Simultaneous evolutionary expansion and constraint of genomic heterogeneity in multifocal lung cancer.

Recent genomic analyses have revealed substantial tumor heterogeneity across various cancers. However, it remains unclear whether and how genomic heterogeneity is constrained during tumor evolution. Here, we sequence a unique cohort of multiple synchronous lung cancers (MSLCs) to determine the relative diversity and uniformity of genetic drivers upon identical germline and environmental background. We find that each multicentric primary tumor harbors distinct oncogenic alterations, including novel mutations that are experimentally demonstrated to be functional and therapeutically targetable. However, functional studies show a strikingly constrained tumorigenic pathway underlying heterogeneous genetic variants. These results suggest that although the mutation-specific routes that cells take during oncogenesis are stochastic, genetic trajectories may be constrained by selection for functional convergence on key signaling pathways. Our findings highlight the robust evolutionary pressures that simultaneously shape the expansion and constraint of genomic diversity, a principle that holds important implications for understanding tumor evolution and optimizing therapeutic strategies.Across cancer types tumor heterogeneity has been observed, but how this relates to tumor evolution is unclear. Here, the authors sequence multiple synchronous lung cancers, highlighting the evolutionary pressures that simultaneously shape the expansion and constraint of genomic heterogeneity

Evidence of genuine quantum effects in nonequilibrium entropy production

Entropy production is a fundamental concept that plays a crucial role in the second law of thermodynamics and the measure of irreversibility. It imposes rigorous constraints on the kinds of transformations allowed in thermodynamic processes. Using an optical setup, here we experimentally demonstrate the division of entropy production of an open quantum system into a population-related component and a coherence-related component, validating previous theoretical predictions. The coherence-related component represents a genuine quantum contribution with no classical counterpart. By adjusting bath temperatures and initial coherences of the system, we first derive the total entropy production due to both populations and coherences, then remove all the coherences of the system to solely obtain the population-related contribution. The difference between these two results permits to isolate the coherence-related term. Based on this division, our experiment ultimately proves that irreversibility at the quantum level can be reduced through properly harnessing the two contributions to entropy production.Comment: 7 pages, 3 figure

Engineering cofactor metabolism for improved protein and glucoamylase production in Aspergillus niger

Background: Nicotinamide adenine dinucleotide phosphate (NADPH) is an important cofactor ensuring intracellular redox balance, anabolism and cell growth in all living systems. Our recent multi-omics analyses of glucoamylase (GlaA) biosynthesis in the filamentous fungal cell factory Aspergillus niger indicated that low availability of NADPH might be a limiting factor for GlaA overproduction. Results: We thus employed the Design-Build-Test-Learn cycle for metabolic engineering to identify and prioritize effective cofactor engineering strategies for GlaA overproduction. Based on available metabolomics and 13C metabolic flux analysis data, we individually overexpressed seven predicted genes encoding NADPH generation enzymes under the control of the\ua0Tet-on gene switch in two A. niger recipient strains, one carrying a single and one carrying seven glaA gene copies, respectively, to test their individual effects on GlaA and total protein overproduction. Both strains were selected to understand if a strong pull towards glaA biosynthesis (seven gene copies) mandates a higher NADPH supply compared to the native condition (one gene copy). Detailed analysis of all 14 strains cultivated in shake flask cultures uncovered that overexpression of the gsdA gene (glucose 6-phosphate dehydrogenase), gndA gene (6-phosphogluconate dehydrogenase) and maeA gene (NADP-dependent malic enzyme) supported GlaA production on a subtle (10%) but significant level in the background strain carrying seven glaA gene copies. We thus performed maltose-limited chemostat cultures combining metabolome analysis for these three isolates to characterize metabolic-level fluctuations caused by cofactor engineering. In these cultures, overexpression of either the gndA or maeA gene increased the intracellular NADPH pool by 45% and 66%, and the yield of GlaA by 65% and 30%, respectively. In contrast, overexpression of the gsdA gene had a negative effect on both total protein and glucoamylase production. Conclusions: This data suggests for the first time that increased NADPH availability can indeed underpin protein and especially GlaA production in strains where a strong pull towards GlaA biosynthesis exists. This data also indicates that the highest impact on GlaA production can be engineered on a genetic level by increasing the flux through the pentose phosphate pathway (gndA gene) followed by engineering the flux through the reverse TCA cycle (maeA gene). We thus propose that NADPH cofactor engineering is indeed a valid strategy for metabolic engineering of A. niger to improve GlaA production, a strategy which is certainly also applicable to the rational design of other microbial cell factories.[Figure not available: see fulltext.]

