Moderate Elevation Research Articles

Destabilization mechanism of the collisional microtearing mode in magnetized slab plasmas

The destabilization mechanism of the collisional microtearing mode driven by an electron temperature gradient is studied using theoretical analyses and gyrokinetic simulations including a comprehensive collision model, in magnetized slab plasmas. The essential destabilization mechanism of the microtearing mode is the lag of the parallel inductive electric field behind the magnetic field owing to the time-dependent thermal force and inertia force induced by the velocity-dependent electron–ion collisions. Quantitative measurements of the collision effects enable us to identify the unstable regime against collisionality and reveal the relevance of the collisional microtearing mode with existing toroidal experiments. A nonlinear simulation demonstrates that the microtearing mode does not drive magnetic reconnection with the explosive release and conversion of the magnetic energy.

Unpredictable fasting transiently alters corticosterone and feeding behavior but not body mass or later HPA axis function in zebra finches (Taeniopygia guttata)

The hypothalamic-pituitary-adrenal (HPA) axis is commonly activated in response to unpredictable conditions, including unstable or inadequate food supply. Extended exposure to unpredictable food resources can alter HPA axis function, with the potential for negative fitness consequences. We addressed the interrelationships of unpredictable food resources, HPA axis activity, and food intake in adult and juvenile zebra finches (Taeniopygia guttata). Finches exposed to prolonged periods of unpredictable food elevate corticosterone (the primary avian glucocorticoid) when food is unavailable; however, whether they experience chronic elevation in baseline corticosterone during periods of unpredictability, even when food is available, is unclear. We subjected adults and juveniles to an extended period of temporally unpredictable food (consisting of a random daily fast) or predictable food supply. We investigated baseline corticosterone under fed conditions and in response to an acute fast (mimicking the daily fasting periods in the unpredictable treatment), and assessed differences in body mass, food intake, and corticosterone responses to restraint. Regardless of sex and age, individuals in both treatment groups elevated corticosterone when fasted, and baseline corticosterone under fed conditions was indistinguishable between groups. Thus, corticosterone levels were not persistently elevated in the unpredictably fed group. Treatment groups did not differ in body mass or corticosterone responses to restraint, but unpredictably fed birds consumed food more rapidly when food was available. Our findings suggest that the unpredictably fed birds experienced repeated, moderate elevations in corticosterone. Such elevations may aid birds in coping with unpredictable food sources, in part by activating compensatory changes in foraging behavior.

Characterization of the absorption properties of 5 nm spherical gold nanoparticles functionalized with dodecanothiol and without functionalization with potential therapeutic applications

Hybrid nanosystems have useful properties for preparing therapeutic systems. Among the most commonly used inorganic components in hybrid nanosystems are gold nanoparticles (AuNP). The design of these nanosystems may require AuNP of hydrophilic or hydrophobic nature. Upon irradiation of AuNP, reactive oxygen species (ROS) are formed, and the temperature of the surrounding medium rises, depending on the size, shape and structure of the nanoparticle. The aim of this work is to evaluate whether irradiating 5 nm spherical gold nanoparticles both ‘bare’ (AuNP) and functionalized with dodecanethiol (AuNPf) with a Nd:YAG pulsed laser (30 ps, and 10 Hz) at wavelengths of 532 nm (0.031 J cm−2) and 1064 nm (1.91 J cm−2) produces ROS and heat sufficiently to induce cytotoxicity, or to demonstrate whether functionalization significantly influences such processes. It was verified by UV–vis spectrophotometry with ABMA and DCPIP that AuNP and AuNPf in solution induced ROS formation. They also produce a moderate elevation of the temperature of the surrounding medium. Irradiation of T47D cells at 532 nm in the presence of AuNP significantly decreased cell viability (>60%) compared to irradiation in the absence of NP (<20%). This effect was less evident when irradiating at 1064 nm because the cytotoxicity in the absence of AuNPs was very high (80%). AuNPf showed in solution a similar behavior to AuNP but due to the solvent in the suspension it was not possible to evaluate the cell toxicity caused by AuNPf. The results obtained indicate that it is feasible to design hybrid nanosystems for therapy from these 5 nm NPs, which would have photodynamic and photothermal effect.

