Pathological Levels Research Articles

APOE genotype and sex modulate Alzheimer's disease pathology in aged EFAD transgenic mice.

Increasing evidence supports that age, APOE and sex interact to modulate Alzheimer's disease (AD) risk, however the underlying pathways are unclear. One way that AD risk factors may modulate cognition is by impacting amyloid beta (Aβ) accumulation as plaques, and/or neuroinflammation Therefore, the goal of the present study was to evaluate the extent to which age, APOE and sex modulate Aβ pathology, neuroinflammation and behavior in vivo. To achieve this goal, we utilized the EFAD mice, which express human APOE3 or APOE4 and have five familial AD mutations (FAD) that result in Aβ42 overproduction. We assessed Aβ levels, reactive glia and Morris water maze performance in 6-, 10-, 14-, and 18-month-old EFAD mice. Female APOE4 mice had the highest Aβ deposition, fibrillar amyloid deposits and neuroinflammation as well as earlier behavior deficits. Interestingly, we found that female APOE3 mice and male APOE4 mice had similar levels of pathology. Collectively our data support that the combination of APOE4 and female sex is the most detrimental combination for AD, and that at older ages, female sex may be equivalent to APOE4 genotype.

JTE-013 Alleviates Pulmonary Fibrosis by Affecting the RhoA/YAP Pathway and Mitochondrial Fusion/Fission.

Pulmonary fibrosis may be due to the proliferation of fibroblasts and the aggregation of extracellular matrix, resulting in the stimulation of inflammation damage, destroying lung tissue structure, seriously affecting the patient's respiratory function, and even leading to death. We investigated the role and mechanism of JTE-013 in attenuating bleomycin (BLM)-induced pulmonary fibrosis. BLM-induced pulmonary fibrosis was established in mice. Type 2 alveolar epithelial cells (MLE-12) were stimulated with sphingosine monophosphate (S1P) in vitro. JTE-013, an S1PR2 (sphingosine 1-phosphate receptor 2) antagonist, and Verteporfin were administered in vivo and in vitro. IL-4, IL-5, TNF-α, and IFN-γ were measured by ELISA. IL-4 and IFN-γ positive cells were detected by flow cytometry. Inhibition of S1PR2 with JTE-013 significantly ameliorated BLM-induced pathological changes and inflammatory cytokine levels. JTE-013 also significantly reduced the expression of RHOA/YAP pathway proteins and mitochondrial fission protein Drp1, apoptosis, and the colocalization of α-SMA with YAP, Drp1, and Tom20, as detected by immunohistochemistry, immunofluorescence staining, TUNEL, and Western blot. In vitro, S1PR2 and YAP knockdown downregulated RHOA/YAP pathway protein expression, Drp1 phosphorylation, and Drp1 translocation, promoted YAP phosphorylation and phenotypic transformation of MFN2, and inhibited the up-regulation of mitochondrial membrane potential, reactive oxygen species production, and cell apoptosis (7.13% vs. 18.14%), protecting the integrity of the mitochondrial dynamics. JTE-013 also inhibited the expression of fibrosis markers α-SMA, MMP-9, and COL1A1, and alleviated the symptoms of pulmonary fibrosis. Conclusively, JTE-013 has great anti-pulmonary fibrosis potential by regulating RHOA/YAP and mitochondrial fusion/fission.

Influence of betrayal trauma on obsessive-compulsive personality pathology.

