Chronic lymphocytic leukemia (CLL) cells change their metabolic program between normoxia and hypoxia, possibly affecting cytotoxic drug potency by altering mitochondria-related cell stress responses (MRCSR) including mitophagy, mitochondrial biogenesis, and mitochondrial proteostasis. We evaluated in CLL cells from nine patients, the single and multiple-combined drug potency of arsenic trioxide (ATO), valproic acid (VPA), vincristine (VCR) and MG132 as four pharmacological sensors influencing mitochondrial apoptosis, mitochondrial biogenesis, mitophagy, and mitochondrial proteostasis respectively, under normoxia and hypoxia to force hypoxia-induced metabolic reprogramming (HMR). Untreated cells from all patients remained viable under O2 levels below 0.5% for 72 h. We obtained 21 measures of drug potency and interaction at 50% effect level that we denoted drug potency signature (DPS). Using the comparative DPS between normoxia and hypoxia, two non-supervised classification algorithms discriminated CLL patients with active disease (ADT) and stable disease (NAD) and showed complete consistency with their clinical characteristics. In ADT group under hypoxia, the potency of MG132 was increased, the interaction of ATO + VPA and ATO + VPA + VCR shifted towards antagonism, and ATO + VPA + VCR + MG132 shifted towards synergism, indicating a prominent role of mitochondrial proteostasis. Classification of patients based on DPS, depended on the contrasting response of drugs under hypoxia and normoxia, owing to HMR. Using these drugs as pharmacological sensors, we linked the metabolic arrangement of CLL cells under hypoxia, to potency of drugs targeting MRCSR, and to the clinical features of individual patients, therefore providing new sources of data on disease progression, drug response and risk prognosis.

Older patients with cognitive impairment exhibit worse masticatory performance (MP), which may be attributed to poorer abilities of control, learning, and adaptation of oral sensorimotor functions. This study tested the hypothesis that the association between the structural signature of the right premotor cortex (which relates to sensorimotor integration) and masticatory performance would differ between cognitively impaired (CI) and healthy older people. Thirty-one CI and 31 non-CI older participants (aged 60-84 years; male: female = 28: 34) were recruited and between-group matched for the average age and sex ratio. All the participants received T1-weighted magnetic resonance imaging (MRI) and assessments of MP and the number of missing teeth (NMT). Voxel-based morphometry (VBM) was performed to quantify the gray matter volume (GMV). VBM analyses revealed that in the non-CI but not the CI group, MP was positively correlated with regional GMV at the right premotor cortex (PMC) (p = 0.036, corrected for familywise error under small volume correction), controlling for the participants' sex, age, NMT, and total intracranial volume. Multiple linear regression models revealed that in the non-CI group, the right PMC (beta = 0.3, p = 0.049) was a significant predictor of individual MP. In the CI group, only NMT (beta = -0.7, p = 0.001) was a significant predictor of MP. In non-CI older people, both the NMT and the regional GMV of the right PMC contributed to individual MP. In contrast, in CI patients, tooth loss was the dominant factor in MP. An altered association of the brain-stomatognathic system could be linked to cognitive impairment.

The neuronal damage and accompanied functional deficits induced by cerebral ischemia are among the most common causes of disabilities in adults. Activation of subtypes of peroxisome proliferator-activated receptors (PPARs); PPAR-α and PPAR-γ have shown neuroprotective effects in different neurodegenerative diseases including stroke. Thus, this study aimed to compare the effects of two different agonists: PPAR-α (fenofibrate) and PPAR-γ (pioglitazone) as well as the effect of their combination in ameliorating post-ischemia behavioral deficits.