Early Maladaptive Schemas and Schema Modes in clinical disorders: A systematic review.

Although schema therapy has been predominantly applied to treat personality disorders, interest into its application in other clinical disorders is growing. Central to schema therapy are Early Maladaptive Schemas (EMS) and Schema Modes. Since existing EMS and Schema Modes were primarily developed in the context of personality disorders, their relevance for clinical disorders is unclear. We conducted a systematic review of the presence of EMS and Schema Modes in clinical disorders according to DSM criteria. Per disorder, we evaluated which EMS and Schema Modes were more pronounced in comparison with clinical as well as non-clinical control groups and which EMS and Schema Modes were most highly endorsed within the disorder. Although evidence concerning EMS was scarce for several disorders, and only few studies on Schema Modes survived inclusion criteria, we identified meaningful relationships and patterns for EMS and Schema Modes in various clinical disorders. The present review highlights the relevance of EMS and Schema Modes for clinical disorders beyond personality disorders. Depending on the theme of the representation, EMS act as vulnerabilities both across diagnoses and for specific disorders. Thus, EMS and resulting Schema Modes are potential, valuable targets for the prevention and treatment of clinical disorders.

Myasthenia Gravis with Idiopathic Inflammatory Myopathy and Sjögren Syndrome, A Triad of Immune-Mediated Diseases

This report illustrates a 73-year-old woman with Sjögren's syndrome and idiopathic inflammatory myopathy with elevated creatine kinase that subsequently deteriorated with an increased dose of steroids, resulting in a myasthenic crisis requiring hospitalization in the intensive care unit; the patient responded successfully to treatment with intravenous immunoglobulin. The patient showed moderate elevation of creatine kinase at the initial diagnosis, with positive anti-Ro/SSA antibodies. Schirmer’s test, anti-Ro52 and anti-Ku antibodies, electromyography, and muscle biopsy were performed to confirm inflammatory myopathy. During the observation in the intensive care unit, creatine kinase increased to 1520 U/L, and a repetitive stimulation test and total anti-acetylcholine receptor antibodies supported the diagnosis of myasthenia gravis. The patient received intravenous immunoglobulin, evolving with clinical improvement. This case is being reported to illustrate the chronic clinical course of a patient with inflammatory myopathy who deteriorated following steroid adjustment, ultimately presenting with myasthenic crisis.

Two new species of Eleutherodactylus from western and central Mexico (Eleutherodactylus jamesdixoni sp. nov., Eleutherodactylus humboldti sp. nov.).

The subgenus Syrrhophus (genus Eleutherodactylus) contains >40 species of small, direct-developing frogs that occur at low to moderate elevations from Texas through Mexico and into Guatemala and Belize, with two species in western Cuba. Morphological conservatism and phenotypic convergence have made species delimitation challenging and resulted in a complicated taxonomic history. Since 2015, molecular systematic work has uncovered eleven new species from western Mexico and one from eastern Mexico, but current taxonomy still underestimates species level diversity and there is confusion surrounding the validity and boundary of several species. We used phylogenetic analysis of 16S ribosomal RNA (rRNA) sequences, multivariate statistical analysis of morphological data, and bioacoustic analysis of male advertisement calls to discover two additional unnamed species of Eleutherodactylus from Central and Western Mexico. We describe those species here. Eleutherodactylus (Syrrhophus) humboldti sp. nov. is described from the Quaternary Valle de Bravo volcanic field of the Eje Neovolcánico in Central Mexico. This species is sister to E. maurus and is 3% divergent in 16S. Eleutherodactylus (Syrrhophus) jamesdixoni sp. nov. is described from the Sierra Madre Occidental of western Mexico. This species is sister to E. nitidus and is 3% divergent. We provide color photographs, advertisement call recordings, and molecular diagnoses of these new species and their sister species to aid future workers.

