Single hormone or synthetic agonist induces Gs/Gi coupling selectivity of EP receptors via distinct binding modes and propagating paths.

To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize the same hormone, and 2) different cellular effectors couple to the same hormone-receptor pair [R.P. Xiao, Sci STKE 2001, re15 (2001); L. Hein, J. D. Altman, B.K. Kobilka, Nature 402, 181-184 (1999); Y. Daaka, L. M. Luttrell, R. J. Lefkowitz, Nature 390, 88-91 (1997)]. Not only these questions lie in the heart of hormone actions and receptor signaling but also dissecting mechanisms underlying these questions could offer therapeutic routes for refractory diseases, such as kidney injury (KI) or X-linked nephrogenic diabetes insipidus (NDI). Here, we identified that Gs-biased signaling, but not Gi activation downstream of EP4, showed beneficial effects for both KI and NDI treatments. Notably, by solving Cryo-electron microscope (cryo-EM) structures of EP3-Gi, EP4-Gs, and EP4-Gi in complex with endogenous prostaglandin E2 (PGE2)or two synthetic agonists and comparing with PGE2-EP2-Gs structures, we found that unique primary sequences of prostaglandin E2 receptor (EP) receptors and distinct conformational states of the EP4 ligand pocket govern the Gs/Gi transducer coupling selectivity through different structural propagation paths, especially via TM6 and TM7, to generate selective cytoplasmic structural features. In particular, the orientation of the PGE2 ω-chain and two distinct pockets encompassing agonist L902688 of EP4 were differentiated by their Gs/Gi coupling ability. Further, we identified common and distinct features of cytoplasmic side of EP receptors for Gs/Gi coupling and provide a structural basis for selective and biased agonist design of EP4 with therapeutic potential.

The GW5-WRKY53-SGW5 module regulates grain size variation in rice.

Grain size is a crucial agronomic trait that affects stable yield, appearance, milling quality, and domestication in rice. However, the molecular and genetic relationships among QTL genes (QTGs) underlying natural variation for grain size remain elusive. Here, we identified a novel QTG SGW5 (suppressor of gw5) by map-based cloning using an F2 segregation population by fixing same genotype of the master QTG GW5. SGW5 positively regulates grain width by influencing cell division and cell size in spikelet hulls. Two nearly isogenic lines exhibited a significant differential expression of SGW5 and a 12.2% increase in grain yield. Introducing the higher expression allele into the genetic background containing the lower expression allele resulted in increased grain width, while its knockout resulted in shorter grain hulls and dwarf plants. Moreover, a cis-element variation in the SGW5 promoter influenced its differential binding affinity for the WRKY53 transcription factor, causing the differential SGW5 expression, which ultimately leads to grain size variation. GW5 physically and genetically interacts with WRKY53 to suppress the expression of SGW5. These findings elucidated a new pathway for grain size regulation by the GW5-WRKY53-SGW5 module and provided a novel case for generally uncovering QTG interactions underlying the genetic diversity of an important trait in crops.

Experimental demonstration of a nanobeam Fano laser.

Microscopic single-mode lasers with low power consumption, large modulation bandwidth, and ultra-narrow linewidth are essential for numerous applications, such as on-chip photonic networks. A recently demonstrated microlaser using an optical Fano resonance between a discrete mode and a continuum of modes to form one of the mirrors, i.e., the so-called Fano laser, holds great promise for meeting these requirements. Here, we suggest and experimentally demonstrate what we believe is a new configuration of the Fano laser based on a nanobeam geometry. Compared to the conventional two-dimensional photonic crystal geometry, the nanobeam structure makes it easier to engineer the phase-matching condition that facilitates the realization of a bound-state-in-the-continuum (BIC). We investigate the laser threshold in two scenarios based on the new nanobeam geometry. In the first, classical case, the gain is spatially located in the part of the cavity that supports a continuum of modes. In the second case, instead, the gain is located in the region that supports a discrete mode. We find that the laser threshold for the second case can be significantly reduced compared to the conventional Fano laser. These results pave the way for the practical realization of high-performance microlasers.

OsMBTB32, a MATH-BTB domain-containing protein that interacts with OsCUL1s to regulate salt tolerance in rice.