Obsessive-compulsive personality disorder (OCPD) is among the most common forms of personality pathology. Research suggests that among the risk factors for OCPD pathology is trauma, although it is unclear which kinds of trauma are most influential. Of particular relevance may be trauma high in interpersonal betrayal, which research suggests has a unique association with many different forms of personality pathology. However, this has not yet been examined for OCPD specifically. In this study, we examined the differential associations between trauma with varying levels of betrayal and OCPD pathology in a sample of women and men recruited online (N = 300) using a Bayesian approach to structural equation modeling. Results suggest that although general interpersonal trauma was associated with OCPD across the sample, interpersonal trauma high in betrayal was uniquely associated with OCPD for men. These findings have implications for future research on the influence of trauma and personality pathology as well as for the treatment of OCPD specifically. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Personality and Lifetime Need Frustration: A Person-Centered Perspective on Interpersonal Problems and Personality Pathology

The current research adopted a person-centered approach to examine whether people’s experiences of lifetime need frustration interact with their personality trait profiles to predict their problems and pathology from the perspectives of both the interpersonal circumplex (IPC) and the five-factor model (FFM). Data (N = 1,026) were analyzed using multilevel modeling. Consistent with prediction, lifetime need frustration predicted participants’ overall levels of interpersonal distress and personality pathology. Furthermore, levels of lifetime need frustration predicted the strength of the relationship between participants’ trait profiles (i.e., IPC and FFM) and their corresponding profiles of interpersonal problems and personality pathology. Findings from the present study demonstrate how between-person differences in lifetime need frustration give rise to the within-person organization of psychological maladjustment and highlight the importance of people’s traits in predicting their unique maladaptations to having their basic psychological needs frustrated.

The Impact of Leadership and Communication on Safety Culture Maturity Level

<div><table cellspacing="0" cellpadding="0" align="left"><tbody><tr><td align="left" valign="top"><p><em>Safety culture is the way workers behave safely when working without supervision. In addition, five levels categorized into pathological, reactive, calculative, proactive, and generative levels are used to evaluate the level of safety culture maturity. This research aims to determine the influence of leadership and communication on the level of maturity of safety culture at the State Electricity Company Project Management Center-Construction Management Implementation Unit IV. The type of research used in this research is quantitative research with a cross sectional research design. The research will be carried out at the limited liability company national electricity company project management center-construction management implementation unit IV which operates in the field of construction management services. The research was conducted from March to August 2023. The sample collection technique was total sampling. The research sample was 71 respondents. The research instrument used was a questionnaire. Data analysis using SEM-PLS or Partial Least Square- Structural Equation Modeling analysis using SmartPLS software.</em><em> </em><em>The research results show that leadership has a significant effect on the level of safety culture maturity (p value < 0.05), and communication has a significant effect on the level of safety culture maturity (p value < 0.05). Leadership and communication simultaneously have a significant influence on the level of safety culture maturity, with a combined contribution of 70.7% from these two variables. Meanwhile, the rest is influenced by other variables not examined in this research.</em><em></em></p><p> </p></td></tr></tbody></table></div><p><strong><em>Keyword: Communication, Leadership, Safety culture maturity level</em></strong></p>

Aerobic exercise mitigates hippocampal neuronal apoptosis by regulating DAPK1/CDKN2A/REDD1/FoXO1/FasL signaling pathway in D-galactose-induced aging mice.

Brain aging is the most important risk factor for neurodegenerative disorders, and abnormal apoptosis is linked to neuronal dysfunction. Specifically, studies have found that exercise effectively inhibits hippocampal neuronal apoptosis, while the molecular mechanism remains unclear. In the present study, we investigated the impact of aerobic exercise on hippocampal neuronal apoptosis in aging mice and the potential involvement of DAPK1 and its downstream pathways based on recent data that DAPK1 may be associated with neuronal death in neurodegenerative diseases. Senescent mice were subjected to 8 weeks of Aerobic training. Following behavioral testing, hippocampal samples were examined histologically and biochemically to detect pathological changes, neuronal apoptosis, and mRNA and protein levels. We found that the exercise intervention improved spatial memory and alleviated neuronal apoptosis in the brain. Notably, exercise down-regulated DAPK1 expression and inhibited Fas death receptor transactivation and the mitochondrial apoptotic pathway in the hippocampus. These results shed new light on the protective effect of regular exercise against brain aging though modulating the DAPK1 pathway.

