Thermosensation provides crucial information, but how temperature representation is transformed from sensation to behavior is poorly understood. Here, we report a preparation that allows control of heat delivery to zebrafish larvae while monitoring motor output and imaging whole-brain calcium signals, thereby uncovering algorithmic and computational rules that couple dynamics of heat modulation, neural activity and swimming behavior. This approach identifies a critical step in the transformation of temperature representation between the sensory trigeminal ganglia and the hindbrain: A simple sustained trigeminal stimulus representation is transformed into a representation of absolute temperature as well as temperature changes in the hindbrain that explains the observed motor output. An activity constrained dynamic circuit model captures the most prominent aspects of these sensori-motor transformations and predicts both behavior and neural activity in response to novel heat stimuli. These findings provide the first algorithmic description of heat processing from sensory input to behavioral output.

Breakthroughs in HIV treatment, especially combination antiretroviral therapy (ART), have massively reduced AIDS-associated mortality. However, ART administration amplifies the risk of non-AIDS defining illnesses including obesity, diabetes, and cardiovascular disease, collectively known as metabolic syndrome. Initial reports suggest that ART-associated risk of metabolic syndrome correlates with socioeconomic status, a multifaceted finding that encompasses income, race, education, and diet. Therefore, determination of causal relationships is extremely challenging due to the complex interplay between viral infection, ART, and the many environmental factors.

Animals make innumerable decisions every day, each of which involves evaluating potential options for action. But how are options generated? Although much is now known about decision making when a fixed set of potential options is provided, surprisingly little progress has been made on self-generated options. Some researchers have proposed that such abilities might be modulated by dopamine. Here, we used a new measure of option generation that is quantitative, objective, and culture fair to investigate how humans generate different behavioral options. Participants were asked to draw as many different paths (options) as they could between two points within a fixed time. Healthy individuals (n = 96) exhibited a trade-off between uniqueness (how individually different their options were) and fluency (number of options), generating either many similar or few unique options. To assess influence of dopamine, we first examined patients with Parkinson's disease (n = 35) ON and OFF their dopaminergic medication and compared them to elderly healthy controls (n = 34). Then we conducted a double-blind, placebo-controlled crossover study of the D2 agonist cabergoline in healthy older people (n = 29). Across both studies, dopamine increased fluency but diminished overall uniqueness of options generated, due to the effect of fluency trading off with uniqueness. Crucially, however, when this trade-off was corrected for, dopamine was found to increase uniqueness for any given fluency. Three carefully designed control studies showed that performance on our option-generation task was not related to executing movements, planning actions, or selecting between generated options. These findings show that dopamine plays an important role in modulating option generation.

Gastric emptying is a critical regulator of postprandial glucose and delayed gastric emptying is an important mechanism of improved glycemic control achieved by short-acting glucagon-like peptide-1 (GLP-1) analogs in clinical practice. Here we report on a novel regulatory mechanism of gastric emptying in humans. We show that increasing interleukin (IL)-6 concentrations delays gastric emptying leading to reduced postprandial glycemia. IL-6 furthermore reduces insulin secretion in a GLP-1-dependent manner while effects on gastric emptying are GLP-1 independent. Inhibitory effects of IL-6 on gastric emptying were confirmed following exercise-induced increases in IL-6. Importantly, gastric- and insulin-reducing effects were maintained in individuals with type 2 diabetes. These data have clinical implications with respect to the use of IL-6 inhibition in autoimmune/inflammatory disease, and identify a novel target that could be exploited pharmacologically to delay gastric emptying and spare insulin, which may be beneficial for the beta cell in type 2 diabetes.

Phencyclidine (PCP) has been used to model cognitive deficits related to schizophrenia in rats and mice. However, the model in mice is not consistent in terms of the PCP effective dose reported. Furthermore, most of the previous studies in mice excluded the presence of drug washout period in the regime. Thus, we aimed to optimize the dose of PCP in producing robust cognitive deficits by implementing it in a PCP regime which incorporates a drug washout period. The regimen used was 7 days' daily injection of PCP or saline for treatment and vehicle groups, respectively; followed by 24 h drug washout period. After the washout period, the test mice were tested in water maze (5 days of acquisition + 1 day of probe trial) for assessment of spatial learning and memory. Initially, we investigated the effect of PCP at 2mg/kg, however, no apparent impairment in spatial learning and memory was observed. Subsequently, we examined the effect of higher doses of PCP at 5, 10 and 20 mg/kg. We found that the PCP at 10 mg/kg produced a significant increase in "latency to reach the platform" during the acquisition days and a significant increase in "latency of first entry to previous platform" during the probe day. There was no significant change observed in "swim speed" during the test days. Thus, we concluded that PCP at 10 mg/kg produced robust deficits in spatial learning and memory without being confounded by motor disturbances.

