Spatial and temporal expression analysis of D-myo-inositol 3-phosphate synthase (MIPS) gene family in Glycine max

Phytic acid, the principal storage form of phosphorus in plant seeds accounts for up to 60 to 80% of the total seed phosphorus content in soybean. Its accumulation increases linearly throughout seed  development and it strongly chelates essential mineral cations and charged proteins decreasing their bioavailability. D-Myo-inositol 3-phosphate synthase (MIPS; EC 5.5.1.4), the evolutionarily conserved enzyme in plants, catalyzes the first and the rate limiting step in phytic acid biosynthetic pathway. Aiming at controlling the level of phytate, we monitored the differential expression profile of four, previously reported, members of the MIPS gene family in developing seeds and vegetative tissues of soybean by quantitative real-time PCR (qRT-PCR). Transcript levels were measured relative to the endogenous reference gene eEF-1á (eukaryotic elongation factor 1-alpha) using SYBER-Green. The qRT-PCR data analysis indicated that the expression of the four highly conserved MIPS genes is both temporally and spatially regulated, information much needed for reverse genetic applications. MIPS1 exhibited high transcript levels in the early developing cotyledons with the levels peaking at around 4 to 6 mm seed size stage. Despite of high level of nucleotide sequence conservation amongst the MIPS gene family members, MIPS2, MIPS3 and MIPS4 were poorly expressed in developing seed tissues, although their transcript levels were relatively high in the other organ tissues. MIPS1 was however moderately expressed in seedlings where MIPS2 showed relatively higher expression levels. Among the four isoforms, MIPS4 had the highest transcript levels in the leaf tissue. The data was clearly indicative of the fact that the four isoforms had diverged regulatory elements resulting in their differential expression. Of the four members of the MIPS gene family, MIPS1 is thus the major isoform that had high expression in the developing seed tissues and can be targeted using the dsRNA induced sequence specific RNA degradation mechanism for reduction of phytate levels without affecting the critical aspects of inositol metabolism in other tissues of the plant.Key words: Soybean, MIPS isoforms, differential expression, endogenous reference gene, qRT-PCR

Microscopic Realization of the Kerr/CFT Correspondence

Supersymmetric M/string compactifications to five dimensions contain BPS black string solutions with magnetic graviphoton charge P and near-horizon geometries which are quotients of AdS_3 x S^2. The holographic duals are typically known 2D CFTs with central charges c_L=c_R=6P^3 for large P. These same 5D compactifications also contain non-BPS but extreme Kerr-Newman black hole solutions with SU(2)_L spin J_L and electric graviphoton charge Q obeying Q^3 \leq J_L^2. It is shown that in the maximally charged limit Q^3 -> J_L^2, the near-horizon geometry coincides precisely with the right-moving temperature T_R=0 limit of the black string with magnetic charge P=J_L^{1/3}. The known dual of the latter is identified as the c_L=c_R=6J_L CFT predicted by the Kerr/CFT correspondence. Moreover, at linear order away from maximality, one finds a T_R \neq 0 quotient of the AdS_3 factor of the black string solution and the associated thermal CFT entropy reproduces the linearly sub-maximal Kerr-Newman entropy. Beyond linear order, for general Q^3<J_L^2, one has a finite-temperature quotient of a warped deformation of the magnetic string geometry. The corresponding dual deformation of the magnetic string CFT potentially supplies, for the general case, the c_L=c_R=6J_L CFT predicted by Kerr/CFT.Comment: 18 pages, no figure

The Role of Parvalbumin-positive Interneurons in Auditory Steady-State Response Deficits in Schizophrenia

© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Despite an increasing body of evidence demonstrating subcellular alterations in parvalbumin-positive (PV+) interneurons in schizophrenia, their functional consequences remain elusive. Since PV+ interneurons are involved in the generation of fast cortical rhythms, these changes have been hypothesized to contribute to well-established alterations of beta and gamma range oscillations in patients suffering from schizophrenia. However, the precise role of these alterations and the role of different subtypes of PV+ interneurons is still unclear. Here we used a computational model of auditory steady-state response (ASSR) deficits in schizophrenia. We investigated the differential effects of decelerated synaptic dynamics, caused by subcellular alterations at two subtypes of PV+ interneurons: basket cells and chandelier cells. Our simulations suggest that subcellular alterations at basket cell synapses rather than chandelier cell synapses are the main contributor to these deficits. Particularly, basket cells might serve as target for innovative therapeutic interventions aiming at reversing the oscillatory deficits.Peer reviewe

Kerr/CFT, dipole theories and nonrelativistic CFTs

We study solutions of type IIB supergravity which are SL(2,R) x SU(2) x U(1)^2 invariant deformations of AdS_3 x S^3 x K3 and take the form of products of self-dual spacelike warped AdS_3 and a deformed three-sphere. One of these backgrounds has been recently argued to be relevant for a derivation of Kerr/CFT from string theory, whereas the remaining ones are holographic duals of two-dimensional dipole theories and their S-duals. We show that each of these backgrounds is holographically dual to a deformation of the DLCQ of the D1-D5 CFT by a specific supersymmetric (1,2) operator, which we write down explicitly in terms of twist operators at the free orbifold point. The deforming operator is argued to be exactly marginal with respect to the zero-dimensional nonrelativistic conformal (or Schroedinger) group - which is simply SL(2,R)_L x U(1)_R. Moreover, in the supergravity limit of large N and strong coupling, no other single-trace operators are turned on. We thus propose that the field theory duals to the backgrounds of interest are nonrelativistic CFTs defined by adding the single Schroedinger-invariant (1,2) operator mentioned above to the original CFT action. Our analysis indicates that the rotating extremal black holes we study are best thought of as finite right-moving temperature (non-supersymmetric) states in the above-defined supersymmetric nonrelativistic CFT and hints towards a more general connection between Kerr/CFT and two-dimensional non-relativistic CFTs.Comment: 48+8 pages, 4 figures; minor corrections and references adde

Genomic heterogeneity underlies multidrug resistance in Pseudomonas aeruginosa: A population-level analysis beyond susceptibility testing.

BACKGROUND: Pseudomonas aeruginosa is a persistent and difficult-to-treat pathogen in many patients, especially those with Cystic Fibrosis (CF). Herein, we describe a longitudinal analysis of a series of multidrug resistant (MDR) P. aeruginosa isolates recovered in a 17-month period, from a young female CF patient who underwent double lung transplantation. Our goal was to understand the genetic basis of the observed resistance phenotypes, establish the genomic population diversity, and define the nature of sequence evolution over time. METHODS: Twenty-two sequential P. aeruginosa isolates were obtained within a 17-month period, before and after a double-lung transplant. At the end of the study period, antimicrobial susceptibility testing, whole genome sequencing (WGS), phylogenetic analyses and RNAseq were performed in order to understand the genetic basis of the observed resistance phenotypes, establish the genomic population diversity, and define the nature of sequence changes over time. RESULTS: The majority of isolates were resistant to almost all tested antibiotics. A phylogenetic reconstruction revealed 3 major clades representing a genotypically and phenotypically heterogeneous population. The pattern of mutation accumulation and variation of gene expression suggested that a group of closely related strains was present in the patient prior to transplantation and continued to change throughout the course of treatment. A trend toward accumulation of mutations over time was observed. Different mutations in the DNA mismatch repair gene mutL consistent with a hypermutator phenotype were observed in two clades. RNAseq performed on 12 representative isolates revealed substantial differences in the expression of genes associated with antibiotic resistance and virulence traits. CONCLUSIONS: The overwhelming current practice in the clinical laboratories setting relies on obtaining a pure culture and reporting the antibiogram from a few isolated colonies to inform therapy decisions. Our analyses revealed significant underlying genomic heterogeneity and unpredictable evolutionary patterns that were independent of prior antibiotic treatment, highlighting the need for comprehensive sampling and population-level analysis when gathering microbiological data in the context of CF P. aeruginosa chronic infection. Our findings challenge the applicability of antimicrobial stewardship programs based on single-isolate resistance profiles for the selection of antibiotic regimens in chronic infections such as CF

