Iron oxide nanoparticles (IONPs) have been tested to remediate aquatic environments polluted by chemicals, such as pesticides. However, their interactive effects on aquatic organisms remain unknown. This study aimed to investigate the genotoxicity and mutagenicity of co-exposure of IONPs (γ-Fe2O3 NPs) and glyphosate-based herbicide (GBH) in the fish Poecilia reticulata. Thus, fish were exposed to citrate-functionalized γ-Fe2O3 NPs (0.3 mg L-1; 5.44 nm) alone or co-exposed to γ-Fe2O3 NPs (0.3 mg L-1) and GBH (65 and 130 μg of glyphosate L-1) during 14 and 21 days. The genotoxicity (DNA damage) was analyzed by comet assay, while the mutagenicity evaluated by micronucleus test (MN test) and erythrocyte nuclear abnormalities (ENA) frequency. The co-exposure induced clastogenic (DNA damage) and aneugenic (nuclear alterations) effects on guppies in a time-dependent pattern. Fish co-exposed to NPs and GBH (130 μg glyphosate L-1) showed high DNA damage when compared to NPs alone and control group, indicating synergic effects after 21 days of exposure. However, mutagenic effects (ENA) were observed in the exposure groups after 14 and 21 days. Results showed the potential genotoxic and mutagenic effects of maghemite NPs and GBH co-exposure to freshwater fish. The transformation and interaction of iron oxide nanoparticles with other pollutants, as herbicides, in the aquatic systems are critical factors in the environmental risk assessment of metal-based NPs.Bile acid synthesis is restricted to hepatocytes and is rate-limited by CYP7A1 (cholesterol 7α hydroxylase). CYP7A1 expression undergoes tight regulation and is repressed after partial hepatectomy to prevent the accumulation of toxic bile acids. Augmenter of Liver Regeneration (ALR) is a hepatotrophic factor shown to support liver regeneration by augmenting cell proliferation and reducing apoptosis. Nevertheless, less is known about ALR’s role in protecting hepatocytes from bile acid accumulation and bile acid-induced apoptosis. Therefore, HepG2 and Huh-7 cells were incubated with recombinant human ALR (rALR) and the expression of CYP7A1, bile acid-induced apoptosis as well as potential molecular mechanisms were analyzed. We found that rALR reduces CYP7A1 expression by increasing nuclear NFκB levels. Moreover, rALR reduced glycochenodeoxycholate (GCDC)-induced-apoptosis by decreased expression of pro-apoptotic Bax and enhanced expression of anti-apoptotic Mcl-1, which is regulated by phosphatidylinositol-3-kinase (PI3K)/Akt activation and glycogen synthase kinase-3β (GSK3β) phosphorylation. Inhibitors for PI3K/Akt (GSK690693) and GSK3β (SB415286) confirmed the specificity of rALR treatment for this pathway. In addition, rALR reduces pro-death signaling by decreasing GCDC-induced JNK phosphorylation. Taken all together, rALR might contribute to protecting hepatocytes from toxic concentrations of bile acids by down-regulating their denovo synthesis, attenuating apoptosis by activation of PI3K/Akt – GSK3β pathway and inhibition of JNK signaling. Thereby this suggests a new role of ALR in augmenting the process of liver regeneration.Human cytomegalovirus (HCMV) infects up to 90-100% of the world population. Although HCMV infection is not a concern for immunocompetent patients, it can be life threatening for immunocompromised individuals. Additionally, congenital HCMV infections can cause serious neurological deficits in neonates. Since viral resistance mutations arise for all current treatments, new treatments targeting novel processes are needed. A well-defined target for HCMV is heparan sulfate, a highly sulfated glycosaminoglycan (GAG) necessary for virion/host cell attachment. In this study, we investigated as possible antiviral agents substitution-inert cationic polynuclear platinum complexes (PPCs) that demonstrate charge-dependent high affinity for GAGs (Katner et al., 2018; Peterson et al., 2017). Certain PPCs had anti-HCMV activities in low micromolar concentrations and antiviral activity correlated with their GAG-binding affinity. Time of addition, removal, and mechanistic studies were consistent with PPCs binding to cells and blocking HCMV virion attachment; however, evidence also suggested that PPC/virion interactions could inhibit fibroblast but not epithelial cell infection. We hypothesize that the PPC-heparan sulfate interaction described here is a general approach to inhibition of virion/host cell attachment and viral entry mediated by other anionic GAGs and sialic acids on the cell surface. Through metalloshielding of the critical sulfate receptors, PPCs offer an attractive alternative to current antiviral compounds, with the potential to target a broad spectrum of viruses that utilize GAGs for attachment and entry.There are tremendous opportunities to advance science, clinical care, sports performance, and societal health if we are able to develop tools for monitoring musculoskeletal loading (e.g., forces on bones or muscles) outside the lab. While wearable sensors enable non-invasive monitoring of human movement in applied situations, current commercial wearables do not estimate tissue-level loading on structures inside the body. Here we explore the feasibility of using wearable sensors to estimate tibial bone force during running. First, we used lab-based data and musculoskeletal modeling to estimate tibial force for ten participants running across a range of speeds and slopes. Next, we converted lab-based data to signals feasibly measured with wearables (inertial measurement units on the foot and shank, and pressure-sensing insoles) and used these data to develop two multi-sensor algorithms for estimating peak tibial force one physics-based and one machine learning. Additionally, to reflect current running wearables highlights the exciting potential to combine wearables, musculoskeletal biomechanics and machine learning to develop more accurate tools for monitoring musculoskeletal loading in applied situations.Energy, generated by the mitochondrial oxidative phosphorylation system, is transferred to the cytosol across the mitochondrial outer membrane (MOM), through the voltage-dependent anion channels (VDACs). The role of the VDAC’s voltage-gating process to control the transfer of ATP, creatine phosphate and other negatively charged metabolites across MOM might be crucial for the cell energy metabolism regulation. However, it depends on the probability of the outer membrane potential (OMP) generation by a currently undefined mechanism that has usually been considered doubtful, based on the assumption that VDACs always stay in the electrically open state. Nevertheless, computational analysis of various possible metabolically-dependent mechanisms of OMP generation suggests that MOM is not a „coarse sieve”, but in fact it functions as an electrical gatekeeper of cell energy metabolism, due to a probable OMP-dependent VDAC’s gating. OMP generation could also be involved in the control of cell death resistance and mechanisms of various diseases.Early adolescence (ages 10-14) encompasses a critical transition period in which food and nutrition decisions are shifting in important ways. Food routines are food-based activities that repeat across days, weeks, seasons, or lives. Examining routines can provide insight into