bioassay.

Liquid droplets rectors have been used in clinical diagnosis, high throughput screening and bioassay. However, it is challenging for droplet reactors to be used in practical applications due to the difficulty of uniformly mixing ultrasmall volumes of samples and the lack of rapid and high-precision detection protocols. Here, we have developed an acoustic droplet system for rapid and efficient biological detection and chemical screening. By employing acoustic wave devices, rapid and nondestructive uniform mixing of ∼nL-µL droplets can be achieved. By the acoustophoretic force, the perturbation of the droplets can quickly concentrate the sample and increase the detection limit by five times. Through the color reaction and the coordinated detection of photodiodes, we have developed a biomarker detection protocol with short reaction time and high accuracy. As a proof-of-concept application, we demonstrated that this system can detect ultrasmall or low-abundance samples faster and more accurately, highlighting its wide application in analytical chemistry, basic research, and clinical medicine.

Computational analysis of GAL pathway pinpoints mechanisms underlying natural variation.

Quantitative traits are measurable phenotypes that show continuous variation over a wide phenotypic range. Enormous effort has recently been put into determining the genetic influences on a variety of quantitative traits with mixed success. We identified a quantitative trait in a tractable model system, the GAL pathway in yeast, which controls the uptake and metabolism of the sugar galactose. GAL pathway activation depends both on galactose concentration and on the concentrations of competing, preferred sugars such as glucose. Natural yeast isolates show substantial variation in the behavior of the pathway. All studied yeast strains exhibit bimodal responses relative to external galactose concentration, i.e. a set of galactose concentrations existed at which both GAL-induced and GAL-repressed subpopulations were observed. However, these concentrations differed in different strains. We built a mechanistic model of the GAL pathway and identified parameters that are plausible candidates for capturing the phenotypic features of a set of strains including standard lab strains, natural variants, and mutants. In silico perturbation of these parameters identified variation in the intracellular galactose sensor, Gal3p, the negative feedback node within the GAL regulatory network, Gal80p, and the hexose transporters, HXT, as the main sources of the bimodal range variation. We were able to switch the phenotype of individual yeast strains in silico by tuning parameters related to these three elements. Determining the basis for these behavioral differences may give insight into how the GAL pathway processes information, and into the evolution of nutrient metabolism preferences in different strains. More generally, our method of identifying the key parameters that explain phenotypic variation in this system should be generally applicable to other quantitative traits.

Computational study on ratio-sensing in yeast galactose utilization pathway.

Metabolic networks undergo gene expression regulation in response to external nutrient signals. In microbes, the synthesis of enzymes that are used to transport and catabolize less preferred carbon sources is repressed in the presence of a preferred carbon source. For most microbes, glucose is a preferred carbon source, and it has long been believed that as long as glucose is present in the environment, the expression of genes related to the metabolism of alternative carbon sources is shut down, due to catabolite repression. However, recent studies have shown that the induction of the galactose (GAL) metabolic network does not solely depend on the exhaustion of glucose. Instead, the GAL genes respond to the external concentration ratio of galactose to glucose, a phenomenon of unknown mechanism that we termed ratio-sensing. Using mathematical modeling, we found that ratio-sensing is a general phenomenon that can arise from competition between two carbon sources for shared transporters, between transcription factors for binding to communal regulatory sequences of the target genes, or a combination of the aforementioned two levels of competition. We analyzed how the parameters describing the competitive interaction influenced ratio-sensing behaviors in each scenario and found that the concatenation of both layers of signal integration could expand the dynamical range of ratio-sensing. Finally, we investigated the influence of circuit topology on ratio-sensing and found that incorporating negative auto-regulation and/or coherent feedforward loop motifs to the basic signal integration unit could tune the sensitivity of the response to the external nutrient signals. Our study not only deepened our understanding of how ratio-sensing is achieved in yeast GAL metabolic regulation, but also elucidated design principles for ratio-sensing signal processing that can be used in other biological settings, such as being introduced into circuit designs for synthetic biology applications.

Polymorphisms in the yeast galactose sensor underlie a natural continuum of nutrient-decision phenotypes.