Research on the Economic Management Model of Tibetan SMEs from the Perspective of Marketing

With the development of Chinese enterprises, marketing and enterprise economic management are taking up an increasingly large proportion in the work of enterprises. It is undeniable that there are many problems in the enterprise economic management of Tibetan SMEs in China at present, such as the lack of relevance of economic management mode, limited to the traditional marketing concept, the organization cannot adapt to the actual development environment, the lack of enterprise economic management personnel, and the enterprise economic management system is not perfect. Measures are proposed accordingly for these problems to promote the marketing of Tibetan SMEs in China to have a rapid growth.

Color Vision in Blue Cone Monochromacy: Outcome Measures for a Clinical Trial.

Blue cone monochromacy (BCM) is an X-linked retinopathy due to mutations in the OPN1LW/OPN1MW gene cluster. Symptoms include reduced visual acuity and disturbed color vision. We studied BCM color vision to determine outcome measures for future clinical trials. Patients with BCM and normal-vision participants were examined with Farnsworth-Munsell (FM) arrangement tests and the Color Assessment and Diagnosis (CAD) test. A retrospective case series in 36 patients with BCM (ages 6-70) was performed with the FM D-15 test. A subset of six patients also had Roth-28 Hue and CAD tests. All patients with BCM had abnormal results for D-15, Roth-28, and CAD tests. With D-15, there was protan-deutan confusion and no bimodal tendency. Roth-28 results reinforced that finding. There was symmetry in color vision metrics between the two eyes and coherence between sessions with the arrangement tests and CAD. Severe abnormalities in red-green sensitivity with CAD were expected. Unexpected were different levels of yellow-blue results with two patterns of abnormal thresholds: moderate elevation in two younger patients and severe elevation in four patients ≥35 years. Coefficients of repeatability and intersession means were tabulated for all test modalities. Given understanding of advantages, disadvantages, and complexities of interpretation of results, both an arrangement test and CAD should be useful monitors of color vision through a clinical trial in BCM. Our pilot studies in BCM of arrangement and CAD tests indicated both were clinically feasible and interpretable in the context of this cone gene disease.

An examination of predictive markers for successful sperm extraction procedures: a linear model and systematic review.

The authors performed a comprehensive review of current literature to create a model comparing commonly evaluated variables in male factor infertility, for example, follicle-stimulating hormone (FSH), testicular volume (TV), and testosterone (T), to better predict sperm retrieval rate (SRR). Twenty-nine studies were included, 9 with data on conventional testicular sperm extraction (cTESE) for a total of 1227 patients and 20 studies including data on microdissection testicular sperm extraction (mTESE) for a total of 4760 patients. A weighted-means value of SRR, FSH, T, and TV was created, and a weighted linear regression was then used to describe associations among SRR, type of procedure, FSH, T, and TV. In this study, weighted-means values demonstrated mTESE to be superior to cTESE with an SRR of 51.9% vs 40.1%. Multiple weighted linear regressions were created to describe associations among SRR, procedure type, FSH, T, and TV. The models showed that for every 1.19 mIU ml-1 increase in FSH, there would be a significant decrease in SRR by 1.0%. Seeking to create a more clinically relevant model, FSH values were then divided into normal, moderate elevation, and significant elevation categories (FSH <10 mIU ml-1, 10-19 mIU ml-1, and >20 mIU ml-1, respectively). For an index patient undergoing cTESE, the retrieval rates would be 57.1%, 44.3%, and 31.2% for values normal, moderately elevated, and significantly elevated, respectively. In conclusion, in a large meta-analysis, mTESE was shown to be more successful than cTESE for sperm retrievals. FSH has an inverse relationship to SRR in retrieval techniques and can alone be predictive of cTESE SRR.

Acute Phase Reactants: Relevance in Dermatology.