MATH-BTB proteins are involved in a variety of cellular processes that regulate cell homeostasis and developmental processes. Previous studies reported the involvement of BTB proteins in the development of various organs in plants; however, the function of BTB proteins in salt stress is less studied. Here, we found a novel MATH-BTB domain-containing OsMBTB32 protein that was highly expressed in leaf, root, and shoot. The up-regulation of the OsMBTB32 transcript in 2-week-old seedlings under salt stress suggests the significant role of the OsMBTB32 gene in salinity. The OsMBTB32 transgenic seedlings (OE and RNAi) exhibited significant differences in various phenotypes, including plumule, radical, primary root, and shoot length, compared to WT seedlings. We further found that OsCUL1 proteins, particularly OsCUL1-1 and OsCUL1-3, interact with OsMBTB32 and may suppress the function of OsMBTB32 during salt stress. Moreover, OsWRKY42, a homolog of ZmWRKY114 which negatively regulates salt stress in rice, directly binds to the W-box of OsCUL1-1 and OsCUL1-3 promoters to promote the interaction of OsCUL1-1 and OsCUL1-3 with OsMBTB32 protein in rice. The overexpression of OsMBTB32 and OsCUL1-3 further confirmed the function of OsMBTB32 and OsCUL1s in salt tolerance in Arabidopsis. Overall, the findings of the present study provide promising knowledge regarding the MATH-BTB domain-containing proteins and their role in enhancing the growth and development of rice under salt stress.MATH-BTB proteins are involved in a variety of cellular processes that regulate cell homeostasis and developmental processes. Previous studies reported the involvement of BTB proteins in the development of various organs in plants; however, the function of BTB proteins in salt stress is less studied. Here, we found a novel MATH-BTB domain-containing OsMBTB32 protein that was highly expressed in leaf, root, and shoot. The up-regulation of the OsMBTB32 transcript in 2-week-old seedlings under salt stress suggests the significant role of the OsMBTB32 gene in salinity. The OsMBTB32 transgenic seedlings (OE and RNAi) exhibited significant differences in various phenotypes, including plumule, radical, primary root, and shoot length, compared to WT seedlings. We further found that OsCUL1 proteins, particularly OsCUL1-1 and OsCUL1-3, interact with OsMBTB32 and may suppress the function of OsMBTB32 during salt stress. Moreover, OsWRKY42, a homolog of ZmWRKY114 which negatively regulates salt stress in rice, directly binds to the W-box of OsCUL1-1 and OsCUL1-3 promoters to promote the interaction of OsCUL1-1 and OsCUL1-3 with OsMBTB32 protein in rice. The overexpression of OsMBTB32 and OsCUL1-3 further confirmed the function of OsMBTB32 and OsCUL1s in salt tolerance in Arabidopsis. Overall, the findings of the present study provide promising knowledge regarding the MATH-BTB domain-containing proteins and their role in enhancing the growth and development of rice under salt stress.

Body Surface Area (BSA) is a Better Osteoporosis Associated Anthropometric Parameter Than Other Anthropometric Parameters in Elderly Population.

Body surface area (BSA) is widely used for adjusting drug dose, while few studies have yet systematically evaluated its association with osteoporosis and compared its advantage with other anthropometric parameters in osteoporotic risk prediction. A total of 10,021 Chinese individuals aged over 65 years were enrolled in our study. Bone mineral density (BMD) was measured, and demographic information was also collected. Pearson correlation analysis, receiver operating characteristic (ROC) curves and predictive analysis were performed to assess the clinical practice of BSA for osteoporosis. BSA had the strongest correlation with BMD (0.544, p < 0.001) compared with conventional anthropometric indices. Besides, BSA had the highest power in osteoporosis prediction, with an area under the curve (AUC) reaching 0.81. After incorporating BSA into the osteoporosis risk prediction model, the AUC improved from 0.82 to 0.83 (p < 0.01). We found BSA provided additional diagnostic value beyond conventional anthropometric information with continuous and category NRIs were 30.40% (p < 0.01) and 3.29% (p < 0.01), respectively, and the IDI was 1.85% (p < 0.01). BSA was positively associated with osteoporosis and showed superior discriminative ability for osteoporosis risk prediction compared with other anthropometric parameters in the Chinese elderly population.