Melatonin: Adjunct therapeutics in ovarian endometrioma

Melatonin (N-acetyl-5-methoxytryptamine) hormone is a methoxyindole primarily released by the pineal gland. Melatonin has dynamicproperties of being a free radical scavenger, inflammatory suppressor, anti-apoptotic agent, reproductive hormone modulator andmediator of several signaling pathways in female reproductive system. The presence of differential localization of melatonin receptorsin the ovary, influence on the ovarian hormones and ovarian cycle has implied the association between ovarian system and melatoninboth at the pathological and physiological levels. On the other hand, the pathophysiology of ovarian endometrioma is remarked byvarious anomalies likely: generation of various reactive oxygen species, followed by follicular damage, oocyte and embryonic defects,inflammation and apoptosis, which the involvement of melatonin can plausibly counteract. The present review evaluated melatonin’sprobable protective role against ovarian endometrioma via diverse signaling pathways.

Modeling and analyzing the action process of monoamine hormones in depression: a Petri nets-based intelligent approach.

In contemporary society, the incidence of depression is increasing significantly around the world. At present, most of the treatment methods for depression are psychological counseling and drug therapy. However, this approach does not allow patients to visualize the logic of hormones at the pathological level. In order to better apply intelligence computing methods to the medical field, and to more easily analyze the relationship between norepinephrine and dopamine in depression, it is necessary to build an interpretable graphical model to analyze this relationship which is of great significance to help discover new treatment ideas and potential drug targets. Petri net (PN) is a mathematical and graphic tool used to simulate and study complex system processes. This article utilizes PN to study the relationship between norepinephrine and dopamine in depression. We use PN to model the relationship between the norepinephrine and dopamine, and then use the invariant method of PN to verify and analyze it. The mathematical model proposed in this article can explain the complex pathogenesis of depression and visualize the process of intracellular hormone-induced state changes. Finally, the experiment result suggests that our method provides some possible research directions and approaches for the development of antidepressant drugs.

Increased Prevalence of Autoimmune Gastritis in Patients with a Gastric Precancerous Lesion.

Background: Autoimmune gastritis (AIG), characterized with the presence of anti-parietal-cell antibodies (APCA), is a risk factor for gastric cancer. However, AIG may go underdiagnosed, especially in the case of H. pylori infection and the presence of gastric precancerous lesions (GPL), due to the ambiguous pathology and delayed symptom onset. Aim: Investigate the prevalence and characteristics of AIG in GPL patients. Methods: Prevalence of AIG was determined with the presence of APCA in patients with GPL (n = 256) and the control group (n = 70). Pathological characteristics and levels of gastrin 17 (G17), pepsinogen (PG) I and II and anti-Helicobacter pylori IgG were assessed in GPL cases, and the severity of intestinal metaplasia and gastric atrophy was scored by expert pathologists. Results: APCA positivity was observed in 18% of cases vs. 7% of controls (p = 0.033). Only 3/256 patients were previously diagnosed with AIG. The presence of APCA was associated with corpus-limited and extended GPL. A receiver operating curve analysis demonstrated that the G17 and PGI/II ratio could identify APCA-positive patients within GPL cases (AUC: 0.884). Conclusions: The prevalence of AIG is higher in patients with GPL but goes undiagnosed. Using G17 and PG I/II as diagnostic markers can help to identify patients with AIG and improve surveillance programs for patients with GPL.