Capsule membranes encapsulated with smart nanogels for facile detection of trace lead(II) ions in water

A novel method based on capsule membranes encapsulated with smart nanogels is successfully developed for facilely detecting trace lead(II) (Pb2+) ions, which are hazardous to both human health and the environment because of their toxicity. The capsule membrane system is composed of a semi-permeable calcium alginate membrane and encapsulated poly(N-isopropylacrylamide-co-acryloylamidobenzo-18-crown-6) (PNB) nanogels. The semi-permeable membrane allows Pb2+ ions and water to pass through quickly, but rejects the encapsulated nanogels and polymers totally. As soon as Pb2+ ions appear in the aqueous environment and enter into the capsule, they can be specifically recognized by encapsulated PNB nanogels via forming 18-crown-6/Pb2+ complexes that cause a Pb2+-induced phase transition of PNB nanogels from hydrophobic to hydrophilic state. As a result, the osmotic pressure inside the capsule membrane increases remarkably, and thus the elastic capsule membrane isothermally swells upon the presence of Pb2+ ions in the environmental aqueous solution. The Pb2+-induced swelling degree of the capsule membrane is dependent on the concentration of Pb2+ ions ([Pb2+]) in water. Thus, the [Pb2+] value in water is able to be easily detected by directly measuring the Pb2+-induced isothermal swelling ratio of the capsule membrane, which we demonstrate by using 15 prepared capsule membranes arranged in a line. The Pb2+-induced swelling ratios of the capsule membrane groups are easily observed with the naked eye, and the detection limit of the [Pb2+] in water is 10-9 mol L-1. Such a proposed method provides an easy and efficient strategy for facile detection of trace threat analytes in water

Clinical and Virological Characteristics of Chronic Hepatitis B Patients with Hepatic Steatosis

Abstract Objective: This study aimed to explore clinical and virological characteristics of chronic hepatitis B (CHB) patients with hepatic steatosis in order to provide a theoretical basis for the prevention and control of hepatic steatosis. Methods: A total of 360 CHB inpatients were recruited from Affiliated Dongnan Hospital of Xiamen University and divided into hepatic steatosis group and non-hepatic steatosis group. The body mass index (BMI), waist-to-hip ratio (WHR), fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), hepatitis B e antigen (HBeAg), hepatitis B virus DNA (HBV DNA) and hepatic histological changes were detected and compared between the two groups. The association of these factors with hepatic steatosis was evaluated in CHB patients. Results: BMI, FPG, TG, TC, GGT, AST and HBV DNA showed statistically significant differences between two groups (P<0.01). The patients with hepatic steatosis had markedly higher BMI, FBG, TG and TC than those without steatosis did. No significant differences were found in ALT and HBeAg between two groups (P>0.05). In male patients, there was marked difference in the WHR between two groups (P < 0.01), which was not found in female patients (P > 0.05). The severity of hepatic steatosis increased in patients with hepatic steatosis, compared to those without steatosis (P < 0. 01), but the severities of inflammation and fibrosis in the non-hepatic steatosis group were dramatically higher than those in the hepatic steatosis group (P < 0. 01). Conclusions: BMI, WHR, FBG, TG and TC appeared to be influencing factors of CHB combined with hepatic steatosis. Hepatic steatosis in CHB patients was closely related to changes in anthropometric indices and metabolic factors but not HBV. It is necessary to improve these factors to effectively prevent hepatic steatosis in CHB patients

Dissection of three quantitative trait loci for grain size on the long arm of chromosome 10 in rice (Oryza sativa L.)

