Antidepressants can induce mutation and enhance persistence toward multiple antibiotics.

Antibiotic resistance is an urgent threat to global health. Antidepressants are consumed in large quantities, with a similar pharmaceutical market share (4.8%) to antibiotics (5%). While antibiotics are acknowledged as the major driver of increasing antibiotic resistance, little attention is paid to the contribution of antidepressants in this process. Here, we demonstrate that antidepressants at clinically relevant concentrations induce resistance to multiple antibiotics, even following short periods of exposure. Antibiotic persistence was also enhanced. Phenotypic and genotypic analyses revealed the enhanced production of reactive oxygen species following exposure to antidepressants was directly associated with increased resistance. An enhanced stress signature response and stimulation of efflux pump expression were also associated with increased resistance and persistence. Mathematical modeling also predicted that antidepressants would accelerate the emergence of antibiotic-resistant bacteria, and persister cells would help to maintain the resistance. Overall, our findings highlight the antibiotic resistance risk caused by antidepressants.

Inverse chirality-induced spin selectivity effect in chiral assemblies of π-conjugated polymers.

Coupling of spin and charge currents to structural chirality in non-magnetic materials, known as chirality-induced spin selectivity, is promising for application in spintronic devices at room temperature. Although the chirality-induced spin selectivity effect has been identified in various chiral materials, its Onsager reciprocal process, the inverse chirality-induced spin selectivity effect, remains unexplored. Here we report the observation of the inverse chirality-induced spin selectivity effect in chiral assemblies of π-conjugated polymers. Using spin-pumping techniques, the inverse chirality-induced spin selectivity effect enables quantification of the magnitude of the longitudinal spin-to-charge conversion driven by chirality-induced spin selectivity in different chiral polymers. By widely tuning conductivities and supramolecular chiral structures via a printing method, we found a very long spin relaxation time of up to several nanoseconds parallel to the chiral axis. Our demonstration of the inverse chirality-induced spin selectivity effect suggests possibilities for elucidating the puzzling interplay between spin and chirality, and opens a route for spintronic applications using printable chiral assemblies.

Pyrotinib is effective in both trastuzumab-sensitive and primary resistant HER2-positive breast tumors.

Objective: Primary resistance to trastuzumab frequently occurs in human epidermal growth factor receptor 2 (HER2)-positive (+) breast cancer patients and remains a clinical challenge. Pyrotinib is a novel tyrosine kinase inhibitor that has shown efficacy in the treatment of HER2+ breast cancer. However, the efficacy of pyrotinib in HER2+ breast cancer with primary trastuzumab resistance is unknown. Methods: HER2+ breast cancer cells sensitive or primarily resistant to trastuzumab were treated with trastuzumab, pyrotinib, or the combination. Cell proliferation, migration, invasion, and HER2 downstream signal pathways were analyzed. The effects of pyrotinib plus trastuzumab and pertuzumab plus trastuzumab were compared in breast cancer cells in vitro and a xenograft mouse model with primary resistance to trastuzumab. Results: Pyrotinib had a therapeutic effect on trastuzumab-sensitive HER2+ breast cancer cells by inhibiting phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and rat sarcoma virus (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase (MAPK)/extracellular-signal regulated kinase (ERK) pathways. In primary trastuzumab-resistant cells, pyrotinib inhibited cell growth, migration, invasion, and HER2 downstream pathways, whereas trastuzumab had no effects. The combination with trastuzumab did not show increased effects compared with pyrotinib alone. Compared with pertuzumab plus trastuzumab, pyrotinib plus trastuzumab was more effective in inhibiting cell proliferation and HER2 downstream pathways in breast cancer cells and tumor growth in a trastuzumab-resistant HER2+ breast cancer xenograft model. Conclusions: Pyrotinib-containing treatments exhibited anti-cancer effects in HER2+ breast cancer cells sensitive and with primary resistance to trastuzumab. Notably, pyrotinib plus trastuzumab was more effective than trastuzumab plus pertuzumab in inhibiting tumor growth and HER2 downstream pathways in HER2+ breast cancer with primary resistance to trastuzumab. These findings support clinical testing of the therapeutic efficacy of dual anti-HER2 treatment combining an intracellular small molecule with an extracellular antibody.