In nature, microbes often need to "decide" which of several available nutrients to utilize, a choice that depends on a cell's inherent preference and external nutrient levels. While natural environments can have mixtures of different nutrients, phenotypic variation in microbes' decisions of which nutrient to utilize is poorly studied. Here, we quantified differences in the concentration of glucose and galactose required to induce galactose-responsive (GAL) genes across 36 wild S. cerevisiae strains. Using bulk segregant analysis, we found that a locus containing the galactose sensor GAL3 was associated with differences in GAL signaling in eight different crosses. Using allele replacements, we confirmed that GAL3 is the major driver of GAL induction variation, and that GAL3 allelic variation alone can explain as much as 90% of the variation in GAL induction in a cross. The GAL3 variants we found modulate the diauxic lag, a selectable trait. These results suggest that ecological constraints on the galactose pathway may have led to variation in a single protein, allowing cells to quantitatively tune their response to nutrient changes in the environment.

[Risk factors for cow's milk protein allergy in infants: a multicenter survey].

OBJECTIVE: To investigate the risk factors for cow's milk protein allergy (CMPA) among infants through a multicenter clinical study. METHODS: A total of 1 829 infants, aged 1-12 months, who attended the outpatient service of the pediatric department in six hospitals in Shenzhen, China from June 2016 to May 2017 were enrolled as subjects. A questionnaire survey was performed to screen out suspected cases of CMPA. Food avoidance and oral food challenge tests were used to make a confirmed diagnosis of CMPA CMPA. A multivariate logistic regression analysis was used to investigate the risk factors for CMPA. RESULTS: Among the 1 829 infants, 82 (4.48%) were diagnosed with CMPA. The multivariate logistic regression analysis showed that maternal food allergy (OR=4.91, 95%CI: 2.24-10.76, P<0.05), antibiotic exposure during pregnancy (OR=3.18, 95%CI: 1.32-7.65, P<0.05), and the introduction of complementary food at an age of <4 months (OR=3.55, 95%CI: 1.52-8.27, P<0.05) were risk factors for CMPA, while exclusive breastfeeding (OR=0.21, 95%CI: 0.08-0.58, P<0.05) and the introduction of complementary food at an age of >6 months (OR=0.38, 95%CI: 0.17-0.86, P<0.05) were protective factors. CONCLUSIONS: The introduction of complementary food at an age of <4 months, maternal food allergy, and antibiotic exposure during pregnancy are risk factors for CMPA in infants.

Natural variation in preparation for nutrient depletion reveals a cost-benefit tradeoff.

Maximizing growth and survival in the face of a complex, time-varying environment is a common problem for single-celled organisms in the wild. When offered two different sugars as carbon sources, microorganisms first consume the preferred sugar, then undergo a transient growth delay, the "diauxic lag," while inducing genes to metabolize the less preferred sugar. This delay is commonly assumed to be an inevitable consequence of selection to maximize use of the preferred sugar. Contrary to this view, we found that many natural isolates of Saccharomyces cerevisiae display short or nonexistent diauxic lags when grown in mixtures of glucose (preferred) and galactose. These strains induce galactose utilization (GAL) genes hours before glucose exhaustion, thereby "preparing" for the transition from glucose to galactose metabolism. The extent of preparation varies across strains, and seems to be determined by the steady-state response of GAL genes to mixtures of glucose and galactose rather than by induction kinetics. Although early GAL gene induction gives strains a competitive advantage once glucose runs out, it comes at a cost while glucose is still present. Costs and benefits correlate with the degree of preparation: strains with higher expression of GAL genes prior to glucose exhaustion experience a larger upfront growth cost but also a shorter diauxic lag. Our results show that classical diauxic growth is only one extreme on a continuum of growth strategies constrained by a cost-benefit tradeoff. This type of continuum is likely to be common in nature, as similar tradeoffs can arise whenever cells evolve to use mixtures of nutrients.

Elevated Transient Receptor Potential Melastatin 8 (TRPM8) Expression Is Correlated with Poor Prognosis in Pancreatic Cancer.