how individuals are influenced in food choices. The objective of this study was to describe current influences on and experiences with food routines during early adolescence. In-depth interviews, using a photo-elicitation approach, were conducted with 30 participants (16 females; 14 males) in the United States. Participants took photos that were then used during the interview to describe food-related decisions and influences. Interviews were audio recorded and transcribed verbatim. Analysis was guided by a grounded theory approach to identify emergent themes related to routines and resulted in the development of a conceptual model for early adolescent food routines. Participants identified a wide range of routines and three main themes emerged family, settings, and meals/foods consumed. Some had highly established routines throughout the week, while others described routines only for certain meals or days. Several participants described increased control or the ability to modify routines around some eating episodes such as snacks, lunches, and weekend breakfasts. Findings revealed how participants viewed eating routines and provided information about food-and nutrition-related behaviors that can inform future research and practice. Early adolescents appear to have complex food routines influenced by structures and different amounts of control.TMEM16A is a calcium-activated chloride channel that is associate with several diseases, including pulmonary diseases, hypertension, diarrhea and cancer. The CaCCinh-A01 (A01) is widely recognized as an efficient blocker of TMEM16A and has been used as a tool drug to inhibit TMEM16A currents in the laboratory. A01 also has excellent pharmacokinetic properties and can be developed as a drug to target TMEM16A. However, the molecular mechanism how A01 inhibits TMEM16A is still elusive, which slows down its drug development process. Here, calculations identified that the binding pocket of A01 was located above the pore, and it was also discovered that the binding of A01 to TMEM16A not only blocked the pore but also led to its collapse. The interaction model analysis predicted that R515/K603/E623 were crucial residues for the binding between TMEM16A and A01, and the site-directed mutagenesis studies confirmed the above results. The binding mode and quantum chemical calculations showed that the carboxyl and the amide oxygen atom of A01 were the key interaction sites between TMEM16A and A01. Therefore, our study proposed the inhibitory mechanism of TMEM16A current by A01 and revealed how A01 inhibits TMEM16A at the molecular level. These findings will shed light on both the development of A01 as a potential drug for TMEM16A dysfunction-related disorders and drug screening targeting the pocket.During early embryogenesis, mammary glands are derived from surface ectoderm and their morphogenesis is controlled by mammary stem cells (MaSCs) and epithelial-mesenchymal transition (EMT). Mammary anlagen stage (E13.5-15.5) is an important stage for fetal mice to achieve EMT dependent mammary morphogenesis. And the characteristics of mammary anlagen repopulating cell population (MaRC) should be identified for understanding its stemness at earlier embryonic stage. Here we quantify and characterize MaSCs proportion at mammary anlagen stage. Compared with adult mouse mammary gland, our data revealed that E14.5 mammary anlagen exhibit higher stem cell activities. Then we purified mammary anlagen cell populations depending on the expression levels of CD24 and CD49f in mouse mammary anlagen, and identified an unique MaRC population (Lin-CD24medCD49f+) by real-time PCR, transplantation and mammosphere forming assays. In addition, by comparing with adult MaSC (Lin-CD24+CD29hi) and differentiated mammary anlagen cells, we find that E14.5 mouse MaRC population exhibit gene expression programs related to mesenchymal properties. To further identify the cell types of E14.5 mouse MaRC population, the expressions of K8, K14, K18, e-cadherin, n-cadherin and vimentin in mammary anlagen Lin-CD24medCD49f + cells were detected by immunofluorescence assay. These findings verified that the undifferentiated E14.5 mouse MaRC population is a heterogeneous population with mesenchymal property, which is associated with cell stemness and mammary duct morphogenesis.Dysfunction in mitochondrial dynamics is believed to contribute to a host of neurological disorders and has recently been implicated in cancer metastasis. The outer mitochondrial membrane adapter protein Miro functions in the regulation of mitochondrial mobility and degradation, however, the structural basis for its roles in mitochondrial regulation remain unknown. Here, we report a 1.7Å crystal structure of N-terminal GTPase domain (nGTPase) of human Miro1 bound unexpectedly to GTP, thereby revealing a non-catalytic configuration of the putative GTPase active site. We identify two conserved surfaces of the nGTPase, the „SELFYY” and „ITIP” motifs, that are potentially positioned to mediate dimerization or interaction with binding partners. Additionally, we report small angle X-ray scattering (SAXS) data obtained from the intact soluble HsMiro1 and its paralog HsMiro2. Taken together, the data allow modeling of a crescent-shaped assembly of the soluble domain of HsMiro1/2. PDB RSEFERENCE Crystal structure of the human Miro1 N-terminal GTPase bound to GTP, 6D71.Trace amine-associated receptors (TAARs) are a class of sensory G protein-coupled receptors that detect biogenic amines, products of decarboxylation of amino acids. The majority of TAARs (TAAR2-TAAR9) have been described mainly in the olfactory epithelium and considered to be olfactory receptors sensing innate odors. However, there is recent evidence that one of the members of this family, TAAR5, is expressed also in the limbic brain areas receiving projection from the olfactory system and involved in the regulation of emotions. In this study, we further characterized a mouse line lacking TAAR5 (TAAR5 knockout, TAAR5-KO mice) that express beta-galactosidase mapping TAAR5 expression. We found that in TAAR5-KO mice the number of dopamine neurons, the striatal levels of dopamine and its metabolites, as well as striatal levels of GDNF mRNA, are elevated indicating a potential increase in dopamine neuron proliferation. Furthermore, an analysis of TAAR5 beta-galactosidase expression revealed that TAAR5 is present in the major neurogenic areas of the brain such as the subventricular zone (SVZ), the subgranular zone (SGZ) and the less characterized potentially neurogenic zone surrounding the 3rd ventricle. Direct analysis of neurogenesis by using specific markers doublecortin (DCX) and proliferating cell nuclear antigen (PCNA) revealed at least 2-fold increase in the number of proliferating neurons in the SVZ and SGZ of TAAR5-KO mice, but no such markers were detected in mutant or control mice in the areas surrounding the 3rd ventricle. These observations indicate that TAAR5 involved not only in regulation of emotional status but also adult neurogenesis and dopamine transmission. Thus, future TAAR5 antagonists may exert not only antidepressant and/or anxiolytic action but may also provide new treatment opportunity for neurodegenerative disorders such as Parkinson’s disease.

