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Calcium-independent phospholipase A2γ (iPLA2γ) is localized in glomerular epithelial cells (GECs)/podocytes at the mitochondria and endoplasmic reticulum, and can mediate release of arachidonic acid and prostanoids. Global knockout (KO) of iPLA2γ in mice did not cause albuminuria, but resulted in mitochondrial structural abnormalities and enhanced autophagy in podocytes. In acute glomerulonephritis, deletion of iPLA2γ exacerbated albuminuria and podocyte injury. This study addresses the role of iPLA2γ in diabetic nephropathy. Hyperglycemia was induced in male mice with streptozotocin (STZ). STZ induced progressive albuminuria in control mice (over 21 weeks), while albuminuria did not increase in iPLA2γ KO mice, remaining comparable to untreated groups. Despite similar exposure to STZ, the STZ-treated iPLA2γ KO mice developed a lower level of hyperglycemia compared to STZ-treated control. However, there was no significant correlation between the degree of hyperglycemia and albuminuria, and even iPLA2γ KO mice with greatest hyperglycemia did not develop significant albuminuria. Mortality at 21 weeks was greatest in diabetic control mice. Sclerotic glomeruli and enlarged glomerular capillary loops were increased significantly in diabetic control compared to diabetic iPLA2γ KO mice. Glomerular matrix was expanded in diabetic mice, with control exceeding iPLA2γ KO. Glomerular autophagy (increased LC3-II and decreased p62) was enhanced in diabetic iPLA2γ KO mice compared to control. Treatment of cultured GECs with H2O2 resulted in increased cell death in control GECs compared to iPLA2γ KO, and the increase was slightly greater in medium with high glucose compared to low glucose. H2O2-induced cell death was not affected by inhibition of prostanoid production with indomethacin. In conclusion, mice with global deletion of iPLA2γ are protected from developing chronic glomerular injury in diabetic nephropathy. This is associated with increased glomerular autophagy.

Mechanisms underlying the attenuation of body weight gain and insulin resistance in response to high fat diet (HFD) by the curry compound curcumin need to be further explored. Although the attenuation of the inflammatory pathway is an accepted mechanism, a recent study suggested that curcumin stimulates Wnt signaling pathway and hence suppresses adipogenic differentiation. This is in contrast with the known repressive effect of curcumin on Wnt signaling in other cell lineages.We conducted the examination on low fat diet, or HFD fed C57BL/6J mice with or without curcumin intervention for 28 weeks. Curcumin significantly attenuated the effect of HFD on glucose disposal, body weight/fat gain, as well as the development of insulin resistance. No stimulatory effect on Wnt activation was observed in the mature fat tissue. In addition, curcumin did not stimulate Wnt signaling in vitro in primary rat adipocytes. Furthermore, curcumin inhibited lipogenic gene expression in the liver and blocked the effects of HFD on macrophage infiltration and the inflammatory pathway in the adipose tissue.We conclude that the beneficial effect of curcumin during HFD consumption is mediated by attenuating lipogenic gene expression in the liver and the inflammatory response in the adipose tissue, in the absence of stimulation of Wnt signaling in mature adipocytes.

Calcium-independent phospholipase A2γ (iPLA2γ) is localized in glomerular epithelial cells (GECs)/podocytes at the mitochondria and endoplasmic reticulum, and can mediate release of arachidonic acid and prostanoids. Global knockout (KO) of iPLA2γ in mice did not cause albuminuria, but resulted in mitochondrial structural abnormalities and enhanced autophagy in podocytes. In acute glomerulonephritis, deletion of iPLA2γ exacerbated albuminuria and podocyte injury. This study addresses the role of iPLA2γ in diabetic nephropathy. Hyperglycemia was induced in male mice with streptozotocin (STZ). STZ induced progressive albuminuria in control mice (over 21 weeks), while albuminuria did not increase in iPLA2γ KO mice, remaining comparable to untreated groups. Despite similar exposure to STZ, the STZ-treated iPLA2γ KO mice developed a lower level of hyperglycemia compared to STZ-treated control. However, there was no significant correlation between the degree of hyperglycemia and albuminuria, and even iPLA2γ KO mice with greatest hyperglycemia did not develop significant albuminuria. Mortality at 21 weeks was greatest in diabetic control mice. Sclerotic glomeruli and enlarged glomerular capillary loops were increased significantly in diabetic control compared to diabetic iPLA2γ KO mice. Glomerular matrix was expanded in diabetic mice, with control exceeding iPLA2γ KO. Glomerular autophagy (increased LC3-II and decreased p62) was enhanced in diabetic iPLA2γ KO mice compared to control. Treatment of cultured GECs with H2O2 resulted in increased cell death in control GECs compared to iPLA2γ KO, and the increase was slightly greater in medium with high glucose compared to low glucose. H2O2-induced cell death was not affected by inhibition of prostanoid production with indomethacin. In conclusion, mice with global deletion of iPLA2γ are protected from developing chronic glomerular injury in diabetic nephropathy. This is associated with increased glomerular autophagy. [ABSTRACT FROM AUTHOR]