Acute phase reactants (APRs) are a heterogeneous group of plasma proteins whose concentration either increases or decreases by at least 25% during an inflammatory process. The conditions that commonly lead to acute phase response are infection, trauma, burns, tissue infarction, inflammatory conditions, and advanced malignancy. APRs are elevated in all infective conditions. In skin and soft tissue infection, the levels of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) help to predict the severity of infection. Procalcitonin can be used to differentiate between viral and bacterial infections. During active stages of systemic lupus erythematosus (SLE), ESR is elevated, but CRP either remains normal or shows only moderate elevation. In the case of superadded bacterial infection in SLE, CRP is elevated. In SLE, ferritin levels are elevated during the active stage of the disease. Serum amyloid antigen (SAA) and CRP levels are significantly higher in patients with early and late stages of diffuse systemic sclerosis. Elevated levels of serum ferritin are seen in rheumatoid arthritis and adult-onset Still's disease. CRP, SAA, and α2-macroglobulin (α 2M) are elevated in active psoriasis. In severe psoriasis, the ferritin-iron ratio is elevated. In drug-induced maculopapular rash, drug-induced hyperaemic vasculitis, and severe drug-induced cutaneous adverse reactions, CRP levels are elevated during the active stages. Neoplastic diseases in general are accompanied by increased serum ferritin. Further detailed studies are required to explore the clinical significance of APRs in dermatology and the scope of their possible application as a diagnostic tool.

Role of Serum Lipids, Blood Glucose and Blood Pressure in Breast Cancer Risk for Women with Type 2 Diabetes Mellitus.

Women with type 2 diabetes mellitus (T2DM) have an increased risk of breast cancer. We aimed to determine the contribution of lipids, glucose and blood pressure to this risk based on the multifactorial nature of T2DM. This population-based cohort study used data from a Dutch database (the Groningen Initiative to Analyse Type 2 Diabetes Treatment) for the period 2004-2013. The cohort included women diagnosed with T2DM, aged 30-80 years, with no history of breast cancer and with follow-up data for at least 1 year. We used Cox proportional hazards models to estimate the associations of exposures with breast cancer occurrence, reporting adjusted hazard ratios (aHR) with 95% confidence intervals (CI). Exposures of interest included total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, glycated hemoglobin A (HbA1c) and systolic blood pressure (SBP). During a median of 4.45 years' follow-up, 183 of 10,183 included women received a breast cancer diagnosis. We observed U-shaped associations with breast cancer incidence for total cholesterol and HDL-C at baseline. Compared with moderate elevations, women had significantly higher breast cancer risks associated with high total cholesterol (aHR, 95% CI: 1.72, 1.15-2.55) and HDL-C (aHR, 95% CI: 1.74, 1.18-2.58) levels, while low total cholesterol (aHR, 95% CI: 1.43, 0.94-2.19) and HDL-C (aHR, 95% CI: 1.44, 0.95-2.17) levels produced marginal effects without significance. Women with high LDL-C levels more often received a breast cancer diagnosis than those with medium levels (aHR, 95% CI: 1.56, 1.03-2.35). This real-world dataset highlights the importance of balancing lipid profiles, particularly total cholesterol and HDL-C. Dysregulation of the lipid profile, not the glucose or blood pressure profiles, may increase the risk of breast cancer in women with T2DM.