The effect of a body shape index (ABSI) and its interaction with low estimated glomerular filtration rate (eGFR) on osteoporosis in elderly Chinese.

BACKGROUND: Both obesity and chronic kidney disease (CKD) contribute to osteoporosis risk, but the effect of a newly developed index (e.g., a body shape index, ABSI) of central obesity and its interaction with low estimated glomerular filtration rate (eGFR) on osteoporosis remains unknown. METHODS: A total of 2534 Chinese individuals were enrolled in our ongoing cohort study: Osteoporosis Preventive Project. ABSI and eGFR were calculated as obesity-related indexes and renal function markers, respectively. A logistic regression model was used to estimate the association between osteoporosis and related clinical parameters (e.g., ABSI, eGFR), and to assess the additive and multiplicative interactions between risk factors and osteoporosis. Relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP) and synergy index (SI) were calculated to assess the additive interaction. RESULTS: High ABSI was significantly associated with an increased risk of osteoporosis in participants compared with the lowest quartile of ABSI in both crude and adjusted models. Individuals in the lower quartiles of eGFR had a significantly increased risk of osteoporosis compared with those in the highest quartiles in crude models. After adding age and other variables in the model, the association was abolished. In addition, after adjusting for variables, high ABSI with low eGFR (RERI: 0.45, 95% CI: 0.15-0.75; AP: 0.39, 95% CI: 0.17-0.60) still displayed a noticeable interaction on the risk of osteoporosis. The multiplicative interactive effect between high ABSI with low eGFR on osteoporosis was statistically significant in the multivariable-adjusted model (P < 0.05). CONCLUSION: Our study indicated that higher ABSI increases the risk of osteoporosis independently and synergistically with low eGFR in Chinese elderly adults. The findings increase our understanding of the interactions of osteoporosis risk factors and may help provide potential interventions for osteoporosis.

Rapid Potentiometric Detection of Chemical Oxygen Demand Using a Portable Self-Powered Sensor Chip.

Chemical oxygen demand (COD) is an important indicator of organic pollutants in water bodies. Most of the present testing methods have the disadvantages of having complicated steps, being time-consuming, and using toxic and hazardous substances. In this work, rapid potentiometric detection of chemical oxygen demand (COD) using a portable self-powered sensor chip was successfully developed. The indium tin oxide (ITO) electrode was etched by laser, and the photocatalytic materials TiO2/CuS and Pt were modified onto the photoanode and the cathode to prepare the sensor chip. Based on the principle of photocatalytic degradation, organic pollutants can be oxidized by TiO2/CuS, and the concentration will affect the generated voltage. The quantitative detection of COD in the range of 0.05-50 mg/L can be rapidly achieved within 5 min by a miniature device. Besides good portability and sensitivity, the proposed sensor also has the advantages of environmental friendliness and ease of use, which is an ideal choice for the on-site detection of water pollution.

High-Throughput Detection of Multiple Contaminants Based on Portable Photoelectrochromic Sensor Chip.

With the increasing concerns about the environment and food safety, it is necessary to develop portable, low-cost, and high-throughput biosensors for the simultaneous detection of multiple contaminates. However, traditional photoelectrochemical (PEC) biosensors lack the ability of multiplexed assays due to the inherent mechanism limitation. Also, specialized instruments are necessary for most PEC biosensors. In this work, a portable high-throughput sensor chip has been successfully developed. By introducing electrochromic materials, the detection is based on color change instead of electric signals, which reduces the limitation of instruments. This designed sensor chip is composed of three parallel sensing channels fabricated by laser etching. Each channel is modified with TiO2/3D-g-C3N4 composites with excellent PEC activity and electrochromic material Prussian blue (PB). Under light illumination, photoinduced electrons generated by TiO2/3D-g-C3N4 are injected into PB, and blue PB is reduced to colorless Prussian white. Three organic contaminates, ochratoxin A, lincomycin, and edifenphos, can be simultaneously detected because the binding of these molecules with aptamers affects the electron transfer and the corresponding color changes. This portable and high-throughput sensor chip provides a convenient choice for multiplexed assays with good sensitivity and accuracy.