In mammals, spermatozoa activate oocytes by triggering a series of intracellular Ca2+ oscillations with phospholipase C zeta (PLCζ), a sperm-borne oocyte-activating factor. Because the introduction of PLCζ alone can induce oocyte activation, it might be a promising reagent for assisted reproductive technologies. To test this possibility, we injected human PLCζ (hPLCζ) mRNA into mouse oocytes at different concentrations. We observed the oocyte activation and subsequent embryonic development. Efficient oocyte activation and embryonic development to the blastocyst stage was achieved only with a limited range of mRNA concentrations (0.1 ng/μl). Higher concentrations of mRNA caused developmental arrest of most embryos, suggesting that excessive PLCζ protein might be harmful at this stage. In a second series of experiments, we aimed to regulate the PLCζ protein concentration in oocytes by applying auxin-inducible degron (AID) technology that allows rapid degradation of the target protein tagged with AID induced by auxin. Injection of the hPLCζ protein tagged with AID and enhanced green fluorescent protein (hPLCζ-AID-EGFP) demonstrated that high EGFP expression levels at the late 1-cell stage were efficiently reduced by auxin treatment, suggesting efficient hPLCζ degradation by this system. Furthermore, the defective development observed with higher concentrations of hPLCζ-AID-EGFP mRNA was rescued following auxin treatment. Full-term offspring were obtained by round spermatid injection with optimized hPLCζ-AID activation. Our results indicate that this AID technology can be applied to regulate the protein levels in mouse oocytes and that our optimized PLCζ system could be used for assisted fertilization in mammals.

The sea surface microlayer (SML) is the uppermost layer of the water column that links the ocean and atmosphere. It accumulates a variety of biogenic surface-active and buoyant substances, including gelatinous material, such as transparent exopolymer particles (TEP) and Coomassie stainable particles (CSP), potentially affecting air-sea exchange processes. Here, we studied the influence of the annual cycle of phytoplankton production on organic matter (OM) accumulation in the SML relative to the subsurface water (SSW). Sampling was performed monthly from April 2012 to November 2013 at the Boknis Eck Time Series Station (Baltic Sea). For SML sampling, we used the Garrett screen, while SSW samples were collected by Niskin bottles at 1 m depth. Samples were analyzed for carbohydrates, amino acids, TEP, CSP, chlorophyll a (SSW only) and bacterial abundance. Our data showed that the SML reflected the SSW during most parts of the year, with changes mainly responding to bloom formation and decay. OM composition during phytoplankton blooms clearly differed from periods of higher bacterial abundance. Of all components investigated, only the enrichment of total carbohydrates in the SML was inversely related to the wind speed indicating that wind-driven mixing also affected the accumulation of OM in the SML during our study.

Commissural lip pits (CLPs) fall among the rare congenital deformities recorded. CLP usually follows dominant hereditary pattern and may be associated with other congenital defects. CLP can appear as unilateral depression or bilateral depression.

The purpose of this study was to investigate the therapeutic mechanism(s) of Clematis chinensis Osbeck/Notopterygium incisum K.C. Ting ex H.T (CN).

The present study aimed to compare a novel cyclodextrin-polymer-drug complex in solution with a dispersed supramolecular nanosize system, made of the same complex, for ability to carry dexamethasone (DEX) across excised rat intestine.

Obesity is a worldwide epidemic affecting millions of people. The current pharmacological treatment of obesity remains limited and ineffective due to drugs' undesirable side effects. Hence, there is a need for novel or improved strategies for long-term therapies that will help prevent the disease progression into other chronic diseases. Nanotechnology holds the future for the treatment of obesity because of its versatility, as shown by improved drug efficiency and safety in cancer clinical trials. Nano-based drug delivery systems could potentially do the same for obesity through targeted drug delivery. This study investigated the use of peptide-functionalized quantum dots (QDs) for the imaging of prohibitin (PHB)-expressing cells in vitro and in diet-induced obese rats, which could potentially be used as nanocarriers of antiobesity drugs.