Межпарадигмальность как состояние современной музыкальной культуры

The aim of this article is to define the problem of the “laminary” state of contemporary musical culture, in which various paradigms of artistic experience that have emerged and established in different periods of cultural history coexist and actively interact with each other. The cultural paradigm is comprehended as a complex hierarchical integrity formed by an internal unity of ideas, intuitions, and feelings that permeate the entire vertical of life. The classical and non-classical universal models of culture with their local-historical and metahistorical dimensions are present at the highest level of paradigmatic generalization. The internally heterogeneous classical paradigm reflects the demand for a creative attitude towards clarity, completeness, perfection, rationally comprehensible order and harmony. The non-classical paradigm, marked in musical creativity from the first modernist experiments to the postmodernist playing with the near and distant past, manifests the setting of “breaking down” traditions, overcoming the inertia of the past, as well as bringing in radical experiments in the field of sound and its organization. Against the background of the “fatigue” from postmodernism at the turn of the 20th and the 21st centuries in music scholarship, there are broad discussions currently happening of such concepts as post-postmodernism, metamodernism, and postnonclassics, all of which assert a breakthrough toward new strategies of art. At the same time, none of these tendencies that lays claim to paradigmatic significance reflects a holistic picture of the art of music in its aesthetic, stylistic, and linguistic plurality. Perhaps the important reason for this is the tendency to remain in the simultaneity of the different models of artistry. This way, it seems natural to examine the borderline artistic phenomena in the direction of interaction of paradigms. In order to determine the relevant processes in music culture, the productivity of the introduction of the term “interparadigmality” is substantiated. Among the key parameters of interparadigmality, the author identifies the simultaneous relevance of various cultural modes, aesthetic values, and genre-style models. Interparadigmality, which fixates the openness and mobility of the boundaries between different cultural models, corresponds with the concept of crisis (as being at the border), with the idea of “creolization” and “creolized systems” (the definition of Yuri Lotman), and the terminology of the “philosophy of instability” created by Ilya Prigozhin. At the same time, it is particularly interparadigmality, by bringing chaos to the borderline areas of paradigm interaction, which becomes applicable to the search for a holistic approach to contemporary musical realities.

5-Formyltetrahydrofolate promotes conformational remodeling in a methylenetetrahydrofolate reductase active site and inhibits its activity

The flavoprotein methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of N5, N10-methylenetetrahydrofolate (CH2-H4folate) to N5-methyltetrahydrofolate (CH3-H4folate), committing a methyl group from the folate cycle to the methionine one. This committed step is the sum of multiple ping-pong electron transfers involving multiple substrates, intermediates, and products all sharing the same active site. Insight into folate substrate binding is needed to better understand this multifunctional active site. Here, we performed activity assays with Thermus thermophilus MTHFR (tMTHFR), which showed pH-dependent inhibition by the substrate analog, N5-formyltetrahydrofolate (CHO-H4folate). Our crystal structure of a tMTHFR•CHO-H4folate complex revealed a unique folate-binding mode; tMTHFR subtly rearranges its active site to form a distinct folate-binding environment. Formation of a novel binding pocket for the CHO-H4folate p-aminobenzoic acid moiety directly affects how bent the folate ligand is and its accommodation in the active site. Comparative analysis of the available active (FAD- and folate-bound) MTHFR complex structures reveals that CHO-H4folate is accommodated in the active site in a conformation that would not support hydride transfer, but rather in a conformation that potentially reports on a different step in the reaction mechanism after this committed step, such as CH2-H4folate ring-opening. This active site remodeling provides insights into the functional relevance of the differential folate-binding modes and their potential roles in the catalytic cycle. The conformational flexibility displayed by tMTHFR demonstrates how a shared active site can use a few amino acid residues in lieu of extra domains to accommodate chemically distinct moieties and functionalities.

Efficacy and Safety of Monacolin K Combined with Coenzyme Q10, Grape Seed, and Olive Leaf Extracts in Improving Lipid Profile of Patients with Mild-to-Moderate Hypercholesterolemia: A Self-Control Study