Mitophagy suppresses motor neuron necroptotic mitochondrial damage and alleviates necroptosis that converges to SARM1 in acrylamide-induced dying-back neuropathy.

Acrylamide (ACR), a common industrial ingredient that is also found in many foodstuffs, induces dying-back neuropathy in humans and animals. However, the mechanisms remain poorly understood. Sterile alpha and toll/interleukin 1 receptor motif-containing protein 1 (SARM1) is the central determinant of axonal degeneration and has crosstalk with different cell death programs to determine neuronal survival. Herein, we illustrated the role of SARM1 in ACR-induced dying-back neuropathy. We further demonstrated the upstream programmed cell death mechanism of this SARM1-dependent process. Spinal cord motor neurons that were induced to overexpress SARM1 underwent necroptosis rather than apoptosis in ACR neuropathy. Mechanically, non-canonical necroptotic pathways mediated mitochondrial permeability transition pore (mPTP) opening, reactive oxygen species (ROS) production, and mitochondrial fission. What's more, the final executioner of necroptosis, phosphorylation-activated mixed lineage kinase domain-like protein (MLKL), aggregated in mitochondrial fractions. Rapamycin intervention removed the impaired mitochondria, inhibited necroptosis for axon maintenance and neuronal survival, and alleviated ACR neuropathy. Our work clarified the functional links among mitophagy, necroptosis, and SARM1-dependent axonal destruction during ACR intoxication, providing novel therapeutic targets for dying-back neuropathies.

Resupply, diffusion, and bioavailability of Hg in paddy soil-water environment with flood-drain-reflood and straw amendment.

Mercury (Hg) poses a significant risk in paddy fields, particularly when it is converted to methylmercury (MeHg) and accumulates in rice. However, the bioavailability and resupply kinetics of Hg in the paddy soil-water environment are not well understood. In this study, the diffusive gradients in thin films (DGT) and the 'DGT-induced fluxes in sediments' model (DIFS) were first adopted to investigate the Hg resupply kinetics, diffusion fluxes and bioavailability in a paddy environment subjected to flood-drain-reflood treatment and straw amendment. Our results show that although the straw amendment limited the bioavailability of Hg (38.2%-47.9% lower than control) in porewater by decreasing its resupply capacity, especially with smaller straw particles, the net production of MeHg in paddy fields was significantly increased after straw amendment (73.5%-77.9% higher than control). The results of microbial sequencing indicate that enhanced methylators (e.g., family Geobacter) and non-Hg methylators (e.g., Methanosarcinaceae) played a crucial role in MeHg production following straw amendment. Moreover, Hg-containing paddy soils generally tend to release Hg into the overlying water, while drain-reflood treatment changes the direction of Hg diffusion fluxes in the paddy soil-water interface. The drainage-reflooded treatment decreases the Hg reactive and resupply capacity of the paddy soil, thereby hindering the release of Hg from soil into overlying water during the early stages of reflooding. Overall, this study provides novel insights into the behavior of Hg in paddy soil-water surface microlayers.

Microbial community function and methylmercury production in oxygen-limited paddy soil.

Methylmercury is a neurotoxic compound that can enter rice fields through rainfall or irrigation with contaminated wastewater, and then contaminate the human food chain through the consumption of rice. Flooded paddy soil has a porous structure that facilitates air exchange with the atmosphere, but the presence of trace amounts of oxygen in flooded rice field soil and its impact on microbial-mediated formation of methylmercury is still unclear. We compared the microbial communities and their functions in oxygen-depleted and oxygen-limited paddy soil. We discovered that oxygen-limited paddy soil had higher methylmercury concentration, which was strongly correlated with soil properties and methylation potential. Compared with oxygen-depleted soil, oxygen-limited soil altered the microbial composition based on 16 S rRNA sequences, but not based on hgcA sequences. Moreover, oxygen-limited soil enhanced microbial activity significantly, increasing the abundance of more than half of the KEGG pathways, especially the metabolic pathways that might be involved in methylation. Our study unveils how microbial communities influence methylmercury formation in oxygen-limited paddy soil. ENVIRONMENTAL IMPLICATIONS: This study examined how low oxygen input affects microbial-induced MeHg formation in anaerobic paddy soil. We found that oxygen-limited soil produced more MeHg than oxygen-depleted soil. Oxygen input altered the microbial community structure of 16 S rRNA sequencing in anaerobic paddy soil, but had little impact on the hgcA sequencing community structure. Microbial activity and metabolic functions related to MeHg formation were also higher in oxygen-limited paddy soil. We suggest that oxygen may not be a limiting factor for Hg methylators, and that insufficient oxygen input in flooded paddy soil increases the risk of human exposure to MeHg from rice consumption.