Protective and immunomodulatory effects of mesenchymal stem cells on multiorgan injury in male rats with heatstroke

Heatstroke (HS) causes multiple organ dysfunction syndrome (MODS) with a mortality rate of 60% after hospitalization. Currently, there is no effective and targeted approach for the treatment of HS. Despite growing evidence that mesenchymal stem cells (MSCs) may reduce multiorgan damage and improve survival through immunomodulatory effects in several diseases, no one has tested whether MSCs have immunomodulatory effects in heatstroke. The present study focused on pathological changes and levels of the cytokines and immunoglobulins to investigate the mechanisms underlying the protective effect and the anti-inflammatory effects of MSCs. We found that MSCs treatment significantly reduced the 28-day mortality rate (P < 0.05), the levels of hepatic and renal function markers on day 1 (P < 0.01) and the pathological lesion scores of multiple organs in HS rats. The levels of IgG1, IgM, and IgA of the HS + MSC group was significantly higher than that in HS group on days 3 and 28(P < 0.05). In conclusion, MSCs contribute to protecting against multiorgan injury, reducing pro-inflammatory cytokines, stabilizing immunoglobulins, and reducing the mortality rate of HS rats.

Supramolecular Nano-Assembly of Caffeate-Strengthened Phenylboronic Ester with Multistep ROS Scavenging Ability for Targeted Therapy of Acute Kidney Injury.

Acute kidney injury (AKI) is a life-threatening complication with a considerable occurrence among patients. AKI is typically accompanied by an elevation in reactive oxidative species (ROS) in renal tissues, which is the main contributor to kidney damage. Herein, a supramolecular nano-assembly (Ser-HPEC) containing an ethyl caffeate-strengthened phenylboronic ester with ROS-triggered antioxidative ability is proposed for AKI-targeted therapy. Nano-assemblies can rapidly accumulate in the ischemia-reperfusion-injured kidney via kidney injury molecule-1 (Kim-1)-mediated homing ability of l-serine. By consuming pathological levels of ROS, two different antioxidants, ethyl caffeate and 4-hydroxybenzyl alcohol, are spontaneously released from a single module to relieve oxidative stress and diminish acute inflammation in injured renal tissue. The multistep ROS scavenging strategy combined with a precise targeting capability endows the aforementioned nano-assembly with effectiveness in preserving the integrity and functions of the injured kidney, providing new inspiration for the treatment of inflammatory diseases, including AKI.

Characterization of the SARS-CoV-2 BA.5.5 and BQ.1.1 Omicron variants in mice and hamsters.

The continued evolution and emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have resulted in challenges to vaccine and antibody efficacy. The emergence of each new variant necessitates the need to re-evaluate and refine animal models used for countermeasure testing. Here, we tested a recently circulating SARS-CoV-2 Omicron lineage variant, BQ.1.1, in multiple rodent models including K18-human ACE2 (hACE2) transgenic, C57BL/6J, and 129S2 mice, and Syrian golden hamsters. In contrast to a previously dominant BA.5.5 Omicron variant, inoculation of K18-hACE2 mice with BQ.1.1 resulted in substantial weight loss, a characteristic seen in pre-Omicron variants. BQ.1.1 also replicated to higher levels in the lungs of K18-hACE2 mice and caused greater lung pathology than the BA.5.5 variant. However, in C57BL/6J mice, 129S2 mice, and Syrian hamsters, BQ.1.1 did not cause increased respiratory tract infection or disease compared to animals administered BA.5.5. Moreover, the rates of direct contact or airborne transmission in hamsters were not significantly different after BQ.1.1 and BA.5.5 infections. Taken together, these data suggest that the BQ.1.1 Omicron variant has increased virulence in rodent species that express hACE2, possibly due to the acquisition of unique spike mutations relative to earlier Omicron variants. IMPORTANCE As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve, there is a need to rapidly assess the efficacy of vaccines and antiviral therapeutics against newly emergent variants. To do so, the commonly used animal models must also be re-evaluated. Here, we determined the pathogenicity of the BQ.1.1 SARS-CoV-2 variant in multiple SARS-CoV-2 animal models including transgenic mice expressing human ACE2 (hACE2), two strains of conventional laboratory mice, and Syrian hamsters. While BQ.1.1 and BA.5.5 infection resulted in similar levels of viral burden and clinical disease in hamsters and the conventional strains of laboratory mice tested, increases in lung infection were detected in hACE2-expressing transgenic mice, which corresponded with greater levels of pro-inflammatory cytokines and lung pathology. Taken together, our data highlight important differences in two closely related Omicron SARS-CoV-2 variant strains and provide a foundation for evaluating countermeasures.