Background Thousand grain weight is a key component of grain yield in rice, and a trait closely related to grain length (GL) and grain width (GW) that are important traits for grain quality. Causal genes for 16 quantitative trait loci (QTL) affecting these traits have been cloned, but more QTL remain to be characterized for establishing a genetic regulating network. A QTL controlling grain size in rice, qGS10, was previously mapped in the interval RM6100–RM228 on chromosome 10. This study aimed to delimitate this QTL to a more precise location. Method A total of 12 populations were used. The ZC9 population comprised 203 S1:2 families derived from a residual heterozygous (RH) plant in the F9 generation of the indica rice cross Teqing (TQ)/IRBB52, segregating the upper region of RM6100–RM228 and three more regions on chromosomes 1, 9, and 11. The Ti52-1 population comprised 171 S1 plants derived from one RH plant in F7 of TQ/IRBB52, segregating a single interval that was in the lower portion of RM6100–RM228. The other ten populations were all derived from Ti52-1, including five S1 populations with sequential segregating regions covering the target region and five near isogenic line (NIL) populations maintaining the same segregating pattern. QTL analysis for 1,000-grain weight, GL, and GW was performed using QTL IciMapping and SAS procedure GLM. Result Three QTL were separated in the original qGS10 region. The qGL10.1 was located in the upper region RM6704–RM3773, shown to affect GL only. The qGS10.1 was located within a 207.1-kb interval flanked by InDel markers Te20811 and Te21018, having a stable and relatively high effect on all the three traits analyzed. The qGS10.2 was located within a 1.2-Mb interval flanked by simple sequence repeat markers RM3123 and RM6673. This QTL also affected all the three traits but the effect was inconsistent across different experiments. QTL for grain size were also detected in all the other three segregating regions. Conclusion Three QTL for grain size that were tightly linked on the long arm of chromosome 10 of rice were separated using NIL populations with sequential segregating regions. One of them, qGS10.1, had a stable and relatively high effect on grain weight, GL, and GW, providing a good candidate for gene cloning. Another QTL, qGS10.2, had a significant effect on all the three traits but the effect was inconsistent across different experiments, providing an example of genotype-by-environmental interaction

Control of the dipole layer of polar organic molecules adsorbed on metal surfaces via different charge-transfer channels

Organic molecules with a permanent electric dipole moment have been widely used as a template for further growth of molecular layers in device structures. Key properties of the resulting organic films such as energy level alignment (ELA), work function, and injection/collection barrier are linked to the magnitude and direction of the dipole moment at the interface. Using angle-resolved photoemission spectroscopy (ARPES), we have systematically investigated the coverage-dependent work function and spectral line shapes of occupied molecular energy states (MES) of chloroaluminium-phthalocyanine (ClAlPc) grown on Ag(111). We demonstrate that the dipole orientation of the first ClAlPc layer can be controlled by adjusting the deposition rate and post annealing conditions; the ELA at the interface differs by ~0.4 eV between the Cl-up and -down configurations of the adsorbed ClAlPc molecules. These observations are rationalized by density-functional-theory (DFT) calculations based on a realistic model of the ClAlPc/Ag(111) interface, which reveal that the different orientations of the ClAlPc dipole layer lead to different charge-transfer channels between the adsorbed ClAlPc and Ag(111) substrate. Our findings provide a useful framework towards method development for ELA tuning

Depressive Neurosis Treated by Acupuncture for Regulating the Liver —A Report of 176 Cases

ObjectiveTo observe therapeutic effect of acupuncture for regulating the liver on depressive neurosis.MethodsIn a multi-center randomized controlled trial, 440 patients were divided into 3 groups: Acupuncture group for regulating the liver (Acup., 176 cases) was treated by acupuncture at Siguan Points, i.e. bilateral Hegu (LI 4) and Taichong (LR 3), Baihui (GV 20) and Yintang (EX-HN3) plus ear-acupuncture, Prozac group (P., 176 cases) by oral administration of Prozac, and Non-acupoint needling group (NAN, 88 cases) by acupuncture at non-acupoints as acupuncture placebo. Self-rating Depression Scale (SDS) was examined before treatment, and one month, two and three months after treatment respectively to evaluate therapeutic effect, and Rating Scale for Side Effects (SERS) was used to evaluate the safety.ResultsAfter one month of treatment, SDS scores in Acup. Group were significantly lower than that in P. Group (P<0.05) and than that in NAN Group (P<0.01), and SDS scores in P. Group were lower than that in NAN Group (P<0.05), showing the SDS scores in Acup. Group <P. Group <NAN Group. After 2 months of treatment, SDS scores in Acup. Group were also significantly lower than that in P. Group (P<0.01) and than that in NAN Group (P<0.01), and SDS scores in P. Group were also lower than that in NAN Group (P<0.05), showing the SDS scores in Acup. Group <P. Group <NAN Group. After 3 months of treatment, SDS scores in Acup. Group were also significantly lower than that in P. Group (P<0.01) and than that in NAN Group (P<0.01), and SDS scores in P. Group were also lower than that in NAN Group (P<0.01), showing the SDS score in Acup. Group <P. Group <NAN Group. After treatment, SERS scores were 0.16±0.95, 6.51±5.09 and 0.23±1.36 in Acup. Group, P. Group and NAN Group respectively. A significant difference existed between Acup. Group and P. Group (P<0.05), but no significant difference between Acup. Group and NAN Group (P>0.05), showing the SERS scores in Acup. Group <NAN Group <P. Group. No side effect was found in Acup. and NAN groups.ConclusionThe therapeutic effect of acupuncture on depressive neurosis is better than or similar to that of Prozac but with less side effect