The objective of the present study was to assess the lipid-lowering efficacy and safety of a novel dietary supplement containing monacolin K combined with the coenzyme Q10 and grape seed and olive tree leaf extracts (Arichol®®) on the lipid profile of adults with moderate cholesterol elevations and an absence of concomitant risk factors. We recruited patients from our Endocrinology Clinics in Greece who had low-density lipoprotein cholesterol (LDL-C) 140–180 mg/dL, were on no medications affecting serum lipid concentrations, and consented to participate in the present study. All subjects received 8-weeks supplementation with Arichol®® once daily. We measured total cholesterol (TC), high-density lipoprotein cholesterol (HDL), LDL-C, triglycerides (TG), and liver enzymes with enzymatic colorimetric assays at baseline and at the end of the study, and documented complaints potentially attributable to muscle injury. We recruited a total of 37 subjects, 33 females and 4 males (with a mean age of 55.89 ± 1.50 [mean ± standard error mean, SEM]). The treatment resulted in a statistically significant reduction in TC (from 258.9 ± 4.0 mg/dL to 212.7 ± 4.5 mg/dL, p &lt; 0.001), LDL-C (from 173.8 ± 3.5 to 129.0 ± 4.5 mg/dL, p &lt; 0.001), and TG (from 127.0 ± 12.2 to 117.0 ± 9.2, mg/dL, p = 0.012) concentrations, while HDL-C concentrations remained unchanged. There were no alterations in liver enzymes or symptoms of muscle pain in any subject. These promising results suggest that supplementation with this nutraceutical mixture favorably influences lipid concentrations during a short period of administration while exhibiting an excellent safety profile. Larger controlled studies are required to assess the potential for cardiovascular risk reduction with the above compound.

Coumarin-Induced Hepatotoxicity: A Narrative Review.

Coumarin is an effective treatment for primary lymphoedema, as well as lymphoedema related to breast cancer radiotherapy or surgery. However, its clinical use is limited in several countries due to the possible occurrence of hepatotoxicity, mainly in the form of mild to moderate transaminase elevation. It is worth noting that only a few cases of severe hepatotoxicity have been described in the literature, with no reported cases of liver failure. Data available on coumarin absorption, distribution, metabolism, and excretion have been reviewed, focusing on hepatotoxicity studies carried out in vitro and in vivo. Finally, safety and tolerability data from clinical trials have been thoroughly discussed. Based on these data, coumarin-induced hepatotoxicity is restricted to a small subset of patients, probably due to the activation in these individuals of alternative metabolic pathways involving specific CYP450s isoforms. The aim of this work is to stimulate research to clearly identify patients at risk of developing hepatotoxicity following coumarin treatment. Early identification of this subset of patients could open the possibility of more safely exploiting the therapeutical properties of coumarin, allowing patients suffering from lymphoedema to benefit from the anti-oedematous activity of the treatment.

Prospective cholestanol screening of cerebrotendinous xanthomatosis among patients with juvenile-onset unexplained bilateral cataracts

BackgroundCerebrotendinous xanthomatosis (CTX) is a rare genetic disorder related to CYP27A1 biallelic mutations, leading to decreased synthesis of bile acids and increased cholestanol. Juvenile bilateral cataracts are one of the most common findings in the disease, frequently occurring before the onset of neurological manifestations. While early treatment with chenodeoxycholic acid can prevent the onset of neurological impairment, poor awareness of CTX accounts for a markedly delayed diagnosis. The objective of this study was to evaluate the utility of plasma cholestanol analysis at the moment of cataract diagnosis and before the onset of neurological impairment in CTX.MethodsMulticenter prospective cohort study of patients with juvenile-onset unexplained bilateral cataracts recruited from seven French ophthalmology departments. Plasma cholestanol analysis was performed at diagnosis from January 2018 to January 2020. CYP27A1 genetic testing was performed at the ophthalmologist’s discretion. Cholestanol levels were compared with those of a similar population of patients without cataracts (control cohort).Results30 patients were finally recruited, with a mean age at cataract diagnosis of 7.1 years (± 4.8 SD, range 1–19 years). One patient had a very high cholestanol level (68 μmol/L, reference < 10) and carried two pathogenic heterozygous mutations in CYP27A1 confirming CTX. This patient was a 19-year-old female, reporting chronic diarrhea only in childhood, and diagnosed with bilateral posterior cataracts with cortical fleck-like opacities. Therefore, the incidence of CTX in our cohort of patients was 3.3%. Five further patients (5/29; 17.2%) had moderate elevations of cholestanol level (between 10.3 and 16.5 μmol/L), compared to 12/286 (4.2%) in the control cohort (p = 0.014) after adjustment for age.ConclusionOur study argue for the relevance of plasma cholestanol CTX screening in all patients with juvenile-onset unexplained cataracts, even without other CTX identified manifestations. Whether moderate elevations of plasma cholestanol unrelated to CTX may be a risk factor for bilateral cataracts occurrence needs further examination.