Comparative transcriptomic analysis reveals the mechanistic basis of Pib-mediated broad spectrum resistance against Magnaporthe oryzae.

Rice blast, caused by the fungus Magnaporthe oryzae, is a highly damaging disease. Introducing genes, which confer a broad spectrum resistance to the disease, such as Pib, makes an important contribution to protecting rice production. However, little is known regarding the mechanistic basis of the products of such genes. In this study, transcriptome of the cultivar Lijiangxintuanheigu (LTH) and its monogenic IRBLb-B which harbors Pib treated with M. oryzae were compared. Among the many genes responding transcriptionally to infection were some encoding products involved in the metabolism of ROS (reactive oxygen species), in jasmonate (JA) metabolism, and WRKY transcription factors, receptor kinases, and resistance response signal modulation. The down-regulation of genes encoding peroxiredoxin and glutathione S transferases implied that the redox homeostasis is essential for the expression of Pib-mediated resistance. The up-regulation of seven disease resistance-related genes, including three encoding a NBS-LRR protein, indicated that disease resistance-related genes are likely tend to support the expression of Pib resistance. These data revealed that potential candidate genes and transcriptional reprogramming were involved in Pib-mediated resistance mechanisms.

Portable Photoelectrochromic Visualization Sensor for Detection of Chemical Oxygen Demand.

Chemical oxygen demand (COD) is an important parameter to estimate water quality, and many methods have been developed to measure COD. However, these methods are not satisfying because of the use of hazardous materials, the interference of chloride, and complicated operations. Meanwhile, the development of portable sensors for field testing COD is still at an early stage. In this work, we propose a new portable COD sensor based on the photoelectrochromic principle. The whole detection can be conducted with a small indium tin oxide (ITO) electrode modified with photocatalytic material TiO2/g-C3N4 and the electrochromic material Prussian blue. Under light illumination, organic pollution can be photocatalytically oxidized by TiO2/g-C3N4 and photogenerated electrons are transferred to Prussian blue, which will be reduced to colorless Prussian white. So the COD value can be obtained through the color change of the ITO electrode. By adjusting the electrode size, the detection range is flexible from 0.025 to 750 mg/L, and this sensor has a good repeatability and stability. Meanwhile, this portable visualization PEC sensor has been successfully applied in actual wastewater sample detection, which has a good prospect in COD monitoring.

Comparative genomics analysis of Nitriliruptoria reveals the genomic differences and salt adaptation strategies.

The group Nitriliruptoria, recently classified as a separate class of phylum Actinobacteria, has five members at present, which belong to halophilic or halotolerant Actinobacteria. Here, we sequenced the genomes of Egicoccus halophilus EGI 80432T and Egibacter rhizosphaerae EGI 80759T, and performed a comparative genomics approach to analyze the genomic differences and salt adaptation mechanisms in Nitriliruptoria. Phylogenetic analysis suggested that Euzebya tangerina F10T has a closer phylogenetic relationship to Euzebya rosea DSW09T, while genomic analysis revealed highest genomic similarity with Nitriliruptor alkaliphilus ANL-iso2T and E. halophilus EGI 80432T. Genomic differences of Nitriliruptoria were mainly observed in genome size, gene contents, and the amounts of gene in per functional categories. Furthermore, our analysis also revealed that Nitriliruptoria possess similar synthesis systems of solutes, such as trehalose, glutamine, glutamate, and proline. On the other hand, each member of Nitriliruptoria species possesses specific mechanisms, K+ influx and efflux, betaine and ectoine synthesis, and compatible solutes transport to survive in various high-salt environments.

Distinct Expression of the Two NO-Forming Nitrite Reductases in Thermus antranikianii DSM 12462T Improved Environmental Adaptability.