BACKGROUND The transient receptor potential melastatin 8 (TRPM8) was found to be expressed abnormally in a variety of tumors and is associated with unfavorable prognosis in human cancers. However, its clinical significance in pancreatic cancer (PC) is mostly unknown. MATERIAL AND METHODS qRT-PCR was performed to measure the expression of TRPM8 in 110 pairs of PC tissues and the adjacent non-cancerous tissues. The association of TRPM8 expression with the clinical characters of PC patients was analyzed using the chi-square test. Furthermore, the prognostic value of TRPM8 was determined with Kaplan-Meier survival curve and Cox regression analysis. RESULTS We found that the expression level of TRPM8 was significantly elevated in PC tissues compared to the non-cancerous controls (P<0.001). In addition, a close relationship was observed between elevated TRPM8 expression with large tumor size (P=0.001), advanced TNM (P=0.013), and distant metastasis (P=0.034). Survival analysis suggested that patients with high TRPM8 expression has worse OS (P=0.001) and DFS (P<0.001) than those with low TRPM8 expression. Moreover, TRPM8 was confirmed as a valuable prognostic biomarker for OS (HR=1.913; 95% CI: 1.020-3.589; P=0.043) or DFS (HR=2.374; 95% CI: 1.269-4.443; P=0.007) of PC patients. CONCLUSIONS This study shows that TRPM8 expression is significantly up-regulated in PC and it might be a useful prognostic factor for patients with PC.

Synthesis and antitumor activity evaluation of asiatic acid derivatives as survivin inhibitor.

A series of asiatic acid derivatives were synthesized and their cytotoxicities in vitro against two cancer cell lines (HepG2 and SGC7901) were evaluated by MTT assay. The results showed that compounds I2, I6, and II6 have more potent anticancer activity than that of the positive control drug paclitaxel. The interactions between the compounds I2, I6, and II6 and survivin were also studied by docking simulations.

Peripheral Amplification of Multi-Resonance Induced Thermally Activated Delayed Fluorescence for Highly Efficient OLEDs.

Multi-resonance induced by boron and nitrogen atoms in opposite resonance positions endows a thermally activated delayed fluorescence (MR-TADF) emitter with a strikingly small full width at half maximum of only 26 nm and excellent photoluminescence quantum yield of up to 97.48 %. The introduction of a carbazole unit in the para position of the B-substituted phenyl-ring can significantly boost up the resonance effect without compromising the color fidelity, subsequently enhancing the performances of the corresponding pure blue TADF-OLED, with an outstanding external quantum efficiency (EQE) up to 32.1 % and low efficiency roll-off, making it one of the best TADF-OLEDs in the blue region to date. Furthermore, utilizing this material as host for a yellow phosphorescent emitter, the device also shows a significantly reduced turn-on voltage of 3.2 V and an EQEmax of 22.2 %.

Functional analysis of a novel missense mutation in AXIN2 associated with non-syndromic tooth agenesis.

Tooth agenesis is a congenital anomaly frequently seen in humans. Several genes have been associated with non-syndromic tooth agenesis, including msh homeobox 1 (MSX1), paired box 9 (PAX9), axis inhibition protein 2 (AXIN2), ectodysplasin A (EDA), and wingless-type MMTV integration site family member 10A (WNT10A). In this study, we investigated a Chinese family with non-syndromic tooth agenesis. A novel missense mutation (c.C1978T) in AXIN2 was identified in affected members. The mutation results in a His660Tyr substitution located between the Axin beta-catenin binding domain and the DIX domain of the axis inhibition protein 2 (AXIN2). We analysed this novel AXIN2 mutant, together with two reported AXIN2 mutants [c.1966C>T (p.Arg656Stop) and c.1994delG (p.Leu688Stop)] that cause colorectal cancer with and without oligodontia, to study the effect of the mutant p.His660Tyr on the Wnt/ß-catenin signaling pathway and to compare the molecular pathogenesis of different AXIN2 mutants in tooth agenesis and carcinogenesis. Further in vitro experiments indicated that the mutant p.His660Tyr caused inhibition of the Wnt/ß-catenin pathway, and the mutants p.Arg656Stop and p.Leu688Stop resulted in over-activation of the Wnt/ß-catenin pathway. In line with previous AXIN2 mutation studies, we suggest that AXIN2 mutations with different levels of severity may have distinct effects on the Wnt pathway and the phenotype of disease. Our study provides functional evidence supporting the notion that both inhibition and over-activation of the Wnt pathway may lead to tooth agenesis.

Emergence of human-like H3N2 influenza viruses in pet dogs in Guangxi, China.