Drugs that are effective against diseases in the central nervous system and reach the brain via blood must pass through the blood-brain barrier (BBB), a unique interface that protects against potential harmful molecules. This presents a major challenge in neuro-drug delivery. This study attempts to fabricate the cefuroxime-loaded nanoemulsion (CLN) to increase drug penetration into the brain when parenterally administered.

Staphylococcus aureus, particularly methicillin-resistant S. aureus (MRSA), in mothers can cause serious outcomes in neonates. We aimed to elucidate the associations of S. aureus and MRSA carriage between mothers and neonates.

Nonspecific and delayed diagnosis of neurologic damage contributes to the development of neuropathies in patients with severe sepsis. The present study assessed the electrophysiologic parameters related to the excitability and conductibility of sciatic and vagus nerves during early stages of sepsis.

Recently, we reported that astrocytes in the trigeminal caudal nucleus (Vc) of the brain stem express a purinergic receptor P2X3, which is involved in the craniofacial pathologic pain. Although we observed protein expression of P2X3 receptors (P2X3 Rs) in the astrocyte of the Vc, it is still unclear that astrocyte has functional P2X3Rs in Vc. To address this issue, we recorded asrtocytic P2X3Rs by using whole cell voltage-clamp recording in the Vc of the GFAP-GFP mice, which was used as a guide to astrocytes with green fluorescence. While measuring voltage ramp-induced astrocytic membrane current, we found the amplitude of the current was increased when we applied P2-purinoreceptor agonist, α,β-meATP. This increase was blocked by co-application of A317491, P2X3R antagonist. These results demonstrate that astrocytes in the Vc express functional P2X3Rs, which might be critical in craniofacial pathologic pain.

Rice is the most commonly consumed grain in the world. Black rice has been suggested to contain various bioactive compounds including anthocyanin antioxidants. There is currently little information about the nutritional benefits of black rice on brain pathology. Here, we investigated the effects of black rice (Oryza sativa L., Poaceae) extract (BRE) on the hippocampal neuronal damage induced by ischemic insult. BRE (300 mg/kg) was orally administered to adult male C57BL/6 mice once a day for 21 days. Bilateral common carotid artery occlusion (BCCAO) was performed for 23 min on the 8th day of BRE or vehicle administration. Histological analyses conducted on the 22nd day of BRE or vehicle administration revealed that administering BRE profoundly attenuated neuronal cell death, inhibited reactive astrogliosis, and prevented loss of glutathione peroxidase expression in the hippocampus when compared to vehicle treatment. In addition, BRE considerably ameliorated BCCAO-induced memory impairment on the Morris water maze test from the 15th day to the 22nd day of BRE or vehicle administration. These results indicate that chronic administration of BRE is potentially beneficial in cerebral ischemia.

Artemisinin is an anti-malarial drug that has been in use for almost half century. Recently, novel biological effects of artemisinin on cancer, inflammation-related disorders and cardiovascular disease were reported. However, neuroprotective actions of artemisinin against glutamate-induced oxidative stress have not been investigated. In the current study, we determined the effect of artemisinin against oxidative insult in HT-22 mouse hippocampal cell line. We found that pretreatment of artemisinin declined reactive oxygen species (ROS) production, attenuated the collapse of mitochondrial membrane potential induced by glutamate and rescued HT-22 cells from glutamate-induced cell death. Furthermore, our study demonstrated that artemisinin activated Akt/Bcl-2 signaling and that neuroprotective effect of artemisinin was blocked by Akt-specific inhibitor, MK2206. Taken together, our study indicated that artemisinin prevented neuronal HT-22 cell from glutamate-induced oxidative injury by activation of Akt signaling pathway.