No abstract available

Gap junction (GJ) channels formed by Cx45 exist in nodal cells in the heart where the action potential propagation is the slowest. The cellular mechanisms of slow propagation speed (or longer junctional delay) in nodal cells could be a combination of several factors, including lack of voltage-gated sodium channels, smaller cell size, and a lower GJ coupling conductance of Cx45. Compared to other cardiac GJs, Cx45 GJs possess not only the lowest unitary channel conductance, but also the highest extent and the fastest kinetics of the transjunctional voltage-dependent gating (Vj-gating) together with a slow recovery. These unique gating properties could make Cx45 GJs more vulnerable for dynamic uncoupling to a much lower coupling level, especially when junctional delay is lengthened and/or the heart rate is elevated. The molecular mechanisms determining the Vj-gating properties of Cx45 (a connexin belongs to γ group) GJs have not been studied. Previous functional studies on the amino terminal (NT) domain chimeras or point variants of other connexins belong to α or β group showed that their NT domains played an important role in determining their Vj-gating properties. The crystal and cryo-electron microscope structures of homologous connexin GJs showed that the NT domain lines the GJ pore, a position that could serve a role in Vj-sensing and gating. We hypothesize that the residues in the NT domain of Cx45 are important for its Vj-gating properties. Protein sequence alignment of human Cx45 NT domain with the connexins in the α and β groups revealed that the second and the eighth residues in Cx45 are different from most of these connexins. We generated a total of 14 variants on these two residues and studied their ability to form functional GJs and their Vj-gating properties in model cells. Our results revealed an important role of these two residues on fast Vj-gating kinetics and formation of morphological and functional GJ channels. In contrast, no Vj-gating change was observed on a GFP tagged Cx45 at its carboxyl terminus.

The antidepressant effect of repetitive transcranial magnetic stimulation (rTMS) has been extensively studied; growing evidence suggests that changes in lipid composition may be involved in the pathogenesis of depression and may be a targeted mechanism for treatment. However, the influence of rTMS on lipid composition and the differences between these effects compared to antidepressants like fluoxetine (Flx) have never been investigated. Using a chronic unpredictable stress (CUS) model in rats, we assessed the antidepressive effects of rTMS and Flx treatments and evaluated changes in lipid composition in the hippocampus and prefrontal cortex (PFC) using a mass spectrometry-based lipidomic approach. Both rTMS and Flx treatments ameliorated depressive-like behaviors induced by CUS. Moreover, changes in lipid composition, especially glycerophospholipids, sphingolipids, and glycerolipids induced by CUS in the hippocampus were more robust than those observed in the PFC. CUS led to decreased levels of 20 carbon-containing fatty acyls and polyunsaturated fatty acyls in the PFC, and decreased levels of acyl carnitines (AcCa) in both the hippocampus and PFC. Notably, rTMS treatment had higher impact than Flx on composition of glycerophospholipids and sphingolipids in the hippocampus that were altered by CUS, while Flx attenuated CUS-induced changes in the PFC to a greater extent than rTMS. However, neither was able to restore fatty acyls and AcCa to baseline levels. Altogether, modulation of the brain lipidome may be involved in the antidepressant action of rTMS and Flx, and the degree to which these treatments induce changes in lipid composition within the hippocampus and PFC might explain their differential antidepressant effects.

Smallanthus sonchifolius (Poepp. & Endl.) H. Robinson, commonly known as yacon, is a medicinal plant belonging to the Asteraceae family used in traditional folk medicine. Its roots and leaves have been used by people suffering from diabetes or from various digestive or renal disorders.

Qiang-Gan formula is a traditional Chinese medicine formula, which has been widely used in treating liver diseases in China.

Jiao Mei Gu (JMG), Cayratia albifolia C.L.Li, is a type of Dong plant widely growing in Dong autonomous counties, Hunan province, China. As a type of traditional herbal medicine, the root of JMG plant has been used to treat inflammatory-related diseases such as arthritis because of its prominent anti-inflammatory effects in Dong medicine.

'Non-parametric directionality' (NPD) is a novel method for estimation of directed functional connectivity (dFC) in neural data. The method has previously been verified in its ability to recover causal interactions in simulated spiking networks in Halliday et al. (2015).

Connectivity hyperalignment can be used to estimate a single shared response space across disjoint datasets. We develop a connectivity-based shared response model that factorizes aggregated fMRI datasets into a single reduced-dimension shared connectivity space and subject-specific topographic transformations. These transformations resolve idiosyncratic functional topographies and can be used to project response time series into shared space. We evaluate this algorithm on a large collection of heterogeneous, naturalistic fMRI datasets acquired while subjects listened to spoken stories. Projecting subject data into shared space dramatically improves between-subject story time-segment classification and increases the dimensionality of shared information across subjects. This improvement generalizes to subjects and stories excluded when estimating the shared space. We demonstrate that estimating a simple semantic encoding model in shared space improves between-subject forward encoding and inverted encoding model performance. The shared space estimated across all datasets is distinct from the shared space derived from any particular constituent dataset; the algorithm leverages shared connectivity to yield a consensus shared space conjoining diverse story stimuli.