Targeting eosinophils in respiratory diseases: Biological axis, emerging therapeutics and treatment modalities

Eosinophils are bi-lobed, multi-functional innate immune cells with diverse cell surface receptors that regulate local immune and inflammatory responses. Several inflammatory and infectious diseases are triggered with their build up in the blood and tissues. The mobilization of eosinophils into the lungs is regulated by a cascade of processes guided by Th2 cytokine generating T-cells. Recruitment of eosinophils essentially leads to a characteristic immune response followed by airway hyperresponsiveness and remodeling, which are hallmarks of chronic respiratory diseases. By analysing the dynamic interactions of eosinophils with their extracellular environment, which also involve signaling molecules and tissues, various therapies have been invented and developed to target respiratory diseases. Having entered clinical testing, several eosinophil targeting therapeutic agents have shown much promise and have further bridged the gap between theory and practice. Moreover, researchers now have a clearer understanding of the roles and mechanisms of eosinophils. These factors have successfully assisted molecular biologists to block specific pathways in the growth, migration and activation of eosinophils. The primary purpose of this review is to provide an overview of the eosinophil biology with a special emphasis on potential pharmacotherapeutic targets. The review also summarizes promising eosinophil-targeting agents, along with their mechanisms and rationale for use, including those in developmental pipeline, in clinical trials, or approved for other respiratory disorders

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Palliative Radiation Therapy for Vertebral Metastases and Metastatic Cord Compression in Patients Treated With Anti-PD-1 Therapy

Background: There is increasing use of immune checkpoint blockade (ICB) across multiple cancer types, including in patients at risk for vertebral metastases and cord compression. These patients are often treated with palliative radiotherapy (PRT); however, data evaluating the combination of PRT and ICB in patients with vertebral metastases is limited. Furthermore, patients with cord compression are generally excluded from prospective clinical trials. Therefore, we retrospectively evaluated outcomes following PRT and PD-1 inhibition in patients with vertebral metastases.Methods: We performed a retrospective chart review of 37 consecutive patients (total 57 lesions) treated with radiation for vertebral metastases who also received PD-1 inhibition. Patient, treatment and outcomes data were abstracted from the medical records.Results: Histologies included non-small cell lung cancer (n = 21), renal cell carcinoma (n = 9) and melanoma (n = 7). Out of 57 lesions,18 involved &gt;1 segments of the vertebral column. There were isolated lesions in thoracic (16), lumbar (9), cervical (6), and sacral (8) vertebrae. Presenting symptoms included pain (19), numbness (10), and weakness (3). Eleven patients were asymptomatic. Radiologic cord compression was present in 12, epidural extension in 28 and compression fracture in 14. Eleven patients underwent surgical decompression prior to the onset of RT. Median radiation dose was 24 Gy (range 8–30 Gy). Stereotactic radiation was delivered in 4 patients; 33 patients received conformal RT. 21 patients received PD-1 inhibition after RT, 9 before RT and 7 with RT. Seven patients received concurrent CTLA-4 inhibitors with anti-PD-1 therapy.Treatment was in general well-tolerated. Toxicities included fatigue (6), transient pain flare (1), nausea/vomiting (1) and G1 skin changes (1). All patients reported some degree of pain relief. Numbness/weakness was improved in 6 of 13 patients with baseline symptoms (46%) and this was more likely in patients that received vertebral radiation after starting PD-1 inhibitors (71 vs. 17%, p = 0.04). Most patients (22 of 33 evaluable patients, 67%) had stability of irradiated lesions on subsequent follow up imaging performed at median of 30 days from RT, whereas 3 had a complete local response and 4 had a partial local response.Conclusions: We demonstrate that PRT administered to vertebral metastases was well-tolerated and effective in patients treated with PD-1 inhibitors. There was an encouraging rate of pain reduction and neurological improvement