Purpose: To investigate spontaneous brain activity amplitude alterations in single and relapsing optic neuritis (sON and rON, respectively) and their relationships with clinical variables. Methods: In total, 42 patients with sON, 35 patients with rON and 50 healthy volunteers were recruited. Resting-state functional Magnetic Resonance Imaging (rs-fMRI) scans were acquired for all participants and compared to investigate the changes in the amplitude of low-frequency fluctuations (ALFFs) among the three groups. The relationships between the ALFFs in regions with significant differences in the groups and clinical variables, including the logarithm of minimal angle of resolution (LogMAR), Expanded Disability Status Scale (EDSS) score and disease duration, were further explored. Results: Compared with healthy volunteers, the sON and rON patients showed significantly decreased ALFFs in several regions of the occipital and temporal lobes (i.e., inferior occipital gyrus and superior temporal gyrus; corrected p < 0.01 using AlphaSim). The sON patients showed significantly increased ALFFs in the left caudate and certain regions in the frontal lobes (i.e., medial frontal gyrus), whereas the rON patients showed increased ALFFs in the bilateral inferior temporal gyrus and left medial frontal gyrus (corrected p < 0.01 using AlphaSim). Significantly decreased ALFFs were observed in the right inferior parietal lobule (IPL), left posterior cingulate and precuneus in the rON patients compared with those in the sON patients (corrected p < 0.01 using AlphaSim). Significant correlations were observed between the disease duration and ALFF in the left middle temporal gyrus, left inferior occipital gyrus, right lingual gyrus and right IPL (p < 0.05). Conclusion: Functional impairment and adaptation occurred in both the sON and rON patients. Impairment mainly involved the occipital cortex, and functional adaptions predominantly occurred in the frontal lobe. Functional damage was more severe in the rON patients than in the sON patients and correlated with the disease duration.

Cytokine-induced killer (CIK) cells, a heterogeneous T cell population obtained by in vitro differentiation of peripheral blood mononuclear cells (PBMC), represent a promising immunological approach in cancer. Numerous studies have explored the role of CD38, CD39, CD203a/PC-1, and CD73 in generating extracellular adenosine (ADO) and thus in shaping the tumor niche in favor of proliferation. The findings shown here reveal that CIK cells are able to produce extracellular ADO via traditional (CD39/CD73) and/or alternative (CD38/CD203a/CD73 or CD203a/CD73) pathways. Transcriptome analysis showed the mRNA expression of these molecules and their modulation during PBMC to CIK differentiation. When PBMC from normal subjects or cancer bearing patients were differentiated into CIK cells under normoxic conditions, CD38 and CD39 were greatly up-regulated while the number of CD203a, and CD73 positive cells underwent minor changes. Since hypoxic conditions are often found in tumors, we asked whether CD39, CD38, CD203a, and CD73 expressed by CIK cells were modulated by hypoxia. PBMC isolated from cancer patients and differentiated into CIK cells in hypoxic conditions did not show relevant changes in CD38, CD39, CD73, CD203a, and CD26. CIK cells also expressed A1, A2A, and A2B ADO receptors and they only underwent minor changes as a consequence of hypoxia. The present study sheds light on a previously unknown functional aspect of CIK cells, opening the possibility of pharmacologically modulated ADO-generating ectoezymes to improve CIK cells performance.

Background: Pulmonary hypertension (PH) is a progressive cardiovascular disease, characterized by endothelial and smooth muscle dysfunction and vascular remodeling, followed by right heart failure. Group III PH develops secondarily to chronic lung disease such as idiopathic pulmonary fibrosis (IPF), and both hastens and predicts mortality despite of all known pharmacological interventions. Thus, there is urgent need for development of newer treatment strategies. Objective: Angiotensin converting enzyme 2 (ACE2), a member of the renin angiotensin family, is therapeutically beneficial in animal models of pulmonary vascular diseases and is currently in human clinical trials for primary PH. Although previous studies suggest that administration of ACE2 prevents PH secondary to bleomycin-induced murine IPF, it is unknown whether ACE2 can reverse or treat existing disease. Therefore, in the present study, we tested the efficacy of ACE2 in arresting the progression of group 3 PH. Methods: To establish pulmonary fibrosis, we administered 0.018 U/g bleomycin 2x/week for 4 weeks in adult FVB/N mice, and sacrificed 5 weeks following the first injection. ACE2 or vehicle was administered via osmotic pump for the final 2 weeks, beginning 3 weeks after bleomycin. Echocardiography and hemodynamic assessment was performed prior to sacrifice and tissue collection. Results: Administration of bleomycin significantly increased lung collagen expression, pulmonary vascular remodeling, and pulmonary arterial pressure, and led to mild right ventricular hypertrophy. Acute treatment with ACE2 significantly attenuated vascular remodeling and increased pulmonary SOD2 expression without measurable effects on pulmonary fibrosis. This was associated with nonsignificant positive effects on pulmonary arterial pressure and cardiac function. Conclusion: Collectively, our findings enumerate that ACE2 treatment improved pulmonary vascular muscularization following bleomycin exposure, concomitant with increased SOD2 expression. Although it may not alter the pulmonary disease course of IPF, ACE2 could be an effective therapeutic strategy for the treatment of group 3 PH.