Influenza vaccines administered intramuscularly exhibit poor mucosal immune responses in the respiratory tract which is the prime site of the infection. Intranasal vaccination is a potential route for vaccine delivery which has been demonstrated effective in inducing protective immune responses in both systemic and mucosal compartments. For this purpose, nanoparticles have been used as antigen delivery systems to improve antigen capture by immune cells. In this paper we demonstrate efficient delivery of viral antigens to airway epithelial cells, macrophages and dendritic cells, using polysaccharide nanoparticles (NPL), leading to a strong protection against influenza virus infection. A formulation combining split Udorn virus antigens with NPL and the mucosal protein adjuvant CTA1-DD was administered intranasally and resulted in an enhanced specific humoral immune response. Furthermore, NPL carrying split Udorn, with or without CTA1-DD, inhibited virus transmission from infected to uninfected naive mice. These results demonstrate that an intranasal delivery system combining NPL, mucosal adjuvant CTA1-DD and split virus antigens confers robust protection against influenza infection and inhibits virus transmission.

Although monoclonal antibodies (mAbs) have revolutionized cancer treatment, their accumulation in solid tumors is limited and requires improvement to enhance therapeutic efficacy. Here we developed a strategy to modify mAb with a donor of nitric oxide (NO) because NO functions to vasodilate as well as to enhance the permeability of vascular endothelium, which will contribute to enhancing the tumor accumulation of mAb. We selected S-nitrosothiol as a NO donor and established the procedure to modify S-nitrosothiol group on mAb under ambient conditions. The modified mAb (Ab-SNO) thus obtained released NO in a preferable speed and maintained its original properties such as binding affinity to a target antigen and efficacy to induce antibody-dependent cellular cytotoxicity. We demonstrated that Ab-SNO enhanced the tumor accumulation of co-administered proteins such as antibody and serum albumin.

TRPA1 is a calcium permeable non-selective cation channel, its expression is up-regulated in atherosclerosis plaque, yet its function in macrophages activation is unknown. We sought to establish the role of TRPA1 in inflammatory macrophages activation.

Obesity is a key risk factor for many secondary chronic illnesses, including type 2 diabetes and cardiovascular disease. Canonical Wnt/β-catenin signaling is established as an important endogenous inhibitor of adipogenesis. This pathway is operative in mature adipocytes; however, its roles in this context remain unclear due to complexities of Wnt signaling and differences in experimental models. In this study, we used novel cultured cell and mouse models to investigate functional roles of Wnts secreted from adipocytes.

Aquatic pollution is one of the most common threats to the ecological health of aquatic ecosystems and its biota. Fish as lower vertebrates are excellent model to study the impact and responses of aquatic pollution. In fish, gill is the main organ indicator of whole animal health as it comes in contact with the surrounding water and absorbs many pollutants and contaminants; therefore, investigations on alterations in fish gill at transcriptome level could provide newer insights to the stress response mechanism(s) and pathways. For comprehensive evaluation of the impacts of pollutants (joint toxicity) prevalent in the riverine environment, comparative transcriptome analysis, by Next Generation Sequencing under Illumina HiSeq 2500 platform, was carried out in gill tissues of Rita rita collected from two stretches of river Ganga (Kanpur and Farakka) and results were validated by RT-qPCR. Out of 154,077 unigenes (Accession SRR548008), a total of 2024 differentially expressed genes (DEGs) including 942 up-regulated and 1082 down-regulated genes were identified by DESeq program. Further, Gene Ontology (GO) of DEGs showed that ribosomal large subunit biogenesis, mitochondrial ribosome and box H/ACA SnoRNA binding categories are highly affected by pollution. Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis showed the involvement of the DEGs in energy metabolism, translational and transcriptional machinery, protein folding and degradation suggesting that these signalling pathways are highly affected by aquatic pollution. Among the DEGs, up-regulation of cytochrome c oxidase subunit (cox) 7a2 (69.47 fold), hsp70 subunit 14 (hsp70-14, 5.27 fold), muscle related coiled-coil protein (MURC, 21.55 fold), lysozyme G (40.14 fold), cox17 (29.36 fold) were the conspicuous ones which showed similar trends in expression when analysed by RT-qPCR. Based on fold change, perturbation values, correlation analysis by PCA and RT-qPCR validation, up-regulation of cox7a2, MURC and hsp70-14 appeared to be the most promising biomarker responses and could be useful in the evaluation of gill health and possibly be extended towards aquatic ecosystem health assessment.