Hot spring ecosystems are analogous to some thermal environments on the early Earth and represent ideal models to understand life forms and element cycling on the early Earth. Denitrification, an important component of biogeochemical nitrogen cycle, is highly active in hot springs. Nitrite (NO2-) reduction to nitric oxide (NO) is the significant and rate-limiting pathway in denitrification and is catalyzed by two types of nitrite reductases, encoded by nirS and nirK genes. NirS and NirK were originally considered incompatible in most denitrifying organisms, although a few strains have been reported to possess both genes. Herein, we report the functional division of nirS and nirK in Thermus, a thermophilic genus widespread in thermal ecosystems. Transcriptional levels of nirS and nirK coexisting in Thermus antranikianii DSM 12462T were measured to assess the effects of nitrite, oxygen, and stimulation time. Thirty-nine Thermus strains were used to analyze the phylogeny and distribution of nirS and nirK; six representative strains were used to assess the denitrification phenotype. The results showed that both genes were actively transcribed and expressed independently in T. antranikianii DSM 12462T. Strains with both nirS and nirK had a wider range of nitrite adaptation and revealed nir-related physiological adaptations in Thermus: nirK facilitated adaptation to rapid changes and extended the adaptation range of nitrite under oxygen-limited conditions, while nirS expression was higher under oxic and relatively stable conditions.

Laparoscopic-assisted cyst excision and ductoplasty plus widened portoenterostomy for choledochal cysts with a narrow portal bile duct.

BACKGROUND: Complete cyst excision with Roux-en-Y hepaticojejunostomy is the standard procedure for choledochal cysts (CCs). In recent years, neonates have been increasingly diagnosed with CCs prenatally. Earlier treatment has been recommended to avoid complications. For type IVa malformation without extensive intrahepatic bile duct dilatation, laparoscopic hepaticojejunostomy is technically challenging, and anastomotic stricture is a concern. Therefore, we propose laparoscopic synthetical techniques-laparoscopic excision of cyst and ductoplasty plus widened portoenterostomy to avoid stricture in CCs with a narrow hilar duct. METHODS: An anastomosis was created around the transected end of the common bile duct in 12 minipigs (Group A), and another 12 minipigs (Group B) received conventional cholangiojejunostomy. Anastomotic diameter measurements and cholangiography were conducted at different times. Histological findings of inflammation and scarring were compared. The expression levels of TGF-ß1 and type I collagen were detected by real-time quantitative PCR. Between January 2012 and January 2016, laparoscopic excision of cyst and ductoplasty plus widened portoenterostomy were performed on 29 children with confirmed CCs with a narrow portal bile duct who were followed up for 12-48 months. RESULTS: Group A survived well without obstruction. Slight inflammation and fibrotic tissue were confined to the bile duct periphery. In Group B, five pigs developed stricture. Severe inflammation and diffuse fibrosis affected the whole layer of the anastomosis. Fibrotic biomarkers were significantly higher postoperatively in Group B. Clinically, 29 patients exhibited satisfactory outcomes. No anastomotic stricture has been observed to date. CONCLUSIONS: Laparoscopic synthetical techniques may be a superior option to prevent anastomotic stricture in treating CCs with a narrow portal bile duct.

Preparation of an AgI/CuBi2O4 heterojunction on a fluorine-doped tin oxide electrode for cathodic photoelectrochemical assays: application to the detection of L-cysteine.

Photocathodic methods in photoelectrochemical (PEC) analysis are based on the use of functional photocathodes. Heterojunction cathodes consisting of different kinds of semiconductors are being considered as favorite schemes when compared to the single-component ones. A semiconductor heterojunction between CuBi2O4 (CBO) and other semiconductors has not been exploited in PEC assays so far. Herein, CBO nanospheres were initially electrochemically deposited on a fluorine-doped tin oxide (FTO) conductive glass and then coupled to chemically deposited AgI nanoparticles to obtain an electrode of type AgI/CBO/FTO. It was applied as a cathode in the PEC detection of L-cysteine as a model analyte. The sensor can selectively detect L-cysteine, and it is assumed that this is due to the selective interaction between the L-cysteine and both copper and silver via the formation of Cu-S and Ag-S bonds. The photocurrent of the electrode increases linearly with the logarithm of the cysteine concentration in the range from 0.1 and 50 µM, and the detection limit is 0.1 µM. Graphical abstract Schematic presentation of the preparation of an AgI/CuBi2O4 (AgI/CBO) heterojunction on a fluorine-doped tin oxide (FTO) electrode and its application to the cathodic photoelectrochemical detection of L-cysteine.

Preparation and In vitro Evaluation of FDM 3D-Printed Ellipsoid-Shaped Gastric Floating Tablets with Low Infill Percentages.