This work extends the understanding of how toxic exposures to amphetamine (AMPH) adversely affect the immune system and lead to tissue damage. Importantly, it determines which effects of AMPH are and are not due to pronounced hyperthermia. Whole blood messenger RNA (mRNA) and whole blood and serum microRNA (miRNA) transcripts were identified in adult male Sprague-Dawley rats after exposure to toxic AMPH under normothermic conditions, AMPH when it produces pronounced hyperthermia, or environmentally-induced hyperthermia (EIH). mRNA transcripts with large increases in fold-change in treated relative to control rats and very low expression in the control group were a rich source of organ-specific transcripts in blood. When severe hyperthermia was produced by either EIH or AMPH, significant increases in circulating organ-specific transcripts for liver (Alb, Fbg, F2), pancreas (Spink1), bronchi/lungs (F3, Cyp4b1), bone marrow (Np4, RatNP-3b), and kidney (Cesl1, Slc22a8) were observed. Liver damage was suggested also by increased miR-122 levels in the serum. Increases in muscle/heart-enriched transcripts were produced by AMPH even in the absence of hyperthermia. Expression increases in immune-related transcripts, particularly Cd14 and Vcan, indicate that AMPH can activate the innate immune system in the absence of hyperthermia. Most transcripts specific for T-cells decreased 50-70% after AMPH exposure or EIH, with the noted exception of Ccr5 and Chst12. This is probably due to T-cells leaving the circulation and down-regulation of these genes. Transcript changes specific for B-cells or B-lymphoblasts in the AMPH and EIH groups ranged widely from decreasing ≈ 40% (Cd19, Cd180) to increasing 30 to 100% (Tk1, Ahsa1) to increasing ≥500% (Stip1, Ackr3). The marked increases in Ccr2, Ccr5, Pld1, and Ackr3 produced by either AMPH or EIH observed in vivo provide further insight into the initial immune system alterations that result from methamphetamine and AMPH abuse and could modify risk for HIV and other viral infections.

In the United States (US), cardiovascular (CV) disease accounts for nearly 20% of national health care expenses. Since costs are expected to increase with the aging population, informative research is necessary to address the growing burden of CV disease and sex-related differences in diagnosis, treatment, and outcomes. Hypertension is a major risk factor for CV disease and mortality. To evaluate whether there are sex-related differences in the effect of systolic blood pressure (SBP) on the risk of CV disease and mortality, we performed a systematic review and meta-analysis. We conducted a comprehensive search using PubMed and Google Scholar to identify US-based studies published prior to 31 December, 2015. We identified eight publications for CV disease risk, which provided 9 female and 8 male effect size (ES) observations. We also identified twelve publications for CV mortality, which provided 10 female and 18 male ES estimates. Our meta-analysis estimated that the pooled ES for increased risk of CV disease per 10 mmHg increment in SBP was 25% for women (95% Confidence Interval (CI): 1.18, 1.32) and 15% for men (95% CI: 1.11, 1.19). The pooled increase in CV mortality per 10 mm Hg SBP increment was similar for both women and men (Women: 1.16; 95% CI: 1.10, 1.23; Men: 1.17; 95% CI: 1.12, 1.22). After adjusting for age and baseline SBP, the results demonstrated that the risk of CV disease per 10 mm Hg SBP increment for women was 1.1-fold higher than men (P