Different associations between amyloid-βeta 42, amyloid-βeta 40, and amyloid-βeta 42/40 with soluble phosphorylated-tau and disease burden in Alzheimer’s disease: a cerebrospinal fluid and fluorodeoxyglucose-positron emission tomography study

BackgroundDespite the high sensitivity of cerebrospinal fluid (CSF) amyloid beta (Aβ)42 to detect amyloid pathology, the Aβ42/Aβ40 ratio (amyR) better estimates amyloid load, with higher specificity for Alzheimer’s disease (AD). However, whether Aβ42 and amyR have different meanings and whether Aβ40 represents more than an Aβ42-corrective factor remain to be clarified. Our study aimed to compare the ability of Aβ42 and amyR to detect AD pathology in terms of p-tau/Aβ42 ratio and brain glucose metabolic patterns using fluorodeoxyglucose-positron emission tomography (FDG-PET).MethodsCSF biomarkers were analyzed with EUROIMMUN ELISA. We included 163 patients showing pathological CSF Aβ42 and normal p-tau (A + T − = 98) or pathological p-tau levels (A + T + = 65) and 36 control subjects (A − T −). A + T − patients were further stratified into those with normal (CSFAβ42 + /amyR − = 46) and pathological amyR (CSFAβ42 + /amyR + = 52). We used two distinct cut-offs to determine pathological values of p-tau/Aβ42: (1) ≥ 0.086 and (2) ≥ 0.122. FDG-PET patterns were evaluated in a subsample of patients (n = 46) and compared to 24 controls.ResultsCSF Aβ40 levels were the lowest in A − T − and in CSFAβ42 + /amyR − , higher in CSFAβ42 + /amyR + and highest in A + T + (F = 50.75; p < 0.001), resembling CSF levels of p-tau (F = 192; p < 0.001). We found a positive association between Aβ40 and p-tau in A − T − (β = 0.58; p < 0.001), CSFAβ42 + /amyR − (β = 0.47; p < 0.001), and CSFAβ42 + /amyR + patients (β = 0.48; p < 0.001) but not in A + T + . Investigating biomarker changes as a function of amyR, we observed a weak variation in CSF p-tau (+ 2 z-scores) and Aβ40 (+ 0.8 z-scores) in the normal amyR range, becoming steeper over the pathological threshold of amyR (p-tau: + 5 z-scores, Aβ40: + 4.5 z-score). CSFAβ42 + /amyR + patients showed a significantly higher probability of having pathological p-tau/Aβ42 than CSFAβ42 + /amyR − (cut-off ≥ 0.086: OR 23.3; cut-off ≥ 0.122: OR 8.8), which however still showed pathological values of p-tau/Aβ42 in some cases (cut-off ≥ 0.086: 35.7%; cut-off ≥ 0.122: 17.3%) unlike A − T − . Accordingly, we found reduced FDG metabolism in the temporoparietal regions of CSFAβ42 + /amyR − compared to controls, and further reduction in frontal areas in CSFAβ42 + /amyR + , like in A + T + .ConclusionsPathological p-tau/Aβ42 and FDG hypometabolism typical of AD can be found in patients with decreased CSF Aβ42 levels alone. AmyR positivity, associated with higher Aβ40 levels, is accompanied by higher CSF p-tau and widespread FDG hypometabolism.