Substance use disorders and social stress are currently associated with changes in the immune system response by which they induce a proinflammatory state in neurons and glial cells that eventually modulates the reward system.

The aim of the present work was to assess the role of the immune TLR4 (Toll-like receptors 4) and its signaling response in the increased contextual reinforcing effects of cocaine and reinforcing effects of ethanol (EtOH) induced by social defeat (SD) stress.

Adult male C57BL/6J wild-type (WT) mice and mice deficient in TLR4 (TLR4-KO) were assigned to experimental groups according to stress condition (exploration or SD). Three weeks after the last SD, conditioned place preference (CPP) was induced by a subthreshold cocaine dose (1mg/kg), while another set underwent EtOH 6% operant self-administration (SA). Several inflammatory molecules were analyzed in the hippocampus and the striatum.

SD induced higher vulnerability to the conditioned rewarding effects of cocaine only in defeated WT mice. Similarly, defeated WT mice exhibited higher 6% EtOH consumption, an effect that was not observed in the defeated TLR4-KO group. However, the motivation to obtain the drug was observed in both genotypes of defeated animals. Notably, a significant upregulation of the protein proinflammatory markers NFkBp-p65, IL-1β, IL-17A and COX-2 were observed only in the defeated WT mice, but not in their defeated TLR4-KO counterparts.

These results suggest that TLR4 receptors mediate the neuroinflammatory response underlying the increase in the rewarding effects of cocaine and EtOH induced by social stress.

These results suggest that TLR4 receptors mediate the neuroinflammatory response underlying the increase in the rewarding effects of cocaine and EtOH induced by social stress.Compatible (positive approaching and negative avoiding) and incompatible (positive avoiding and negative approaching) behavior are of great significance for biological adaptation and survival. Previous research has found that reaction times of compatible behavior are shorter than the incompatible behavior, which is termed the stimulus-response compatibility (SRC) effect. However, the underlying neurophysiological mechanisms of the SRC effect applied to affective stimuli is still unclear. Here, we investigated preparatory activities in both the left and right primary motor cortex (M1) before the execution of an approaching-avoiding behavior using the right index finger in a manikin task based on self-identity. The results showed significantly shorter reaction times for compatible than incompatible behavior. Most importantly, motor-evoked potential (MEP) amplitudes from left M1 stimulation were significantly higher during compatible behavior than incompatible behavior at 150 and 200 ms after stimulus presentation, whereas the reversed was observed for right M1 stimulation with lower MEP amplitude in compatible compared to incompatible behavior at 150 ms. The current findings revealed the compatibility effect at both behavioral and neurophysiological levels, indicating that the affective SRC effect occurs early in the motor cortices during stimulus processing, and MEP modulation at this early processing stage could be a physiological marker of the affective SRC effect.To examine the relationship between changes in participant’s knowledge, beliefs, dietary behavior, diabetes self-management and program outcomes in West Virginia Dinning with Diabetes (DWD) program. We used a longitudinal pre-test and post-test study design and data from 2745 individuals with diabetes who participated from 2007 to 2012. The DWD was offered in community-based settings across the state as an educational program (five classes over a 3-month period). Associations between changes in the variables were examined by structural equation modeling using a path model in which changes in nutritional knowledge, beliefs and depression predicted changes in dietary behaviors and diabetes self-management which subsequently predicted program outcomes (e.g., follow-up with healthcare providers for diabetes care and education). Standardized regression weights are presented. Participant’s mean age and duration of diabetes was 63 ± 11.5 and 7.2 ± 8.0 years, respectively. The majority were females, Whites and with less than high school education. Improvements in nutrition knowledge and belief predicted improvements in dietary behavior (β = 0.60, p less then .001 and β = 0.11, p less then .001, respectively) and diabetes self-management (β = 0.61, p less then .001 and β = 0.10, p less then .001, respectively) which in turn predicted improvements in program outcome (β = 0.41, p less then .001). Diabetes self-management mediated the relationship between knowledge, dietary behavior and program outcomes. The indexes of fit for the tested model indicated a good fit [TLI =0.99, CFI = 0.95, and Root Mean Square Error of Approximation (RMSEA) =0.05]. Results indicate DWD group sessions can be effective in supporting individuals with diabetes to change knowledge, dietary behaviors, adherence to self-management and follow-up provider visits for diabetes care.