This study aims to examine the effects of cystine and theanine (CT), which increases glutathione biosynthesis, on the survival rate and acute radiation injury of the small intestine and bone marrow using a rat model. CT pre-treatment (280 mg/kg for 5 days) significantly improved weight loss and survival rate of rats as compared with the control group after 5 Gy. CT pre-treatment significantly increased the rate of mucosa and crypt length, and decreased the number of apoptotic cells, TUNEL and cleaved caspase-3 positive cells, while increasing the number of mitotic cells and Ki-67 positive cells in jejunal crypts and villi compared to control rats post-irradiation. CT also suppressed bone marrow cell loss and reduced the number of apoptotic cells in bone marrow. These results suggest a protective effect of CT pre-treatment for acute injury after irradiation through apoptosis inhibition and increased proliferative activity in jejunal crypt cells and bone marrow cells.

Many animals perceive features of higher-order visual motion that are beyond the spatiotemporal correlations of luminance defined in first-order motion. Although the neural mechanisms of first-order motion detection have become understood in recent years, those underlying higher-order motion perception remain unclear. Here, we established a paradigm to assess the detection of theta motion-a type of higher-order motion-in freely walking Drosophila. Behavioral screening using this paradigm identified two clusters of neurons in the central brain, designated as R18C12, which were required for perception of theta motion but not for first-order motion. Furthermore, theta motion-activated R18C12 neurons were structurally and functionally located downstream of visual projection neurons in lobula, lobula columnar cells LC16, which activated R18C12 neurons via interactions of acetylcholine (ACh) and muscarinic acetylcholine receptors (mAChRs). The current study provides new insights into LC neurons and the neuronal mechanisms underlying visual information processing in complex natural scenes.

Cell-mediated immunity including T-cells (T helper and cytotoxic) plays an essential role in efficient antiviral responses against coronavirus disease-2019 (COVID-19). Therefore, in this study, we evaluated the ratio and expression of CD4 and CD8 markers in COVID-19 patients to clarify the immune characterizations of CD4 and CD8 T-cells in COVID-19 patients.

The social motivation hypothesis posits that people with autism spectrum disorder (ASD) find social stimuli less rewarding and are therefore less motivated towards social interaction than people with neuro-typical development (TD). However, the less rewarding social stimuli characteristics during social interaction for people with ASD are largely unknown. The contingent positive responsiveness of others relevant to self-action motivates the early development of social interaction, thus representing a social reward. As individuals with ASD often exhibit atypical responses to self-relevant stimuli in their early life, we hypothesized that the self-relevant responses of others are less rewarding for individuals with ASD. To test this hypothesis, we conducted a functional magnetic resonance imaging study using a social contingency task. During the task, the participants attempted to make the audience laugh by telling funny jokes and thus activating the anterior rostral medial prefrontal cortex (arMPFC) of TD individuals (Sumiya et al., 2017). We explicitly predicted that the atypical activation of the arMPFC is related to the reduced reward value of self-relevant responses to others in individuals with ASD. Thirty-one adults with ASD and 24 age- and intelligence quotient-matched TD adults participated in the study. Participants with ASD reported significantly lower pleasure after the audience's responses to their own actions than those in the TD group. Correspondingly, the self-related activation of the arMPFC, defined by the results of our previous study, was attenuated in the ASD group compared to the TD group. The present findings indicate that weak self-relevant outcome processing mediated by the arMPFC of individuals with ASD dampens the rewarding nature of social interaction.