Engineering of cyanine-based nanoplatform with tunable response toward reactive species for ratiometric NIR-II fluorescent imaging in mice

High-quality second near-infrared (NIR-II) nanoprobes are of great significance for real-time bioimaging and medical diagnosis. Cyanine is an important class of fluorophores to construct activatable probes; however, there are still significant challenges hindering their biological applications, including weak fluorescence in aqueous solution, instability, and insufficient specificity. Herein, an integrated engineering strategy is conducted to develop the cyanine-based activatable NIR-II nanoplatforms with bright, stable emission and high specificity. Specifically, poly(styrene-co-maleic anhydride) (PSMA) is employed to encapsulate NIR-II fluorescent molecules (IR1048) to render the stable and bright NIR-II nanoparticles (PSMA@IR1048 NPs). By charge-modulated strategy, a series of cyanine-fluorophores are loaded on the surface of PSMA@IR1048 NPs and exhibit tunable response toward reactive species. Combing those two strategies, NIR-II ratiometric fluorescent nanoprobes (RNPs, including RNP1, RNP2, and RNP3) are constructed; among them, RNP2 displays hypochlorous acid (HClO) responsive performance and generates a higher NIR-II fluorescent ratio (FL2/FL1) signal. Such nanoprobe can reliably report the pathological HClO level in models of diabetic liver injury and lower limb ischemia–reperfusion (I/R) injury mice. Our study paves an engineering strategy to construct cyanine-based stable, bright, and specific NIR-II probes for bioimaging.

118 Bouveret Syndrome: A Rare Case of a Huge Gallstone causing Gastric Outlet Obstruction

Abstract Introduction Bouveret syndrome is a rare case of gallstone ileus resulting from an acquired fistula connecting the gallbladder and either the stomach or duodenum and cause intestinal obstruction. Case Summary A 85-year-old female presented with epigastric pain non-bilious vomiting and absolute constipation for five days. She patient was tachycardiac and was dehydrated. Abdomen was distended. Bowel sounds were absent. Digital rectal examination was unremarkable. Abdominal radiography did not demonstrate pathological air-fluid levels, rather revealed a dilated gastric shadow, suggestive of gastric outlet obstruction. The patient was immediately managed with nasogastric intubation and intravenous hydration. Subsequent esophagogastroduodenoscopy (EGD) was planned to rule out carcinoma owing to the age of the patient. EGD revealed a dilated stomach and a hard, golf-ball-sized gallstone in the third part of the duodenum. The scope could not be passed beyond the impacted stone, nor could it be extracted endoscopically. CT tomography revealed a distended stomach with a large gallstone obstructing duodenum and pneumobilia . One-stage surgical procedure was planned. Intraoperative findings included a thick-walled gallbladder with surrounding inflammation and a fistulous tract connecting the gallbladder with the duodenum. A gallstone measuring 3.7cm in diameter was retrieved from the third part of duodenum via enterotomy. The fistulous tract was closed, and cholecystectomy was performed and drain was placed. Patient was discharged on 4th postop day. Conclusion Bouveret syndrome is an infrequent presentation causing gastric outlet obstruction and is often overlooked owing to its rarity. High index of suspicion is necessary when patients present with bowel obstruction and a history of gallstones to prevent morbidity and mortality from Bouveret syndrome.

WTP4.10 Utility of CT Imaging in a Successful Ambulatory Emergency Surgical Unit

Abstract Aim Drives towards ambulatory management in emergency surgery have resulted in increased availability of urgent imaging to expedite decision making. This review of CT usage aimed to assess frequency of surgical pathology identified, and subsequent management. Methods All acute general surgery referrals to an established ambulatory clinic between 01/01/2021 and 22/07/2022 were included. Information regarding presentation, imaging, and diagnosis were collected in prospectively maintained databases, and subsequently analysed. Results 3154 patients were seen over an 18-month period with a 91.7% successful ambulation rate (n=2938). CT was performed in 577 patients (18.2%); the majority were contrast CT abdomen/pelvis (CTAP, 58.3%, n=331), or CT Kidney/Ureter/Bladder (CTKUB, 40.1%, n=228). The majority of CTAPs were diagnostic (77.0%, 242/331), with 16.0% (n=53) resulting in admission; admission rate for non-diagnostic CTAPs was 4.5% (n=4/89). Subsequent operations occurred in 9.6% (32/331) who underwent CTAP; 5.1% (17/331) underwent emergency operation, urgent ambulatory operations in 3.0% (10/331), and 1.5% (5/331) were listed electively. CTKUBs identified urological pathology in 40.4% (n=92), whilst 7.4% (n=17) identified other pathology. Diagnostic CTKUB led to a 17.5% admission rate (n=17, including 5 non-urological). Conclusion Selective ambulatory CT scanning is a useful adjunct to diagnosis, and admission avoidance. CTKUBs identify lower, but acceptable levels of pathology including non-urological conditions. Judicious use of CT is important to balance resource utilisation, whilst limiting admissions.