The aim of the study is to investigate the feasibility of fabricating FDM 3D-printed gastric floating tablets with low infill percentages and the effect of infill percentage on the properties of gastric floating tablets in vitro. Propranolol hydrochloride was selected as a model drug, and drug-loaded polyvinyl alcohol (PVA) filaments were produced by hot melt extrusion (HME). Ellipsoid-shaped gastric floating tablets with low infill percentage of 15% and 25% (namely E-15 and E-25) were then prepared respectively by feeding the extruded filaments to FDM 3D printer. Thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), and scanning electron microscopy (SEM) were employed to characterize the filaments and 3D-printed tablets, and a series of evaluations were performed to the 3D-printed tablets, including the weight variation, drug content, hardness, in vitro floating behavior, and drug release of the tablets. The SEM results showed that the drug-loaded filaments and 3D-printed tablets appeared intact without defects, and the printed tablets were composed of filaments deposited uniformly layer by layer. The model drug and the excipients were thermally stable under the process temperature of extruding and printing, with a small amount of drug crystals dispersing in the drug-loaded filaments and 3D-printed tablets. Both E-15 and E-25 could float on artificial gastric fluids without any lag time and released in a sustained manner. Compared with E-15, the E-25 presented less weight variation, higher tablet hardness, shorter floating time, and longer drug release time.

Two-Photon DNAzyme-Gold Nanoparticle Probe for Imaging Intracellular Metal Ions.

RNA-cleaving DNAzymes have been demonstrated as a promising platform for sensing metal ions. However, the poor biological imaging performance of RNA-cleaving DNAzyme-based fluorescent probes has limited their intracellular applications. Compared with traditional one-photon fluorescence imaging, two-photon (TP) fluorescent probes have shown advantages such as increased penetration depth, lower tissue autofluorescence, and reduced photodamage. Herein, for the first time, we developed an RNA-cleaving DNAzyme-based TP imaging probe (TP-8-17ES-AuNP) for Zn2+ detection in living cells by modifying a Zn2+-specific DNAzyme (8-17) with a TP fluorophore (TP-8-17ES) and using gold nanoparticles (AuNPs) for intracellular delivery. The modified TP-8-17ES exhibits good two-photon properties and excellent photostability. For the TP-8-17ES-AuNP, in the absence of Zn2+, the TP fluorophore is quenched by both AuNPs and the molecular quencher. Only in the presence of Zn2+ does the DNAzyme cleave the TP fluorophore-labeled substrate strand, resulting in fluorescence enhancement and TP imaging. Such probe shows remarkable selectivity of Zn2+ over other metal ions existing in the biological environment. Benefiting from the labeled TP fluorophore, the near-infrared (NIR) excited probe has the capability of TP imaging of Zn2+ in living cells and tissue with a deep tissue penetration up to 160 µm. This method can be generally applied to detect other metal ions in biological systems under TP imaging with higher tissue penetration ability and lower phototoxicity.

The Listeria monocytogenes PASTA Kinase PrkA and Its Substrate YvcK Are Required for Cell Wall Homeostasis, Metabolism, and Virulence.

Obstacles to bacterial survival and replication in the cytosol of host cells, and the mechanisms used by bacterial pathogens to adapt to this niche are not well understood. Listeria monocytogenes is a well-studied Gram-positive foodborne pathogen that has evolved to invade and replicate within the host cell cytosol; yet the mechanisms by which it senses and responds to stress to survive in the cytosol are largely unknown. To assess the role of the L. monocytogenes penicillin-binding-protein and serine/threonine associated (PASTA) kinase PrkA in stress responses, cytosolic survival and virulence, we constructed a ΔprkA deletion mutant. PrkA was required for resistance to cell wall stress, growth on cytosolic carbon sources, intracellular replication, cytosolic survival, inflammasome avoidance and ultimately virulence in a murine model of Listeriosis. In Bacillus subtilis and Mycobacterium tuberculosis, homologues of PrkA phosphorylate a highly conserved protein of unknown function, YvcK. We found that, similar to PrkA, YvcK is also required for cell wall stress responses, metabolism of glycerol, cytosolic survival, inflammasome avoidance and virulence. We further demonstrate that similar to other organisms, YvcK is directly phosphorylated by PrkA, although the specific site(s) of phosphorylation are not highly conserved. Finally, analysis of phosphoablative and phosphomimetic mutants of YvcK in vitro and in vivo demonstrate that while phosphorylation of YvcK is irrelevant to metabolism and cell wall stress responses, surprisingly, a phosphomimetic, nonreversible negative charge of YvcK is detrimental to cytosolic survival and virulence in vivo. Taken together our data identify two novel virulence factors essential for cytosolic survival and virulence of L. monocytogenes. Furthermore, our data demonstrate that regulation of YvcK phosphorylation is tightly controlled and is critical for virulence. Finally, our data suggest that yet to be identified substrates of PrkA are essential for cytosolic survival and virulence of L. monocytogenes and illustrate the importance of studying protein phosphorylation in the context of infection.