Methods were developed to evaluate the stability of rat whole blood expression obtained from RNA sequencing (RNA-seq) and assess changes in whole blood transcriptome profiles in experiments replicated over time. Expression was measured in globin-depleted RNA extracted from the whole blood of Sprague-Dawley rats, given either saline (control) or neurotoxic doses of amphetamine (AMPH). The experiment was repeated four times (paired control and AMPH groups) over a 2-year span. The transcriptome of the control and AMPH-treated groups was evaluated on: 1) transcript levels for ribosomal protein subunits; 2) relative expression of immune-related genes; 3) stability of the control transcriptome over 2 years; and 4) stability of the effects of AMPH on immune-related genes over 2 years. All, except one, of the 70 genes that encode the 80s ribosome had levels that ranked in the top 5% of all mean expression levels. Deviations in sequencing performance led to significant changes in the ribosomal transcripts. The overall expression profile of immune-related genes and genes specific to monocytes, T-cells or B-cells were well represented and consistent within treatment groups. There were no differences between the levels of ribosomal transcripts in time-matched control and AMPH groups but significant differences in the expression of immune-related genes between control and AMPH groups. AMPH significantly increased expression of some genes related to monocytes but down-regulated those specific to T-cells. These changes were partially due to changes in the two types of leukocytes present in blood, which indicate an activation of the innate immune system by AMPH. Thus, the stability of RNA-seq whole blood transcriptome can be verified by assessing ribosomal protein subunits and immune-related gene expression. Such stability enables the pooling of samples from replicate experiments to carry out differential expression analysis with acceptable power.

The discrete data structure and large sequencing depth of RNA sequencing (RNA-seq) experiments can often generate outlier read counts in one or more RNA samples within a homogeneous group. Thus, how to identify and manage outlier observations in RNA-seq data is an emerging topic of interest. One of the main objectives in these research efforts is to develop statistical methodology that effectively balances the impact of outlier observations and achieves maximal power for statistical testing. To reach that goal, strengthening the accuracy of outlier detection is an important precursor. Current outlier detection algorithms for RNA-seq data are executed within a testing framework and may be sensitive to sparse data and heavy-tailed distributions. Therefore, we propose a univariate algorithm that utilizes a probabilistic approach to measure the deviation between an observation and the distribution generating the remaining data and implement it within in an iterative leave-one-out design strategy. Analyses of real and simulated RNA-seq data show that the proposed methodology has higher outlier detection rates for both non-normalized and normalized negative binomial distributed data.

Calcium-independent phospholipase A2γ (iPLA2γ) is localized in glomerular epithelial cells (GECs)/podocytes at the mitochondria and endoplasmic reticulum, and can mediate release of arachidonic acid and prostanoids. Global knockout (KO) of iPLA2γ in mice did not cause albuminuria, but resulted in mitochondrial structural abnormalities and enhanced autophagy in podocytes. In acute glomerulonephritis, deletion of iPLA2γ exacerbated albuminuria and podocyte injury. This study addresses the role of iPLA2γ in diabetic nephropathy. Hyperglycemia was induced in male mice with streptozotocin (STZ). STZ induced progressive albuminuria in control mice (over 21 weeks), while albuminuria did not increase in iPLA2γ KO mice, remaining comparable to untreated groups. Despite similar exposure to STZ, the STZ-treated iPLA2γ KO mice developed a lower level of hyperglycemia compared to STZ-treated control. However, there was no significant correlation between the degree of hyperglycemia and albuminuria, and even iPLA2γ KO mice with greatest hyperglycemia did not develop significant albuminuria. Mortality at 21 weeks was greatest in diabetic control mice. Sclerotic glomeruli and enlarged glomerular capillary loops were increased significantly in diabetic control compared to diabetic iPLA2γ KO mice. Glomerular matrix was expanded in diabetic mice, with control exceeding iPLA2γ KO. Glomerular autophagy (increased LC3-II and decreased p62) was enhanced in diabetic iPLA2γ KO mice compared to control. Treatment of cultured GECs with H2O2 resulted in increased cell death in control GECs compared to iPLA2γ KO, and the increase was slightly greater in medium with high glucose compared to low glucose. H2O2-induced cell death was not affected by inhibition of prostanoid production with indomethacin. In conclusion, mice with global deletion of iPLA2γ are protected from developing chronic glomerular injury in diabetic nephropathy. This is associated with increased glomerular autophagy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Cybulsky et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A patient with a neuroendocrine tumor and history of coronary artery disease underwent PET with 68Ga-DOTATATE PET tracer for tumor visualization. Analysis of the scan showed uptake of 68Ga-DOTATATE in the left ventricle corresponding to previous myocardial infarct. 68Ga-DOTATATE binds by somatostatin receptors (SSTR) and it has been proposed that it may be useful for the detection of cardiac inflammatory lesions. We aimed to test whether SSTR could be upregulated in cardiac fibrotic scar. We analyzed SSTR in cardiac samples from patients with end-stage ischemic cardiomyopathy (ICM, n = 8) and control hearts (n = 5). In mature ICM tissue, SSTR1 and SSTR2 expression was unchanged and SSTR5 expression was significantly decreased in ICM samples vs. control. Immunohistochemistry showed increased SSTR1 and SSTR2 in ICM. Areas with SSTR1 or SSTR2 staining were often adjacent to fibrotic areas. The majority of SSTR1 and SSTR2 staining localized in cardiomyocytes in fibrotic scar-rich areas where CD68 macrophage staining was not present. SSTR are occasionally upregulated in cardiac fibrotic areas. When using 68Ga-DOTATATE PET tracer to detect cardiac sarcoidosis or atherosclerotic plaque, the possibility of tracer uptake in fibrotic areas should be considered., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Castillero et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The aim of the present study was to investigate the effects of video presentations of natural landscapes on European starlings' (Sturnus vulgaris) stereotypic behaviours (SBs) and other abnormal repetitive behaviours (ARBs) and to evaluate the impact of past experience by comparing wild-caught and hand-reared starlings' reactions. Ten wild-caught and five hand-reared starlings were presented 1-hour videos of landscapes twice a day for five successive days, while a control group of eight wild-caught and four hand-reared starlings was presented a grey screen for the same amount of time. The analysis of the starlings' behaviour revealed that the video presentations of landscapes appeared to have a positive but limited and experience-dependent effect on starlings' SBs and other ARBs compared to the controls. Indeed, whereas video presentations seemed to modulate high rates of SBs and ARBs, they did not appear to be enriching enough to prevent the emergence or the development of SBs and ARBs in an impoverished environment. They even appeared to promote a particular type of SB (somersaulting) that is thought to be linked to escape motivation. The fact that this effect was observed in hand-reared starlings suggests that videos of landscapes could elicit motivation to escape even in birds that never experienced outdoor life. These results highlight the importance of investigating stereotypic behaviour both quantitatively and qualitatively in order to provide crucial clues on animal welfare.