The Association of Selected GWAS Reported AD Risk Loci with CSF Biomarker Levels and Cognitive Decline in Slovenian Patients.

Alzheimer's disease (AD) is the most common neurodegenerative disease, with a complex genetic background. Apart from rare, familial cases, a combination of multiple risk loci contributes to the susceptibility of the disease. Genome-wide association studies (GWAS) have identified numerous AD risk loci. Changes in cerebrospinal fluid (CSF) biomarkers and imaging techniques can detect AD-related brain changes before the onset of clinical symptoms, even in the presence of preclinical mild cognitive impairment. In this study, we aimed to assess the associations between SNPs in well-established GWAS AD risk loci and CSF biomarker levels or cognitive test results in Slovenian patients with cognitive decline. The study included 82 AD patients, 28 MCI patients with pathological CSF biomarker levels and 35 MCI patients with normal CSF biomarker levels. Carriers of at least one polymorphic TOMM40 rs157581 C allele had lower Aβ42 (p = 0.033) and higher total tau (p = 0.032) and p-tau181 levels (p = 0.034). Carriers of at least one polymorphic T allele in SORCS1 rs1358030 had lower total tau (p = 0.019), while polymorphic SORCS1 rs1416406 allele was associated with lower total tau (p = 0.013) and p-tau181 (p = 0.036). In addition, carriers of at least one polymorphic T allele in BCHE rs1803274 had lower cognitive test scores (p = 0.029). The study findings may contribute to the identification of genetic markers associated with AD and MCI and provide insights into early disease diagnostics.

Morpho-cultural, pathological and molecular variability in Phloeospora maculans causing leaf spot of mulberry (Morus species) in India.

Leaf spot disease (LSD) of mulberry caused by Phloeospora maculans is a major threat to the silk industry of Jammu and Kashmir, India, therefore, it was necessary to study the population structure of the pathogen for successful management of the disease. To understand the diversity in the Phloeospora maculans, a combination of conventional (morphological, cultural and pathological) and molecular (ISSR markers) approaches were employed to discern the variability in 27 isolates collected from Srinagar, Bandipora, and Baramulla districts of Jammu and Kashmir, India. The studies revealed a high level of variability in the pathogen. Based on the morpho-cultural and pathological studies, the pathogen isolates were grouped into different categories based on colony growth, texture, margin and colour besides changes in colour of medium, incubation period, leaf area infected, etc.A high level of polymorphism was observed in different isolates of P. maculans using ISSR markers, which indicated that these markers are suitable for studying the genetic diversity in this pathogen. All the isolates (27) of P. maculans were clustered into two groups or populations as indicated by mean delta K value. Analysis of molecular variance revealed the low genetic variation among the populations (1.08%) and a high level of genetic variation within the populations (98.91%). Fst value was found to be 0.01 indicating smaller amount of genetic differentiation between the populations against calculated P-value of 0.29. A high level of diversity based on morphological, cultural, pathological and molecular levels was observed in Phloeospora maculans collected from various districts of Kashmir valley, which indicates that the study of population structure is necessary for successful management of the disease.

Reversal of pathological motor behavior in a model of Parkinson's disease by striatal dopamine uncaging.