Quantized Exciton Motion and Fine Energy-Level Structure of a Single Perovskite Nanowire.

The quantum-confinement effect profoundly influences the exciton energy-level structures and recombination dynamics of semiconductor nanostructures but remains largely unexplored in traditional one-dimensional nanowires mainly due to their poor optical qualities. Here, we show that in defect-tolerant perovskite material of highly luminescent CsPbBr3 nanowires, the exciton's center-of-mass motion perpendicular to the axial direction is severely confined. This is reflected in the two sets of photoluminescence spectra emitted from a single CsPbBr3 nanowire, each of which consists of doublet peaks with linear polarizations perpendicular and parallel to the axial direction. Moreover, different exciton states can be mixed by the Rashba spin-orbit coupling effect, resulting in two single photoluminescence peaks with linear polarizations both along the nanowire axis. The above findings mark the emergence of an ideal platform for the exploration of intrinsic one-dimensional exciton photophysics and optoelectronics, thus bridging the long-missing research gap between the well-studied two- and zero-dimensional semiconductor nanostructures.

Rice straw as microalgal biofilm bio-carrier: Effects of indigenous microorganisms on rice straw and microalgal biomass production.

Microalgal biofilm cultivation is a promising method for efficient microalgae production. However, expensive, difficult-to-obtain and non-durable carriers hinder its up-scaling. This study adopted both sterilized and unsterilized rice straw (RS) as a carrier for the development of microalgal biofilm, with polymethyl methacrylate as control. The biomass production and chemical composition of Chlorella sorokiniana, as well as the microbial community composition during cultivation were examined. The physicochemical properties of RS before and after utilized as carrier were investigated. The biomass productivity of unsterilized RS biofilm exceeded that of suspended culture by 4.85 g m-2·d-1. The indigenous microorganisms, mainly fungus, could effectively fixed microalgae to the bio-carrier and enhance its biomass production. They could also degrade RS into dissolved matters for microalgal utilization, leading to the physicochemical properties change of RS in the direction which favored its energy conversion. This study showed that RS can be used effectively as a microalgal biofilm carrier, thus presenting a new possibility for the recycling of rice straw.

Revealing the Intrinsic Chiroptical Activity in Chiral Metal-Halide Semiconductors.

The combination of chirality and semiconducting properties has enabled chiral metal-halide semiconductors (MHS) to be promising candidates for spin- and polarization-resolved optoelectronic devices. Although several chiral MHS with rich chemical and structural diversity have been reported lately, the macroscopic origin of chiroptical activity remains elusive. Here, combining spectroscopic measurements and Mueller matrix analysis, we discover that the previously reported "apparent" anisotropy factor measured from circular dichroism (CD) in chiral MHS thin films is not an intrinsic chiroptical property, but rather, arising from an interference between the film's linear birefringence (LB) and linear dichroism (LD). We verify the presence of LB and LD effects in both one-dimensional and zero-dimensional chiral MHS thin films. We establish spectroscopic methods to decouple the genuine CD from other spurious contributions, which allows a quantitative comparison of the intrinsic chiroptical activity across different chiral MHS. The relationship between the structure and the genuine chiroptical activity is then uncovered, which is well described by the chirality-induced spin-orbit coupling in the chiral structures. Our study unveils the macroscopic origin of chiroptical activity of chiral MHS and provides design principles for obtaining high anisotropic factors for future chiral optoelectronic applications.

Prognostic value of gamma-interferon-inducible lysosomal thiol reductase expression in female patients diagnosed with breast cancer.