The objective was a large-scale analysis of the relation between hypertension, memory problems, and brain function.

The study design was to measure the association between a history of hypertension, and the functional connectivity between 94 brain regions, and prospective and numeric memory, in 19,507 participants from the UK Biobank, with cross-validation in 1,002 participants in the Human Connectome Project, and 13,441 individuals in the second release of the UK Biobank. A history of hypertension was measured by whether individuals were admitted to hospital for the treatment of hypertension, with the control group admissions for other reasons.

A history of hypertension was associated with reduced functional connectivity of the hippocampus, and with reduced prospective memory score (FDR correction p<0.01). The reduced functional connectivity mediated the association between the hypertension history and the prospective memory score. A graded linear relation between both the hippocampal functional connectivity and memory impairment, was found across a wide range of blood pressure (r=-0.04). In 502,537 participants from the UK Biobank, a history of hypertension was associated with impaired prospective memory (p=9.1×10

, Cohen’s d=-0.08) and numeric memory (p=4.7×10

, Cohen’s d=-0.10). The association between hypertension, functional connectivity, and impaired memory was cross-validated with 1,002 participants from the Human Connectome Project; and for functional connectivity in 13,441 individuals in the second release of the UK Biobank imaging dataset.

The reduced functional connectivity of the hippocampus, and the memory impairments, both related to hypertension across a wide range of blood pressure, are important for clinical practice.

The reduced functional connectivity of the hippocampus, and the memory impairments, both related to hypertension across a wide range of blood pressure, are important for clinical practice.

The pathogenesis of airway allergic disorders (AAD) needs to be further investigated. Eosinophils (Eos) are the canonical effector cells in AAD attacks. Bcl2 like protein-12 (Bcl2L12) is an apoptosis inhibitor and an immune regulator. Eos have the defects of apoptosis. This study aims to investigate the role of Bcl2L12 in the AAD pathogenesis by regulating Eo activities.

Human nasal lavage fluids (NLF) and mouse bronchoalveolar lavage fluids (BALF) was collected. Eos in NLF and BALF were analyzed by flow cytometry. A murine AAD model was developed with ovalbumin as a specific antigen.

We found that Eos isolated from NLF or BALF of AAD subjects expressed high levels of Bcl2L12 and showed defects of apoptosis. The Bcl2L12 expression in Eos was positively correlated with the AAD response. High lipopolysaccharide levels were detected in the AAD airways, that promoted the Bcl2L12 expression in Eos. Bcl2L12 mediated the LPS-induced autocrine eotaxin 1 expression in Eos through activating the MAPK p38/STAT6/NF-κB signal pathway. Depletion of Bcl2L12 in Eos suppressed experimental AAD in mice.

AAD Eos express high levels of Bcl2L12, the latter is associated with AAD response by regulating the autocrine eotaxin 1 in Eos. Depletion of Bcl2L12 in Eos attenuates experimental AAD, suggesting that to suppress the Bcl2L12 Eos has the translational potential in the treatment of AAD.