Motor deficits observed in Parkinson's disease (PD) are caused by the loss of dopaminergic neurons and the subsequent dopamine depletion in different brain areas. The most common therapy to treat motor symptoms for patients with this disorder is the systemic intake of L-DOPA that increases dopamine levels in all the brain, making it difficult to discern the main locus of dopaminergic action in the alleviation of motor control. Caged compounds are molecules with the ability to release neuromodulators locally in temporary controlled conditions using light. In the present study, we measured the turning behavior of unilateral dopamine-depleted mice before and after dopamine uncaging. The optical delivery of dopamine in the striatum of lesioned mice produced contralateral turning behavior that resembled, to a lesser extent, the contralateral turning behavior evoked by a systemic injection of apomorphine. Contralateral turning behavior induced by dopamine uncaging was temporarily tied to the transient elevation of dopamine concentration and was reversed when dopamine decreased to pathological levels. Remarkably, contralateral turning behavior was tuned by changing the power and frequency of light stimulation, opening the possibility to modulate dopamine fluctuations using different light stimulation protocols. Moreover, striatal dopamine uncaging recapitulated the motor effects of a low concentration of systemic L-DOPA, but with better temporal control of dopamine levels. Finally, dopamine uncaging reduced the pathological synchronization of striatal neuronal ensembles that characterize unilateral dopamine-depleted mice. We conclude that optical delivery of dopamine in the striatum resembles the motor effects induced by systemic injection of dopaminergic agonists in unilateral dopamine-depleted mice. Future experiments using this approach could help to elucidate the role of dopamine in different brain nuclei in normal and pathological conditions.

Galectin-3 Mediates Vascular Dysfunction in Obesity by Regulating NADPH Oxidase 1.

Obesity is associated with increased risk of cardiovascular disease, but underlying mechanisms remain elusive. Metabolic dysfunction, especially hyperglycemia, is thought to be a major contributor, but how glucose impacts vascular function is unclear. GAL3 (galectin-3) is a sugar-binding lectin upregulated by hyperglycemia, but its role as a causative mechanism of cardiovascular disease remains poorly understood. Therefore, the objective of this study was to determine the role of GAL3 in regulating microvascular endothelial vasodilation in obesity. GAL3 was measured and found to be markedly increased in the plasma of overweight and obese patients, as well as in the microvascular endothelium of diabetic patients. To investigate causative mechanisms in cardiovascular disease, mice deficient in GAL3 were bred with obese db/db mice to generate lean, lean GAL3 knockout, obese, and obese GAL3 knockout genotypes. Endothelial cell-specific GAL3 knockout mice with novel AAV-induced obesity recapitulated whole-body knockout studies to confirm cell specificity. Deletion of GAL3 did not alter body mass, adiposity, or plasma indices of glycemia and lipidemia, but levels of plasma reactive oxygen species as assessed by plasma thiobarbituric acid reactive substances were normalized in obese GAL3 knockout mice. Obese mice exhibited profound endothelial dysfunction and hypertension, both of which were rescued by GAL3 deletion. Isolated microvascular endothelial cells from obese mice had increased expression of NOX1 (nicotinamide adenine dinucleotide phosphate oxidase 1), which we have previously shown to contribute to increased oxidative stress and endothelial dysfunction, which was normalized in microvascular endothelium from mice lacking GAL3. Cell-specific deletion confirmed that endothelial GAL3 regulates obesity-induced NOX1 overexpression and subsequent microvascular function. Furthermore, improvement of metabolic syndrome by increasing muscle mass, improving insulin signaling, or treating with metformin decreased microvascular GAL3, and thereby NOX1, expression levels. Deletion of GAL3 normalizes microvascular endothelial function in obese db/db mice, likely through a NOX1-mediated mechanism. Pathological levels of GAL3, and in turn NOX1, are amenable to improvements in metabolic status, presenting a potential therapeutic target to ameliorate pathological cardiovascular consequences of obesity.