Because of the high heterogeneity of breast cancer outcome, identification of novel prognostic biomarkers is critical to improve patient stratification and guide precise treatment. We examined the prognostic value of gamma-interferon-inducible lysosomal thiol reductase (GILT) expression in a training set of 416 breast cancer patients and a validation set of 210 patients, and performed functional studies to investigate the functions and underlying mechanisms of GILT on breast cancer prognosis. Our results indicated that high GILT expression in breast cancer cells was associated with improved disease-free survival (DFS; hazard ratio [HR] = 0.189, 95% confidence interval [CI]: 0.099-0.361) and breast cancer-specific survival (BCSS; HR = 0.187, 95% CI: 0.080-0.437) of breast cancer patients both in the training set and the external validation set (HR = 0.453, 95% CI: 0.235-0.873 for DFS, HR = 0.488, 95% CI: 0.245-0.970 for BCSS). In vitro and in vivo studies showed that GILT overexpression inhibited breast cancer cells proliferation, invasion, migration and tumor formation in nude mice and increased sensitivity of breast cancer cells to standard treatment. Proteomics analysis indicated that GILT inhibited reactive oxygen species (ROS) and autophagy activation in breast cancer cells, and GILT overexpression-mediated tumor growth was further enhanced in the presence of autophagy or ROS inhibitors. Our results demonstrate that GILT expression can be effectively used to predict the prognosis and guide treatment strategies of breast cancer patients.

The Impact of Reproductive Factors on the Risk of Breast Cancer by ER/PR and HER2: A Multicenter Case-Control Study in Northern and Eastern China.

BACKGROUND: Previous studies have suggested that reproductive factors are associated with breast cancer risk. Breast cancer subtypes have distinct natural characteristics and may also have unique risk profiles. The purpose of this study was to determine whether reproductive factors affect the risk of breast cancer by estrogen receptor (ER)/progesterone receptor (PR) and HER2 status. METHODS: A multicenter, case-control study was conducted. There were 1170 breast cancer patients and 1170 age- and hospital-matched females included in the analysis. Self-reported data were collected about lifestyle behaviors, including reproductive factors. Breast cancer cases were categorized subtypes according to ER, PR, and HER2 expression as HR- positive, HER2-enriched, and triple negative breast cancer (TNBC). Multivariable logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Having ≤1 child increased risk of HR-positive breast cancer (OR 1.882; 95%CI 1.29-2.74), especially in the premenopausal group (OR 2.212; 95%CI 1.23-3.99). Compared with women who first gave birth after age 30 years, earlier age at first birth decreased the risk of HR-positive breast cancer (≤23 years: OR 0.209; 95%CI 0.14-0.30; 24-29 years: OR 0.256; 95%CI 0.18-0.36; P < .001). Compared with those who had an average breastfed/birth period of more than 2 years, those with an average period less than 6 months had an elevated risk of all subtypes (HR positive: OR 2.690; 95%CI 1.71-4.16, P < .001; HER2-enriched: OR 3.779; 95%CI, 1.62-8.79, P = .001; TNBC: OR 2.564; 95%CI 1.11-5.94, P = .022). For postmenopausal patients, shorter period of lifetime menstrual cycles (≤30 years) had an obviously decreased risk in HR-positive cases (OR 0.397; 95%CI 0.22-0.71), while there was no similar appearance in other molecular subtypes. CONCLUSION: The results suggest that reproductive behaviors affect risk of breast cancer differently according to ER/PR and HER2 status.

Neoadjuvant endocrine therapy for strongly hormone receptor-positive and HER2-negative early breast cancer: results of a prospective multi-center study.