Gut microbiota from essential tremor patients aggravates tremors in mice

Background and objectiveEssential tremor (ET) lacks effective treatments because its underlying mechanism is largely unknown, but may involve gut microbiota via the microbiome-gut-brain axis. We explored the effects of gut microbiota on ET in mice.MethodsSpecific pathogen-free C57BL/6J mice were gavaged with stools from ET patients or matched healthy individuals. After 3 weeks of gavaging, behavioral tests were performed on all mice. Next, each mouse was injected with harmaline to induce tremors. The tremor duration was recorded; the tremor score was estimated every 30 min. Behavioral tests were repeated after modeling. Intestinal tissues and fecal samples of the mice were examined using histology and 16Sr DNA sequencing, respectively.ResultsCompared with mice receiving microbiota from healthy controls, mice receiving fecal suspensions from ET patients showed worse performance in the pre-modeling behavioral tests. After modeling, ET-group mice showed significantly greater tremor scores, longer tremor duration, and worse motor performance. They also had significantly lower body weight and lower fecal pellet count. Pathological scoring revealed more severe intestinal lesions in ET-group mice. The 16S rDNA sequencing data revealed significant differences in microbiota indices, and a correlation between these indices and tremors in mice. Functional predictions indicated that the abundance of GABA-related enzymes was altered in ET-group mice.ConclusionMice transplanted with gut microbiota from ET patients showed worse performance in behavioral tests. After modeling, ET-group mice presented longer tremor duration, higher tremor score, and worse motor performance. This study provides evidence for gut microbiota dysbiosis that may affect the pathogenesis of ET

Lot-to-lot consistency study of an Escherichia coli -produced bivalent human papillomavirus vaccine in adult women: a randomized trial.

An Escherichia. coli -produced HPV-16/18 bivalent vaccine has been proved to be well-tolerated and highly efficacious against diseases associated with vaccine HPV types. As a part of the multi-center, randomized, double-blind phase III clinical trial, this lot-to-lot consistency study aimed to assess the safety and immunogenicity consistency of this novel HPV vaccine, which is also one of the objectives of the phase III trial. A total of 3689 healthy women aged 18-45 years were enrolled and randomly assigned 1:1:1 to three lots of the HPV vaccine groups. The primary outcomes were the IgG antibody level at 1 month after the last dose (month 7). In the immunogenicity per-protocol set (PPS), almost all of the participants seroconverted at month 7 and remained seropositive at month 42. For each paired comparison of the three lot groups, the two-sides of 90% CIs of GMC ratios for both IgG and neutralizing antibodies for HPV-16 and HPV-18 at month 7 were within the equivalence interval [0.5, 2]. Lot consistency was also demonstrated at month 42. The majority of recorded solicited reactions were mild or moderate. The incidences of solicited reactions of Lot 2 and Lot 3 were slightly higher than Lot 1. However, the incidences of solicited reactions of ≥ grade 3 and solicited reactions by symptoms were all similar among the three lot groups. None of the SAEs was considered related to vaccination by the investigator. In conclusion, this study demonstrates lot-to-lot consistency of the 3 consecutive lots of the E. coli -produced HPV-16/18 bivalent vaccine