AAD Eos express high levels of Bcl2L12, the latter is associated with AAD response by regulating the autocrine eotaxin 1 in Eos. Depletion of Bcl2L12 in Eos attenuates experimental AAD, suggesting that to suppress the Bcl2L12 Eos has the translational potential in the treatment of AAD.Combined environmental exposures to the volatile organic compounds (VOCs) Benzene, Toluene, Ethylbenzene, and Xylene (BTEX) pose clear risks to public health. Research into these risks is under-studied even as BTEX levels in the atmosphere are predicted to rise. This review focuses on the available literature using single- and combined-BTEX component inhaled solvent exposures in animal models, necessarily also drawing on findings from models of inhalant abuse and occupational exposures. Health effects of these exposures are discussed for multiple organ systems, but with particular attention on neurobehavioral outcomes such as locomotor activity, impulsivity, learning, and psychopharmacological responses. It is clear that animal models have significant differences in the concentrations, durations and patterns of exposure. Experimental evidence of the deleterious health and neurobehavioral consequences of exposures to the individual components of BTEX were found, but these effects were typically assessed using concentrations and exposure patterns not characteristic of environmental exposure. Future studies with animal models designed appropriately to explore combined BTEX will be necessary and advantageous to discovering health outcomes and more subtle neurobehavioral impacts of long-term environmental exposures.Brain plasticity refers to the ability of synaptic connections to adapt their function and structure in response to experience, including environmental changes, sensory deprivation and injuries. Plasticity is a distinctive, but not exclusive, property of the developing nervous system. This review introduces the concept of neuroplasticity and describes classic paradigms to illustrate cellular and molecular mechanisms underlying synapse modifiability. Then, we summarize a growing number of studies showing that the adult cerebral cortex retains a significant degree of plasticity highlighting how the identification of strategies to enhance the plastic potential of the adult brain could pave the way for the development of novel therapeutic approaches aimed at treating amblyopia and other neurodevelopmental disorders. Finally, we analyze how the visual system adjusts to neurodegenerative conditions leading to blindness and we discuss the crucial role of spared plasticity in the visual system for sight recovery.Vascular cognitive impairment (VCI) is the second most common cause of dementia after Alzheimer’s disease, and the cognitive impairment is one of the common effects of VCI. Unfortunately, it lacks effective therapeutic treatments at present. In our previous study, environmental enrichment (EE), as an early intervention for lifestyle modification, can ameliorate cognitive impairment by attenuating hippocampal blood-brain barrier (BBB) injury in chronic cerebral hypoperfusion (CCH) rats. However, the underlying mechanism remains unclear. Here, we found CCH rats in the standard environment (SE) developed cognitive impairment and BBB damage, which were significantly alleviated with the EE intervention. Meantime, EE improved the autophagy dysfunction caused by CCH in the hippocampus of rats, suggesting that the effect of EE on cognitive function and BBB may be related to the improvement of autophagy pathway.Dry needling treatment has a promising relieving effect on Myofascial Pain Syndrome (MPS). In China, acupuncture practitioners use acupuncture needle instead to insert the „A-Shi” acupoint to treat MPS which is defined as the same as the trigger point of dry needling. This method has been applied for thousands of years in China. In this study, bupivacaine injection induced gastrocnemius muscle injury in mice. We applied the clinical improved needling method on animal model by making the angle between the skin and needle less than 30 degree. Animals got needling treatment 24 h later at the point where the bupivacaine was injected. Results of muscle H.E. staining showed that, compared to bupivacaine injection group without needling, acupuncture treatment group showed more intact muscle fibers, less inflammatory cell infiltration and fractured muscle fibers. By RNA sequencing analysis, our work firstly demonstrated that the physical stimulation of needling changed the gene expression of muscle tissue to accelerate the muscular regeneration process. Therefore, our study proved that simple needling at „A-Shi” acupoint promoted muscle regeneration and revealed underlying mechanisms of the beneficial effects of acupuncture and dry needle treatments.Serotonin (5-HT) and its innervation have been implicated in various neural functions including circadian systems. Although classical studies have examined the 5-HT innervation pattern in the adult suprachiasmatic nucleus (SCN), the fine-grained morphological study of the development of pathway and terminal projections to the SCN remains scarce. Here, we utilize transgenic mice expressing GFP under the serotonin transporter (SERT) promoter to subserve our developmental mapping study. We demonstrate that the morphology of 5-HT pathway fibers decussating over the supraoptic commissure that projects to the SCN exhibits two distinct developmental patterns. The punctate fibers at the fetal stage gradually become smooth and filamentous, especially during postnatal one week and remain constant thereafter. The innervation field in the SCN develops properly only during postnatal two weeks. Its ventromedial area remains one of the highest 5-HT innervated areas in the adult brain, whereas the dorsolateral area is less innervated. Thus, we provide novel and specific insights on the developmental map of 5-HT system into the SCN using transgenic mouse.

To verify the effect of metformin on spinal cord injury (SCI) through Wnt/β-catenin signaling pathway.

SCI is a serious traumatic disease of the central nervous system. Wnt/β-catenin signaling pathway plays important roles in SCI. Metformin has been reported to exert neuroprotective effects in the central nervous system. Whether metformin could improve SCI through Wnt/β-catenin signaling pathway remains unclear.

Rats were divided into sham group, SCI group, SCI + metformin group, metformin + XAV939 group (XAV939 is an effective inhibitor of the Wnt/β-catenin signaling pathway), and methylprednisolone group. BBB scores were used to detect motor function recovery at different time points (0, 1, 3, 7, 14, 21, and 28 days) in SCI rats. Western blot analysis, immunofluorescence, TUNEL, HE and Nissl staining were used to observe the morphological characteristics of spinal cord tissue and the expression of inflammation and apoptosis in spinal cord neurons.

Metformin(50 mg/kg) promoted motor functional recovery in rats after SCI, increased the expressions of β-catenin and brain derived neurotrophic factor (BDNF), inhibited neuron apoptosis and inflammatory response, and improved the recovery of pathological morphology at the injury site by activating the Wnt/β-catenin signaling pathway.

We found a possible mechanism that metformin could reduce inflammation and apoptosis, and promote functional recovery of SCI rats through activating Wnt/β-catenin signaling pathway.