Evaluation of aqueous magnesium concentration on performance of Pacific white shrimp (Litopenaeus vannamei) cultured in low salinity water of West Alabama, USA

The ionic profile of inland low salinity water sources can be dramatically different with variable concentrations of magnesium (Mg2+). Inland shrimp farmers in Alabama, USA, supplement Mg2+ at the start of each production cycle to reach concentrations >20 mg/L at 1 to 11 g/L salinities. However, this concentration may not be high enough for larger shrimp in the later phase of the production cycle. Therefore, two field trials were conducted on a commercial shrimp farm in west Alabama to evaluate the effects of Mg2+ concentration in low salinity water on growth, survival, and physiology of Pacific white shrimp, Litopenaeus vannamei. In the first study, additional Mg2+ was supplemented to four production ponds (28 mg/L Mg2+) and compared with four control ponds (12.8 mg/L Mg2+). A stocking density of 27 post-larvae/m2 was used in ponds, and shrimp were offered a commercial feed twice daily. After a 23-week pond trial, whole-body Mg2+ concentrations were higher in shrimp reared in Mg2+ treated ponds, while no significant differences in other study variables were observed between pond groups. After week 15 (shrimp weight > 22 g), weekly body weights of shrimp were significantly lower in the control group compared to the elevated Mg2+ treatment. This could be due to size-dependent deficiency in the availability of adenosine triphosphate (ATP) and Mg2+ to support growth of larger adult shrimp. The second experiment was conducted to evaluate performance of larger shrimp (∼13 g initial weight) reared in two on-levee flow-through tank systems. One tank system received water from a control pond with 12 mg/L Mg2+, while the second system was sourced with water from a production pond with a higher amount of Mg2+ (37 mg/L). In each system, twelve 800 L tanks were stocked with shrimp at three different densities (24, 29, and 35 shrimp/m2) to evaluate possible interactions between stocking density and Mg2+ concentration in water. Following an 8-week tank trial, no significant effect of Mg2+ concentration, stocking density, or their interaction was observed on growth, survival, or physiology of shrimp. Overall, these results confirm that even moderate elevations in Mg2+ in low salinity water are advantageous to adult shrimp (>22 g) in later stages of the production cycle compared to post-larvae, juveniles, or sub-adult shrimp.

The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities.

The glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor that controls metabolic and homeostatic processes essential for life. Although numerous crystal structures of the GR ligand-binding domain (GR-LBD) have been reported, the functional oligomeric state of the full-length receptor, which is essential for its transcriptional activity, remains disputed. Here we present five new crystal structures of agonist-bound GR-LBD, along with a thorough analysis of previous structural work. We identify four distinct homodimerization interfaces on the GR-LBD surface, which can associate into 20 topologically different homodimers. Biologically relevant homodimers were identified by studying a battery of GR point mutants including crosslinking assays in solution, quantitative fluorescence microscopy in living cells, and transcriptomic analyses. Our results highlight the relevance of non-canonical dimerization modes for GR, especially of contacts made by loop L1-3 residues such as Tyr545. Our work illustrates the unique flexibility of GR's LBD and suggests different dimeric conformations within cells. In addition, we unveil pathophysiologically relevant quaternary assemblies of the receptor with important implications for glucocorticoid action and drug design.