PURPOSE: For estrogen receptor (ER)-positive breast cancer, neoadjuvant endocrine therapy (NET) has been shown to be as effective as neoadjuvant chemotherapy (NACT). We evaluated the prognostic significance of Preoperative Endocrine Prognostic Index (PEPI). METHODS: We conducted a prospective, multi-center, non-randomized, controlled trial that enrolled postmenopausal early-stage strongly ER-positive (≥ 50%) and HER2-negative breast cancer patients. All patients were given 4-month NET before surgery. The primary objective was to investigate the 5-year recurrence-free survival (RFS) in patients who had PEPI 0-1 or pathological complete response (pCR) without chemotherapy. Patients who had PEPI 0-1 or pCR were recommended to receive adjuvant endocrine therapy only and patients had PEPI ≥ 2 may receive adjuvant chemotherapy at the discretion of the treating physician. RESULTS: A total of 410 patients were included and 352 patients constituted the per-protocol population. Overall, 9 patients (2.5%) had pCR (ypT0/is ypN0), 128 patients (36.4%) had PEPI = 0, and 56 patients (15.9%) had PEPI = 1. After a median follow-up of 60 months (4-104 months), patients who had PEPI 0-1 or pCR showed an improved 5-year RFS [99.5% (95% CI 98.5-99.9%) for PEPI 0-1 or pCR group vs. 93.7% (95% CI 89.6-97.8%) for PEPI ≥ 2 group, P = 0.028]. No survival difference was detected between patients received adjuvant chemotherapy vs. no chemotherapy among PEPI ≥ 2 cases. CONCLUSION: PEPI 0-1 or pCR may be used to define a group of ER-positive and HER2-negative postmenopausal early breast cancer patients with low relapse risk for whom adjuvant chemotherapy can be safely withheld. Studies on the identification and alternative treatment options for endocrine-resistant tumors are warranted. CLINICAL TRIAL REGISTRATION: NCT01613560.

Using machine learning to identify gene interaction networks associated with breast cancer.

BACKGROUND: Breast cancer (BC) is one of the most prevalent cancers worldwide but its etiology remains unclear. Obesity is recognized as a risk factor for BC, and many obesity-related genes may be involved in its occurrence and development. Research assessing the complex genetic mechanisms of BC should not only consider the effect of a single gene on the disease, but also focus on the interaction between genes. This study sought to construct a gene interaction network to identify potential pathogenic BC genes. METHODS: The study included 953 BC patients and 963 control individuals. Chi-square analysis was used to assess the correlation between demographic characteristics and BC. The joint density-based non-parametric differential interaction network analysis and classification (JDINAC) was used to build a BC gene interaction network using single nucleotide polymorphisms (SNP). The odds ratio (OR) and 95% confidence interval (95% CI) of hub gene SNPs were evaluated using a logistic regression model. To assess reliability, the hub genes were quantified by edgeR program using BC RNA-seq data from The Cancer Genome Atlas (TCGA) and identical edges were verified by logistic regression using UK Biobank datasets. Go and KEGG enrichment analysis were used to explore the biological functions of interactive genes. RESULTS: Body mass index (BMI) and menopause are important risk factors for BC. After adjusting for potential confounding factors, the BC gene interaction network was identified using JDINAC. LEP, LEPR, XRCC6, and RETN were identified as hub genes and both hub genes and edges were verified. LEPR genetic polymorphisms (rs1137101 and rs4655555) were also significantly associated with BC. Enrichment analysis showed that the identified genes were mainly involved in energy regulation and fat-related signaling pathways. CONCLUSION: We explored the interaction network of genes derived from SNP data in BC progression. Gene interaction networks provide new insight into the underlying mechanisms of BC.

Triclosan Promotes Conjugative Transfer of Antibiotic Resistance Genes to Opportunistic Pathogens in Environmental Microbiome.

Although triclosan, as a widely used antiseptic chemical, is known to promote the transmission of antibiotic resistance to diverse hosts in pure culture, it is still unclear whether and how triclosan could affect the transmission of broad-host-range plasmids among complex microbial communities. Here, bacterial culturing, fluorescence-based cell sorting, and high-throughput 16S rRNA gene amplicon sequencing were combined to investigate contributions of triclosan on the transfer rate and range of an IncP-type plasmid from a proteobacterial donor to an activated sludge microbiome. Our results demonstrate that triclosan significantly enhances the conjugative transfer of the RP4 plasmid among activated sludge communities at environmentally relevant concentrations. High-throughput 16S rRNA gene sequencing on sorted transconjugants demonstrates that triclosan not only promoted the intergenera transfer but also the intragenera transfer of the RP4 plasmid among activated sludge communities. Moreover, triclosan mediated the transfer of the RP4 plasmid to opportunistic human pathogens, for example, Legionella spp. The mechanism of triclosan-mediated conjugative transfer is primarily associated with excessive oxidative stress, followed by increased membrane permeability and provoked SOS response. Our findings offer insights into the impacts of triclosan on the dissemination of antibiotic resistance in the aquatic environmental microbiome.