We found a possible mechanism that metformin could reduce inflammation and apoptosis, and promote functional recovery of SCI rats through activating Wnt/β-catenin signaling pathway.It has been reported that the Gonadotropin-releasing hormone (GnRH) and its agonist leuprolide acetate (LA) can act as promoters of nerve regeneration. The aim of this study is to evaluate the effect of LA in a complete transection model. Sciatic nerve injury (SNI) was performed using a complete nerve transection and immediately repaired by epineural sutures. Rats were divided into three groups SHAM, SNI treated with LA (SNI + LA) or saline solution (SNI + SS) for 5 weeks. Sciatic nerve regeneration was evaluated by kinematic gait analyzes, electrophysiological, morphological and biochemical tests. SNI + LA group had a functional recovery in kinematic gait, an increase in ankle angle value and a faster walking speed, compound muscle action potential amplitude, nerve conduction velocity (NCV). Furthermore, the number of myelinated axons and microtubule-associated protein 2 (MAP-2) expression were also higher compared to SS group. In conclusion, LA treatment improves of gait, walking speed, NCV, axons morphometry and MAP-2 expression in rats with sciatic nerve complete transection. These results suggest that LA can be a potential treatment for peripheral nerve injuries.The disposal of cacao pod husk, a byproduct of cacao bean processing, can cause serious adverse environmental impacts, motivating scientist to explore and develop potential beneficial applications of this resource. Dried cacao pod husk was extracted with ethanol to obtain a 10.6% pectin of cacao pod husks (pCPH), and its effects on the immunocompetence of Litopenaeus vannamei were estimated. Measured variables included total haemocyte count, differential haemocyte count, phenoloxidase activity, respiratory bursts, as well as phagocytic activity and clearance efficiency against Vibrio alginolyticus after receiving pCPH at 0, 1.5, 3, and 6 μg shrimp-1 for 0, 1, 3 and 7 days via injection, and their resistance to thermal stress and V. alginolyticus infection were further evaluated. No significant differences were observed in total haemocyte count, differential haemocyte count, and respiratory bursts in shrimp receiving pCPH at 1.5 μg shrimp-1 for 1 day; however, these variables were significantly elevated after 1 day, and the significant higher resistance to hypothermal stress and V. alginolyticus infection were found in shrimp received pCPH at 6 μg shrimp-1 for 1 days than those in the other treatments. It is therefore found that pCPH triggers immune responses serving as an immunostimulant capable of enhancing resistance against V. alginolyticus and hypothermal stress.Implementation lessons Establishing a shared 'hub-and-spoke,’ web-based clinical decision support system (CDSS) in an EHR shared by >600 community health centers incurred a myriad of challenges, which are summarized here to guide others seeking to use similar CDSS. Legal and compliance challenges involved ensuring secure data exchanges, determining which entity maintains data records, and deciding which data are sent to the CDSS. Technical challenges involved using lab data from multiple sources and improving the CDSS’ cache routine performance in its new setting. Clinical implementation challenges involved identifying optimal strategies for generating data on CDSS use rates, modifying the CDSS functionality for obtaining clinician/staff feedback, and customizing the risk thresholds that trigger the CDSS for the new setting.Indibulin (D-24851) derivatives with bisphosphonate fragment connected to the N1 atom of imidazole ring were synthesized by alkylation of (indolyl-3)methylglyoxylates with ethylenebisphosphonate. Biological evaluation of targeted compounds 4a-d using the phenotypic sea urchin embryo assay provided evidence that replacing of p-chlorobenzene ring in indibulin by bisphosphonate group did not eliminate antimitotic microtubule destabilizing activity. The most active molecule, tetraacid 5a, at physiological pH formed tetrasodium salt 6a with aqueous solubility value of at least 10 mg/mL. Molecule 5a was more potent in the sea urchin embryo assay than the parent indibulin. This compound also exhibited pronounced cytotoxicity against A549 lung carcinoma and A375 melanoma cell lines.The epithelial cell plays a key role in the transfer of radionuclides from lungs to blood following pulmonary exposure. The present study was designed to evaluate the transfer across human lung epithelial cells of various actinides (plutonium, americium and uranium), the influence of the physicochemical properties of plutonium compounds and of the chelating agent diethylene triamine pentaacetic acid (DTPA). To address this question, Calu-3 cells grown in a bicameral culture system were used. The integrity of the epithelial barrier was evaluated by measuring transepithelial electrical resistance (TEER) and the passage of a fluorescent marker, lucifer yellow. Activity measurement in basal compartment following periodic collection of culture medium was made from 2 h to seven days. To facilitate data handling and analysis, the statistical tool STATBIODIS was used. The results indicate differences in transfer for the different elements, and according to Pu physicochemical properties. Though to various extents, the chelating agent DTPA always increased the transfer of Pu and Am across the epithelial cells, without altering the integrity of the epithelial barrier. This in vitro cell culture model, by mimicking translocation of actinides from lungs to blood, can represent a valuable tool to further understand the underlying mechanisms and properties controlling this process.Heavy metals are the cause of one of the most significant biosphere contamination problems worldwide, as they can be highly reactive and toxic according to their oxidation levels. Their toxic effects are correlated with the elevated production of reactive oxygen species (ROS) and oxidative cellular damage occurring in plants. The aim of the present study was the investigation of the effects of three heavy metals (Ni, Cu, Zn) applied to the soil in biochemical defense-related responses and allergen production in the aromatic plant oregano (Origanum vulgare L.) from the Lamiaceae family. The concentrations of the three heavy metals used, were based on the 2002 Regulation of the Polish Ministry of the Environment on Soil Quality Standards [(i) agricultural land (group B) Ni 100 ppm, Ni 210 ppm, Cu 200 ppm, Cu 500 ppm, Zn 720 ppm and (ii) industrial land (group C) Ni 500 ppm, Cu 1000 ppm, Zn 1500 ppm, Zn 3000 ppm]. The investigated plants accumulated heavy metal ions in aerial parts to a variable extent. For plannolic compounds and total antioxidant capacity. On the basis of these findings, Ni stress in oregano plants appears to be less damaging (in relation to Cu and Zn) and with lower allergenic potential, compared with 1000 ppm Cu. The present study provides novel biochemical insight in the defense and allergenic response of aromatic plants to metal ions present in the rhizosphere; however, more comprehensive research under realistic field conditions is needed to fully decipher this interaction.In this study, a novel combinatorial control strategy was developed to guarantee a stable mainstream deammonification process, with three critical steps including (a) upflow airwater washing, (b) short-term increased nitrogen loading rate (NLR), and (c) low oxygen supply. Results showed that two upflow double-blanket filter (UDBF) reactors effectively performed the mainstream deammonification process with the nitrogen removal efficiency (NRE) 84.5 ± 2.2% and 84.6 ± 1.6%, respectively and nitrogen removal rate (NRR) 123.8 ± 2.9 and 125.5 ± 6.2 g N·(m3·d)-1, respectively. Statistically, temperature and C/N were considered as two vital factors affecting the nitrogen removal pathways, which co-explained 80.9% and 78.4% of the maximum possible contribution of heterotrophic denitrification in both reactors. The deammonification process accounted for more than 59.8% of TN removal in R2 and 54.8% in R1, which cooperated well with heterotrophic denitrification for efficient performance in treating municipal sewage.Current therapies for patients with peritoneal metastases (PM) are only moderately effective. Recently, a novel locoregional treatment method for PM was introduced, consisting of a combination of laparoscopy with intraperitoneal (IP) delivery of anticancer agents as an aerosol. This 'pressurized intraperitoneal aerosol chemotherapy’ (PIPAC) may enhance tissue drug penetration by the elevated IP pressure during CO2 capnoperitoneum. Also, repeated PIPAC cycles allow to accurately stage peritoneal disease and verify histological response to treatment. This review provides an overview of the rationale, indications, and currently used technology for therapeutic IP nebulization, and discusses the basic mechanisms governing aerosol particle transport and peritoneal deposition. We discuss early clinical results in patients with advanced, irresectable PM and highlight the potential of electrostatic aerosol precipitation. Finally, we discuss promising novel approaches, including nebulization of nanoparticles and prolonged release formulations.