There is a lack in our current understanding on the putative interactions of species of the phyla of Acidobacteria and Verrucomicrobia with plants. Moreover, progress in this area is seriously hampered by the recalcitrance of members of these phyla to grow as pure cultures. The purpose of this study was to investigate whether particular members of Acidobacteria and Verrucomicrobia are avid colonizers of the rhizosphere. Based on previous work, rhizosphere competence was demonstrated for the Verrucomicrobia subdivision 1 groups of Luteolibacter and Candidatus genus Rhizospheria and it was hypothesized that the rhizosphere is a common habitat for Acidobacteria subdivision 8 (class Holophagae). We assessed the population densities of Bacteria, Verrucomicrobia subdivision 1 groups Luteolibacter and Candidatus genus Rhizospheria and Acidobacteria subdivisions 1, 3, 4, 6 and Holophagae in bulk soil and in the rhizospheres of grass, potato and leek in the same field at different points in time using real-time quantitative PCR. Primers of all seven verrucomicrobial, acidobacterial and holophagal PCR systems were based on 16S rRNA gene sequences of cultivable representatives of the different groups. Luteolibacter, Candidatus genus Rhizospheria, subdivision 6 acidobacteria and Holophaga showed preferences for one or more rhizospheres. In particular, the Holophaga 16S rRNA gene number were more abundant in the leek rhizosphere than in bulk soil and the rhizospheres of grass and potato. Attraction to, and colonization of, leek roots by Holophagae strain CHC25 was further shown in an experimental microcosm set-up. In the light of this remarkable capacity, we propose to coin strain CHC25 Candidatus Porrumbacterium oxyphilus (class Holophagae, Phylum Acidobacteria), the first cultured representative with rhizosphere competence.

Social animals learn to perceive their social environment, and their social skills and preferences are thought to emerge from greater exposure to and hence familiarity with some social signals rather than others. Familiarity appears to be tightly linked to multisensory integration. The ability to differentiate and categorize familiar and unfamiliar individuals and to build a multisensory representation of known individuals emerges from successive social interactions, in particular with adult, experienced models. In different species, adults have been shown to shape the social behavior of young by promoting selective attention to multisensory cues. The question of what representation of known conspecifics adult-deprived animals may build therefore arises. Here we show that starlings raised with no experience with adults fail to develop a multisensory representation of familiar and unfamiliar starlings. Electrophysiological recordings of neuronal activity throughout the primary auditory area of these birds, while they were exposed to audio-only or audiovisual familiar and unfamiliar cues, showed that visual stimuli did, as in wild-caught starlings, modulate auditory responses but that, unlike what was observed in wild-caught birds, this modulation was not influenced by familiarity. Thus, adult-deprived starlings seem to fail to discriminate between familiar and unfamiliar individuals. This suggests that adults may shape multisensory representation of known individuals in the brain, possibly by focusing the young's attention on relevant, multisensory cues. Multisensory stimulation by experienced, adult models may thus be ubiquitously important for the development of social skills (and of the neural properties underlying such skills) in a variety of species.