BACKGROUND: After the 1968 H3N2 pandemic emerged in humans, H3N2 influenza viruses continuously circulated and evolved in nature. An H3N2 variant was circulating in humans in the 1990s and subsequently introduced into the pig population in the 2000s. This virus gradually became the main subtype of swine influenza virus worldwide. However, there were no reports of infections in dogs with this virus. FINDINGS: In 2013, 35 nasal swabs from pet dogs were positive for Influenza A virus by RT-PCR. Two viruses were isolated and genetically characterized. In the phylogenetic trees of all gene segments, two H3N2 canine isolates clustered with Moscow/10/99 and most H3N2 swine influenza viruses. These results indicated that two H3N2 CIVs possessed high homology with human/swine influenza viruses, which at the same time exhibited some amino acid substitutions in NA, polymerase basic protein 1 (PB1), and nucleoprotein (NP), which probably were related to the interspecies transmission. CONCLUSIONS: These two viruses share the highest homology with swine H3N2, Moscow/99-like viruses, which indicated that these viruses might originate from swine viruses.

Efficient photoelectrochemical water splitting with ultrathin films of hematite on three-dimensional nanophotonic structures.

Photoelectrochemical (PEC) solar water splitting represents a clean and sustainable approach for hydrogen (H2) production and substantial research are being performed to improve the conversion efficiency. Hematite (α-Fe2O3) is considered as a promising candidate for PEC water splitting due to its chemical stability, appropriate band structure, and abundance. However, PEC performance based on hematite is hindered by the short hole diffusion length that put a constraint on the active layer thickness and its light absorption capability. In this work, we have designed and fabricated novel PEC device structure with ultrathin hematite film deposited on three-dimensional nanophotonic structure. In this fashion, the nanophotonic structures can largely improve the light absorption in the ultrathin active materials. In addition, they also provide large surface area to accommodate the slow surface water oxidation process. As the result, high current density of 3.05 mA cm(-2) at 1.23 V with respect to the reversible hydrogen electrode (RHE) has been achieved on such nanophotonic structure, which is about three times of that for a planar photoelectrode. More importantly, our systematic analysis with experiments and modeling revealed that the design of high performance PEC devices needs to consider not only total optical absorption, but also the absorption profile in the active material, in addition to electrode surface area and carrier collection.

[Prognostic analysis of children with Henoch-Schonlein purpura treated by Helicobacter pylori eradication therapy].

OBJECTIVE: To investigate the effect of Helicobacter pylori (Hp) eradication therapy on prognosis in children with Henoch-Schonlein purpura (HSP). METHODS: A total of 153 children with HSP were divided into Hp infection treatment group (n=22), Hp infection control group (n=21), and Hp infection-negative group (n=110). The Hp infection treatment group received one-week triple therapy for Hp eradication in addition to conventional treatment, while the Hp infection control group and Hp infection-negative group received conventional treatment. All patients were followed up for prognostic evaluation. RESULTS: The response rates of the Hp infection treatment, control, and negative groups were 86% (19/22), 90% (19/21) and 85% (94/110), respectively (P>0.05). The recurrence rates of HSP in the Hp infection treatment, control, and negative groups were 14% (3/22), 24% (5/21) and 31% (34/110), respectively (P>0.05). The incidence of Henoch-Schonlein purpura nephritis (HSPN) in the Hp infection-negative group (36%, 40/110) and control group (33%, 7/21) was significantly higher than that in the Hp infection treatment group (5%, 1/22) (P<0.05 for both), but no significant difference in the incidence of HSPN was found between the control and negative groups (P>0.05). CONCLUSIONS: One-week triple therapy for Hp eradication may be useful to reduce the incidence of HSPN in children with HSP infected with Hp.

The interplay between the microbiota and opioid in the treatment of neuropathic pain.

Neuropathic pain (NP) is characterized by its complex and multifactorial nature and limited responses to opioid therapy; NP is associated with risks of drug resistance, addiction, difficulty in treatment cessation, and psychological disorders. Emerging research on gut microbiota and their metabolites has demonstrated their effectiveness in alleviating NP and augmenting opioid-based pain management, concurrently mitigating the adverse effects of opioids. This review addresses the following key points: (1) the current advances in gut microbiota research and the challenges in using opioids to treat NP, (2) the reciprocal effects and benefits of gut microbiota on NP, and (3) the interaction between opioids with gut microbiota, as well as the benefits of gut microbiota in opioid-based treatment of NP. Through various intricate mechanisms, gut microbiota influences the onset and progression of NP, ultimately enhancing the efficacy of opioids in the management of NP. These insights pave the way for further pragmatic clinical research, ultimately enhancing the efficacy of opioid-based pain management.