Mesenchymal stem cells (MSCs) are characterized by the potential to differentiate into multiple cell lineages, high proliferation rates, and self-renewal capacity, in addition to the ability to maintain their undifferentiated state. These cells have been identified in physiological oral tissues such as pulp tissue, dental follicle, apical papilla and periodontal ligament, as well as in pathological situations such as chronic periapical lesions (CPLs). The criteria used for the identification of MSCs include the positive expression of specific surface antigens, with CD73, CD90, CD105, CD44, CD146, STRO-1, CD166, NANOG and OCT4 being the most specific for these cells.

The aim of this review was to explore the literature on markers able to identify MSCs as well as the presence of these cells in the healthy periodontal ligament and CPLs, highlighting their role in regenerative medicine and implications in the progression of these lesions.

Narrative literature review searching the PubMed and Medline databasee lesions.The ability to cope with a novel acute stressor in the context of ongoing chronic stress is of critical adaptive value. The hypothalamic-pituitary-adrenal (HPA) axis contributes to the integrated physiological and behavioural responses to stressors. Under conditions of chronic stress, the posterior portion of the paraventricular thalamic nucleus (pPVT) mediates the 'habituation’ of HPA-axis responses, and also facilitates HPA-axis reactivation to novel acute stressors amidst this habituation. Since pPVT neurons are sensitive to the inhibitory effects of circulating glucocorticoids, a glucocorticoid-insensitive neural pathway to the pPVT is likely essential for this reactivation process. The pPVT receives substantial inputs from neurons of the periaqueductal gray (PAG) region, which is organised into longitudinal columns critical for processing acute and/or chronic stressors. We investigated the columnar organisation of PAG → pPVT projections and for the first time determined their glucocorticoid sensitivity. Retrograde tracer injections were made into different rostro-caudal regions of the pPVT, and their PAG columnar inputs compared. Glucocorticoid receptor immunoreactivity (GR-ir) was quantified in these projection neurons. We found that the dorsolateral PAG projected most strongly to rostral pPVT and the ventrolateral PAG most strongly to the caudal pPVT. Despite abundant GR-ir in the PAG, we report a striking absence of GR-ir in PAG → pPVT neurons. Our data suggests that these pathways, which are insensitive to the direct actions of circulating glucocorticoids, likely play an important role in both the habituation of HPA-axis to chronic stressors and its facilitation to acute stressors in chronically stressed rats.Delayed cerebral ischemia (DCI) is identified as one of the significant contributors to poor patient outcome after aneurysmal subarachnoid hemorrhage (SAH). We previously reported that a supratherapeutic dose of isoflurane conditioning (2%) provided robust protection against SAH-induced DCI. The aim of our current study is to compare the efficacy of the supratherapeutic dose of isoflurane to that typically used to establish general anesthesia or sedation. After IRB approval for animal studies, ten to fourteen-week-old wild-type male mice (C57BL/6) were divided into five groups – sham, SAH alone, or SAH with isoflurane conditioning (0.5%, 1%, and 2%). Conditioning was performed with one-hour of isoflurane initiated one-hour after induction of SAH via endovascular perforation technique. Vasospasm measurement in the middle cerebral artery was assessed 72 h after SAH. Neurological assessment was performed at baseline and for next three days after SAH. It was identified that all tested doses of isoflurane conditioning (0.5%, 1%, and 2%) significantly attenuated large artery vasospasm and markedly improved neurological deficits following SAH. No significant differences in neurovascular outcome were noted between the three doses of isoflurane conditioning. Our data show that isoflurane dosing typically used for general anesthesia (1%) or sedation (0.5%) provide similar levels of DCI protection in SAH as that provided by a supratherapeutic dose (2%). This result has important implications for future translational studies. Additional studies examining the therapeutic potential of anesthetic conditioning for SAH are therefore warranted.PNU-120596 is a classical positive allosteric modulator (PAM) of α7 nicotinic acetylcholine receptor (α7 nAChR) and widely used to investigate the effect of α7 nAChR activation on several inflammation-associated diseases including rheumatoid arthritis, inflammatory bowel disease and cerebral ischemia. In this study, we report that PNU-120596 directly inhibits p38 mitogen-activated protein kinase (MAPK) activity. In 293A cells, p38 MAPK phosphorylation by several factors (oxidative stress, osmotic stress, TNF-α, or muscarinic stimulation) was inhibited by PNU-120596 as well as p38 MAPK inhibitor BIRB-796. Inhibition of p38 MAPK phosphorylation by PNU-120596 was not affected by α7 nAChR antagonist, methyllycaconitine (MLA). In vitro kinase assay revealed that PNU-120596 directly inhibits p38α MAPK-induced activating transcription factor 2 (ATF2) phosphorylation. MKK6-induced phosphorylation of p38α MAPK was also inhibited by PNU-120596. Real-time monitoring of binding to p38α MAPK using fluoroprobe SKF-86002 showed quite rapid binding of PNU-120596 compared to BIRB-796 which is known as a slow binder. Finally, we showed that PNU-120596 suppressed LPS-induced phosphorylation of p38 MAPK and expression of inflammatory factors including TNF-α, IL-6 and COX-2, independent on α7 nAChR activity in microglial cell BV-2. Thus, PNU-120596 might exert an anti-inflammatory effect through not only α7 nAChR potentiation but also direct inhibition of p38 MAPK.