Background: Myostatin is a negative regulator of skeletal muscle mass whose activity is upregulated in adult heart failure (HF); however, its role in congenital heart disease (CHD) is unknown., Methods: We studied myostatin and IGF-1 expression via Western blot in cardiac tissue at varying degrees of myocardial dysfunction and after biventricular support in CHD by collecting myocardial biopsies from four patient cohorts: A) adult subjects with no known cardiopulmonary disease (left ventricle, LV), (Adult Normal), (n = 5); B) pediatric subjects undergoing congenital cardiac surgery with normal RV size and function (right ventricular outflow tract, RVOT), (n = 3); C) pediatric subjects with worsening but hemodynamically stable LV failure [LV and right ventricle (LV, RV,)] with biopsy collected at the time of orthotopic heart transplant (OHT), (n = 7); and D) pediatric subjects with decompensated bi-ventricular failure on BiVAD support with biopsy collected at OHT (LV, RV, BiVAD), (n = 3)., Results: The duration of HF was longest in OHT patients compared to BIVAD. The duration of BiVAD support was 4.3±1.9 days. Myostatin expression was significantly increased in LV-OHT compared to RV-OHT and RVOT, and was increased more than double in decompensated biventricular HF (BiVAD) compared to both OHT and RVOT. An increased myostatin/IGF-1 ratio was associated with ventricular dysfunction., Conclusions: Myostatin expression in increased in CHD, and the myostatin/IGF-1 ratio increases as ventricular function deteriorates. Future investigation is necessary to determine if restoration of the physiologic myostatin/IGF-1 ratio has therapeutic potential in HF.

Songbirds are one of the few vertebrate groups (including humans) that evolved the ability to learn vocalizations. During song learning, social interactions with adult models are crucial and young songbirds raised without direct contacts with adults typically produce abnormal songs showing phonological and syntactical deficits. This raises the question of what functional representation of their vocalizations such deprived animals develop. Here we show that young starlings that we raised without any direct contact with adults not only failed to differentiate starlings' typical song classes in their vocalizations but also failed to develop differential neural responses to these songs. These deficits appear to be linked to a failure to acquire songs' functions and may provide a model for abnormal development of communicative skills, including speech.

Direct social contact and social interaction affect speech development in human infants and are required in order to maintain perceptual abilities; however the processes involved are still poorly known. In the present study, we tested the hypothesis that social segregation during development would prevent the proper development of a central auditory area, using a "classical" animal model of vocal development, a songbird. Based on our knowledge of European starling, we raised young female starlings with peers and only adult male tutors. This ensured that female would show neither social bond with nor vocal copying from males. Electrophysiological recordings performed when these females were adult revealed perceptual abnormalities: they presented a larger auditory area, a lower proportion of specialized neurons and a larger proportion of generalist sites than wild-caught females, whereas these characteristics were similar to those observed in socially deprived (physically separated) females. These results confirmed and added to earlier results for males, suggesting that the degree of perceptual deficiency reflects the degree of social separation. To our knowledge, this report constitutes the first evidence that social segregation can, as much as physical separation, alter the development of a central auditory area.

Categorization is essential to all cognitive processes, but identifying the neural substrates underlying categorization processes is a real challenge. Among animals that have been shown to be able of categorization, songbirds are particularly interesting because they provide researchers with clear examples of categories of acoustic signals allowing different levels of recognition, and they possess a system of specialized brain structures found only in birds that learn to sing: the song system. Moreover, an avian brain nucleus that is analogous to the mammalian secondary auditory cortex (the caudo-medial nidopallium, or NCM) has recently emerged as a plausible site for sensory representation of birdsong, and appears as a well positioned brain region for categorization of songs. Hence, we tested responses in this non-primary, associative area to clear and distinct classes of songs with different functions and social values, and for a possible correspondence between these responses and the functional aspects of songs, in a highly social songbird species: the European starling. Our results clearly show differential neuronal responses to the ethologically defined classes of songs, both in the number of neurons responding, and in the response magnitude of these neurons. Most importantly, these differential responses corresponded to the functional classes of songs, with increasing activation from non-specific to species-specific and from species-specific to individual-specific sounds. These data therefore suggest a potential neural substrate for sorting natural communication signals into categories, and for individual vocal recognition of same-species members. Given the many parallels that exist between birdsong and speech, these results may contribute to a better understanding of the neural bases of speech.