Metabolomics reveals that ferroptosis participates in bisphenol A-induced testicular injury.

Objective: Bisphenol A (BPA) is a common environmental endocrine disruptor that negatively impairs male reproductive ability. This study aimed to explore the alterations in serum metabolomics that occur following BPA exposure and the mechanism via which BPA induces the death of testicular cells in a male mouse model. Methods: The mice were classified into two groups: BPA-exposed and control groups, and samples were collected for metabolomic determination, semen quality analysis, electron microscopy, enzyme-linked immunosorbent assay, quantitative real-time PCR, pathological staining, and Western blot analysis. Results: BPA exposure caused testicular damage and significantly decreased sperm quality in mice. Combined with non-target metabolomic analysis, this was closely related to ferroptosis induced by abnormal metabolites of arachidonic acid and phosphatidylcholine, and the expression of its related genes, acyl CoA synthetase 4, glutathione peroxidase 4, lysophosphatidylcholine acyltransferase 3, and phosphatidylethanolamine-binding protein 1 were altered. Conclusion: BPA induced ferroptosis, caused testicular damage, and reduced fertility by affecting lipid metabolism in male mice. Inhibiting ferroptosis may potentially function as a therapeutic strategy to mitigate the male reproductive toxicity induced by BPA.

Platinum-modulated cobalt nanocatalysts for low-temperature aqueous-phase Fischer-Tropsch synthesis.

Fischer-Tropsch synthesis (FTS) is an important catalytic process for liquid fuel generation, which converts coal/shale gas/biomass-derived syngas (a mixture of CO and H2) to oil. While FTS is thermodynamically favored at low temperature, it is desirable to develop a new catalytic system that could allow working at a relatively low reaction temperature. In this article, we present a one-step hydrogenation-reduction route for the synthesis of Pt-Co nanoparticles (NPs) which were found to be excellent catalysts for aqueous-phase FTS at 433 K. Coupling with atomic-resolution scanning transmission electron microscopy (STEM) and theoretical calculations, the outstanding activity is rationalized by the formation of Co overlayer structures on Pt NPs or Pt-Co alloy NPs. The improved energetics and kinetics from the change of the transition states imposed by the lattice mismatch between the two metals are concluded to be the key factors responsible for the dramatically improved FTS performance.

Colloid solutions for fluid resuscitation in patients with sepsis: systematic review of randomized controlled trials.

BACKGROUND: Colloids are widely used for fluid resuscitation in patients with sepsis. But the optimal type of fluid remains unclear. OBJECTIVE: Our aim was to assess the effects on mortality and safety of different colloid solutions in patients with sepsis requiring volume replacement by examining direct comparisons of colloid solutions. METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, China Biological Medicine Database, VIP Chinese Journals Database, and CNKI China National Knowledge Infrastructure Whole Article Database. Randomized clinical trials comparing different colloids in septic patients needing fluid resuscitation were selected. RESULTS: Seventeen randomized clinical trials with a total 1281 participants met the inclusion criteria. Mortality was obtained in all trials. For intervention of albumin vs. hydroxyethyl starch solution (HES), the relative risk (RR) of death was 0.98 (95% confidence interval [CI] 0.74-1.30). For intervention of albumin vs. gelatin, the RR of death was 2.4 (95% CI 0.31-18.35). For intervention of gelatin vs. HES, the RR of death was 1.02 (95% CI 0.79-1.32). For the intervention of HES vs. dextran, the RR of death was 1.38 (95% CI 0.28-6.78). For the intervention of gelatin vs. dextran, RR of death was not estimable. For albumin vs. dextran, no trial was included. Four trials of intervention of albumin vs. HES recorded the change of severity score. CONCLUSIONS: There is no evidence that one colloid solution is more effective and safer than another for fluid resuscitation in sepsis. The severity score is improved in HES, but the confidence intervals are wide.