This paper aims to provide an explicit theoretical model for the cognitive processes involved in paleopathological diagnosis.

The approach adopted is a dual process model (DPM). DPMs recognize that cognition is a result of both Type 1 (intuitive) and Type 2 (analytical) processes. DPMs have been influential for understanding decision-making in a range of fields, including diagnosis in clinical medicine. Analogies are drawn between diagnosis in a clinical and a paleopathological setting.

In clinical medicine, both Type 1 and Type 2 processes play a part in diagnosis. In paleopathology the role of Type 1 processes has been unacknowledged. However, like clinical diagnosis, paleopathological diagnosis is inherently a result of a combination of both Type 1 and Type 2 processes. A model is presented by which Type 1 processes can be explicitly incorporated into a scientific approach to diagnosis from skeletal remains, and in which diagnosis is formalized as a process of hypothesis testing.

Accurately modelling our diagnostic processes allows us to understand the biases and limitations in our work and potentially helps us to improve our procedures, including how we impart diagnostic skills in pedagogical settings.

This work provides a theoretical model for paleopathological diagnosis. However, such models are by their nature dynamic and developing rather than static entities; it is hoped that this work stimulates further debate and discussion in this important area.

This work provides a theoretical model for paleopathological diagnosis. However, such models are by their nature dynamic and developing rather than static entities; it is hoped that this work stimulates further debate and discussion in this important area.Calpain has been proposed to play a critical role in the development of epilepsy. Here we used conditional calpain-2 knock-out (C2CKO) mice in a C57/Bl6 background and a selective calpain-2 inhibitor to analyze the role of calpain-2 in epilepsy. Neurodegeneration was evident in various hippocampal subfields, in particular in mossy cells in the hilus of the dentate gyrus (DG) in C57/Bl6 mice 7 days after kainic acid (KA)-induced seizures. Calpain-2 activation was still observed in mossy cells 7 days after seizures. Calpain activation, astroglial and microglial activation, neurodegeneration, and cognitive impairment were absent in C2CKO mice and in C57/Bl6 mice treated with a selective calpain-2 inhibitor for 7 days after seizure initiation. Levels of the potassium chloride cotransporter 2 (KCC2) were decreased in mossy cells 7 days after seizures and this decrease was prevented by calpain-2 deletion or selective inhibition. Our results indicate that prolonged calpain-2 activation plays a critical role in neuropathology following seizures. A selective calpain-2 inhibitor could represent a therapeutic treatment for seizure-induced neuropathology.RNA helicase A (RHA) is a ubiquitously expressed DExH-box helicase enzyme that is involved in a wide range of biological processes including transcription, translation, and RNA processing. A number of RNA viruses recruit RHA to the viral RNA to facilitate virus replication. DNA viruses contain a DNA genome and replicate using a DNA-dependent DNA polymerase. RHA has also been reported to associate with some DNA viruses during replication, in which the enzyme acts on the viral RNA or protein products. As shown for Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus, RHA has potential to allow the virus to control a switch in cellular gene expression to modulate the antiviral response. While the study of the interaction of RHA with DNA viruses is still at an early stage, preliminary evidence indicates that the underlying molecular mechanisms are diverse. We now review the current status of this emerging field.Infectious diseases related to viruses, as well as bacterial pathogens, abound in all parts of the world, burdening health and economy. Thus, there is a dire need to find new prevention and treatment strategies to improve clinical practices related to viral infections. Human gut contains trillions of bacteria which have regulatory roles in immune development, homeostasis, and body metabolism. Today, it is difficult to find any prominent viral infection that hasn’t had any link with the human gut microbiota. In this opinion-based review article, I argued the significance of manipulating human gut microbiota as novel therapeutics through probiotics or FMT in alleviating complexities related to viral infections, and pinpointed bottlenecks involved in this research.Split luciferase complementary assay has been used to investigate the effect of WD domain deletion on Apaf-1 oligomerization. Apaf-1 is an adaptor molecule in formation of apoptosome that activates caspase-9, an activation that is a key event in the mitochondrial cell death pathway. Structural studies suggest that normally Apaf-1 is held in an inactive conformation by intramolecular interactions between Apaf-1’s nucleotide binding domain and one of its WD40 domains (WD1). In the prevailing model of Apaf-1 activation, cytochrome c binds to sites in WD1 and in Apaf-1’s second WD40 domain (WD2), moving WD1 and WD2 closer together and rotating WD1 away from the nucleotide binding domain. This allows Apaf-1 to bind dATP or ATP and to form the apoptosome, which activates caspase-9. This model predicts that cytochrome c binding to both WD domains is necessary for apoptosome formation and that an Apaf-1 with only WD1 will be locked in an inactive conformation that cannot be activated by cytochrome c. Here we investigated the effect of removing one WD domain (Apaf-1 1-921) on Apaf-1 interactions and caspase activation.