Understanding the Effect of Free Nitrous Acid on Biofilms.

Free nitrous acid (FNA, i.e., HNO2) has been recently applied to biofilm control in wastewater management. The mechanism triggering biofilm detachment upon exposure to FNA still remains largely unknown. In this work, we aim to prove that FNA induces biofilm dispersal via extracellular polymeric matrix breakdown and cell lysis. Biofilms formed by a model organism, Pseudomonas aeruginosa PAO1, were treated with FNA at concentrations ranging from 0.2 to 15 mg N/L for 24 h (conditions typically used in applications). The biofilms and suspended biomass were monitored both before and after FNA treatment using a range of methods including optical density measurements, viability assays, confocal laser scanning microscopy, and atomic force microscopy. It was revealed that FNA treatment caused substantial and concentration-dependent biofilm detachment. The addition of a reactive nitrogen species (RNS) scavenger, that is, 2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, substantially reduced biofilm dispersal, suggesting that the nitrosative decomposition species of HNO2 (i.e., RNS, e.g., •NO + •NO2) were mainly responsible for the effects. The study provides insight into and support for the use of FNA for biofilm control in wastewater treatment.

Omnidirectional exciton diffusion in quasi-2D hybrid organic-inorganic perovskites.

Exciton transport plays a central role in optoelectronic and photonic devices. In quasi-two-dimensional (2D) hybrid organic-inorganic perovskites (HOIPs), tightly bound excitons are found to diffuse within 2D layers rapidly with a non-monotonic temperature dependence. Surprisingly, the interlayer exciton diffusion is quite effective as well despite the large interlayer distance. This is in sharp contrast to electron transport, where the interlayer mobility is several orders of magnitude smaller than the intralayer one. Here, we show that the unusual exciton diffusion behaviors can be systematically modeled via the excitonic band structure arising from a long-range dipolar coupling. Coherent exciton motion is interrupted by scattering of impurities at low temperatures and of acoustic/optical phonons at high temperatures. Acoustic and optical phonons modulate the dipole-dipole distance and the dipole orientation, respectively. The ratio of intralayer and interlayer diffusion constants, Dxx/Dzz, is comparable to az/ax with az and ax being the interlayer and intralayer lattice constants of 2D HOIPs, respectively. The efficient and omnidirectional exciton diffusion suggests a great potential of 2D HOIPs in novel excitonic and polaritonic applications.

Study on the binding mode of aptamer to ampicillin and its electrochemical response behavior in two different reaction media.

A study was carried out to investigate the binding mode of aptamer to ampicillin (AMP) and its electrochemical response behavior. The binding mode was confirmed using the molecular dynamics (MD) simulation method to obtain the corresponding binding dynamic change process. Following the confirmed binding mode, a qualitative elucidation was provided on the electrochemical response characteristics of a single-probe aptamer-based folding sensor. The results show that there exist two different binding modes in two different solution systems, Phys2 and H2O (0.1 M NaCl). These two binding modes can respectively induce two different contraction changes, thereby driving the methylene blue (MB)-modified aptamer probe to show a "close-to-interface" convergence behavior with different degrees on the actual electrode surface, which validates two apparently different electrochemical response behavior characteristics of "signal-on" for the sensor. By contrast, H2O (0.1 M NaCl) as the reaction medium is more conducive to the formation of a stable aptamer/AMP complex and the development of a high-sensitivity analytical method with a low detection limit of 0.033 µM. The simulation results effectively support the experimental results, which is helpful in gaining a deeper understanding of the relationship between the signaling mechanism and practical analytical performance for aptamer-based folding sensors at the molecular level.

A Rise in ROS and EPS Production: New Insights into the Trichodesmium erythraeum Response to Ocean Acidification.