Deficiency of NMDA receptor subunit GluN3A as a pathogenic factor for endogenous amyloid deposition and sporadic Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disease, evolving amyloidosis and tau protein hyperphosphorylation, synapse dysfunction, neuron degeneration and cognitive deficits. Investigations based on the Aβ/tau hypothesis have been performed in transgenic animal models expression familial/mutated AD genes. However, treatments based on this hypothesis have not provided effective clinical therapies. Hyperactivity of the glutamatergic NMDA receptor (NMDAR) is a common pathophysiology of AD and has been viewed as a consequence of Aβ pathology. Among NMDAR subunits, GluN3A is a unique inhibitory subunit that suppresses NMDA currents and Ca2+ influx. Recent evidence from rodent and human studies shows that GluN3A is widely expressed and plays important functional roles in neonatal and adult brains. Ca2+ overload is a trigger of excitotoxicity, while GluN3A plays a regulatory role of Ca2+ homeostasis. The role of GluN3A regulation in AD is unknown.MethodGluN3A knockout mice, gene modifications, immunohistochemistry, Western blotting, MEA recordings, Ca2+ imaging, pathological examinations, functional and behavioral tests.ResultChronic neuronal hyperactivity and Ca2+ dysregulation caused by GluN3A deficiency lead to slowly advanced “neurodegenerative excitotoxicity”, dementia and AD pathology in an age‐dependent manner. Ca2+ imaging and MultiElectrode Array recordings in GluN3A KO brain slices revealed moderate but sustained elevation of cytosolic Ca2+ levels, neuronal hyperactivity, and impaired synaptic plasticity compared to age matched controls. Aging GluN3A KO mice showed increased Ca2+‐dependent signals, chronic inflammation, neuronal loss and disease symptoms including early onset of olfactory dysfunction followed by cognitive deficits. β‐Amyloid deposition and tau protein hyperphosphorylation were identified as a late pathology in the cortex and hippocampus. Expression of GluN3A in the GluN3A KO brain prevented AD progression. Early treatment at the pre‐clinical stage using the NMDAR antagonist memantine prevented symptoms in GluN3A KO mice. Western blot analysis of AD patient’s brains showed lower levels of GluN3A in the cortex compared to normal aging subjects.ConclusionOur results identified a novel amyloid‐independent mechanism that the deficiency of GluN3A alone causes a slight lifelong Ca2+ dyshomeostasis, leading to AD pathophysiology and amyloid pathology. The long‐term GluN3A modulation of NMDARs signifies new therapeutic targets and possible preventive interventions for a sporadic type of AD.

Extracellular product of Pseudomonas aeruginosa in growth medium is involved in the pro-inflammatory cytokine response of human oral epithelial cells in vitro.

Epithelial cells are the first barrier to any microbial invasion. Finding a safe and affordable substance to stimulate the innate immune response of epithelial cells is one of the main challenges immunologists and vaccine manufacturers are facing. This study aimed to show the comparative effect of sterile bacterial secretion (SBS) and Pseudomonas aeruginosa bacterial cell isolates obtained from burn wound infections on the ability of human epithelial cells (HECs) to produce interleukin (IL)-1β and tumor necrosis factor alpha (TNF-α) in vitro. The HEC cultures were exposed to P. aeruginosa 8 (Pa 8), Pa 2 and Pa 1 bacterial cells (isolated from burn wound infections). The other 3 groups of HECs were exposed to 50 μL of sterile, endotoxin-free SBS of Pa 8, Pa 2 and Pa 1. The time course of changes in IL-1β mRNA, TNF-α mRNA, IL-1β, and TNF-α was examined. Moderate (p < 0.05) elevations of IL-1β mRNA in HECs and IL-1β protein in the supernatant of the HEC culture were observed following exposure to SBS of Pa 8, Pa 2 and Pa 1 at most time points. High elevation (p < 0.05) of IL-1β was seen in the supernatant of the HEC culture that was exposed to bacterial cells (Pa 8, Pa 2 and Pa 1). Similar results were found when TNF-α mRNA was measured in HECs and TNF-α in the supernatant of the HEC cultures after exposure to bacterial cells (Pa 8, Pa 2 and Pa 1) and the SBS of Pa 8, Pa 2 and Pa 1. This is the first time that the capacity of SBS to generate epithelial cell pro-inflammatory cytokines in vitro has been shown. In other words, SBS enhanced a nonspecific immune response, which opens the door to the possibility of using SBS from P. aeruginosa as an adjuvant in the future.