Potential signal pathway between all-trans retinoic acid and LMX1B in hypoxia-induced renal tubular epithelial cell injury.

All-trans retinoic acid (ATRA), an active metabolite of vitamin A, exerts various effects on physiological processes such as cell growth, differentiation, apoptosis and inflammation. LMX1B, a developmental LIM-homeodomain transcription factor, is widely expressed in vertebrate embryos, and it takes part in the development of diverse structures such as limbs, kidneys, eyes, brains, etc. Renal tubular epithelial cell culture was performed, and mRNA and protein expression of some factors were detected. We recently demonstrated that ATRA up-regulated the LMX1B, and down-regulated the transforming growth factor-ß1, collagen IV and fibronectin in a hypoxia/reoxygenation (H-R) injury system in renal tubular epithelial cells (RTEC). In conclusion, ATRA acts as a positive regulator of LMX1B in H-R RTEC.

Association of Megsin gene polymorphism with IgA nephropathy risk.

This meta-analysis was conducted to assess the association of Megsin 2093C/T, 2180C/T, C25663G gene polymorphism with the risk of IgA nephropathy (IgAN). The association literatures were identified from PubMed, Embase, Cochrane Library and CBM-disc (China Biological Medicine Database) on 1 January 2014, and eligible reports were recruited and synthesized. Seven eligible reports were recruited into this meta-analysis for the association of Megsin 2093C/T, 2180C/T, C25663G gene polymorphism with IgAN risk. In this meta-analysis, the association of Megsin 2093C/T TT genotype with IgAN risk in Asians was found. Interestingly, Megsin C25663G G allele and GG genotype were associated with the risk of IgAN in Asian population. However, Megsin 2180C/T gene polymorphism was not associated with IgAN risk in Asians. In conclusion, Megsin 2093C/T TT genotype, and C25663G G allele and GG genotype were associated with the risk of IgAN in Asian population. However, more studies should be performed in the future to confirm this association.

Synthetic lethal therapy for KRAS mutant non-small-cell lung carcinoma with nanoparticle-mediated CDK4 siRNA delivery.

The KRAS mutation is present in ~20% of lung cancers and has not yet been effectively targeted for therapy. This mutation is associated with a poor prognosis in non-small-cell lung carcinomas (NSCLCs) and confers resistance to standard anticancer treatment drugs, including epidermal growth factor receptor tyrosine kinase inhibitors. In this study, we exploited a new therapeutic strategy based on the synthetic lethal interaction between cyclin-dependent kinase 4 (CDK4) downregulation and the KRAS mutation to deliver micellar nanoparticles (MNPs) containing small interfering RNA targeting CDK4 (MNPsiCDK4) for treatment in NSCLCs harboring the oncogenic KRAS mutation. Following MNPsiCDK4 administration, CDK4 expression was decreased, accompanied by inhibited cell proliferation, specifically in KRAS mutant NSCLCs. However, this intervention was harmless to normal KRAS wild-type cells, confirming the proposed mechanism of synthetic lethality. Moreover, systemic delivery of MNPsiCDK4 significantly inhibited tumor growth in an A549 NSCLC xenograft murine model, with depressed expression of CDK4 and mutational KRAS status, suggesting the therapeutic promise of MNPsiCDK4 delivery in KRAS mutant NSCLCs via a synthetic lethal interaction between KRAS and CDK4.