The diazotrophic cyanobacterium Trichodesmium is thought to be a major contributor to the new N in parts of the oligotrophic, subtropical, and tropical oceans. In this study, physiological and biochemical methods and transcriptome sequencing were used to investigate the influences of ocean acidification (OA) on Trichodesmium erythraeum (T. erythraeum). We presented evidence that OA caused by CO2 slowed the growth rate and physiological activity of T. erythraeum. OA led to reduced development of proportion of the vegetative cells into diazocytes which included up-regulated genes of nitrogen fixation. Reactive oxygen species (ROS) accumulation was increased due to the disruption of photosynthetic electron transport and decrease in antioxidant enzyme activities under acidified conditions. This study showed that OA increased the amounts of (exopolysaccharides) EPS in T. erythraeum, and the key genes of ribose-5-phosphate (R5P) and glycosyltransferases (Tery_3818) were up-regulated. These results provide new insight into how ROS and EPS of T. erythraeum increase in an acidified future ocean to cope with OA-imposed stress.

Responses of Marine Diatom Skeletonema marinoi to Nutrient Deficiency: Programmed Cell Death.

Diatoms are important phytoplankton and contribute greatly to the primary productivity of marine ecosystems. Despite the ecological significance of diatoms and the importance of programmed cell death (PCD) in the fluctuation of diatom populations, little is known about the molecular mechanisms of PCD triggered by different nutrient stresses. Here we describe the physiological, morphological, biochemical, and molecular changes in response to low levels of nutrients in the ubiquitous diatom Skeletonema marinoi The levels of gene expression involved in oxidation resistance and PCD strongly increased upon nitrogen (N) or phosphorus (P) starvation. The enzymatic activity of caspase 3-like protein also increased. Differences in mRNA levels and protein activities were observed between the low-N and low-P treatments, suggesting that PCD could have a differential response to different nutrient stresses. When cultures were replete with N or P, the growth inhibition stopped. Meanwhile, the enzymatic activity of caspase 3-like protein and the number of cells with damaged membranes decreased. These results suggest that PCD is an important cell fate decision mechanism in the marine diatom S. marinoi Our results provide important insight into how diatoms adjust phenotypic and genotypic features of their cell-regulated death programs when stressed by nutrient limitations. Overall, this study could allow us to better understand the molecular mechanism behind the formation and termination of diatom blooms in the marine environment.IMPORTANCE Our study showed how the ubiquitous diatom S. marinoi responded to different nutrient limitations with PCD in terms of physiological, morphological, biochemical, and molecular characteristics. Some PCD-related genes (PDCD4, GOX, and HSP90) induced by N deficiency were relatively upregulated compared to those induced by P deficiency. In contrast, the expression of the TSG101 gene in S. marinoi showed a clear and constant increase during P limitation compared to N limitation. These findings suggest that PCD is a complex mechanism involving several different proteins. The systematic mRNA level investigations provide new insight into understanding the oxidative stress- and cell death-related functional genes of diatoms involved in the response to nutrient fluctuations (N or P stress) in the marine environment.

MEF2 impairment underlies skeletal muscle atrophy in polyglutamine disease.

Polyglutamine (polyQ) tract expansion leads to proteotoxic misfolding and drives a family of nine diseases. We study spinal and bulbar muscular atrophy (SBMA), a progressive degenerative disorder of the neuromuscular system caused by the polyQ androgen receptor (AR). Using a knock-in mouse model of SBMA, AR113Q mice, we show that E3 ubiquitin ligases which are a hallmark of the canonical muscle atrophy machinery are not induced in AR113Q muscle. Similarly, we find no evidence to suggest dysfunction of signaling pathways that trigger muscle hypertrophy or impairment of the muscle stem cell niche. Instead, we find that skeletal muscle atrophy is characterized by diminished function of the transcriptional regulator Myocyte Enhancer Factor 2 (MEF2), a regulator of myofiber homeostasis. Decreased expression of MEF2 target genes is age- and glutamine tract length-dependent, occurs due to polyQ AR proteotoxicity, and is associated with sequestration of MEF2 into intranuclear inclusions in muscle. Skeletal muscle from R6/2 mice, a model of Huntington disease which develops progressive atrophy, also sequesters MEF2 into inclusions and displays age-dependent loss of MEF2 target genes. Similarly, SBMA patient muscle shows loss of MEF2 target gene expression, and restoring MEF2 activity in AR113Q muscle rescues fiber size and MEF2-regulated gene expression. This work establishes MEF2 impairment as a novel mechanism of skeletal muscle atrophy downstream of toxic polyglutamine proteins and as a therapeutic target for muscle atrophy in these disorders.