Cinnabar has a long history of uses in Chinese traditional medicines as an ingredient in various remedies. However, the detailed mechanism of cinnabar in medication remains unclear, and the toxicity of cinnabar has been a debate due to its containing mercury sulfide. This study was designed to investigate the differential transport mechanism of cinnabar and other Hg-containing compounds HgCl2, MeHg and HgS, and to determine if organic anion transporters OAT1 and OAT3 were involved in the differential transport mechanism.

Affective neuroscience research suggests that maturational changes in reward circuitry during adolescence present opportunities for new learning, but likely also contribute to increases in vulnerability for psychiatric disorders such as depression and substance abuse. Basic research in animal models and human neuroimaging has made progress in understanding the normal development of reward circuitry in adolescence, yet, few functional neuroimaging studies have examined puberty-related influences on the functioning of this circuitry. The goal of this study was to address this gap by examining the extent to which striatal activation and cortico-striatal functional connectivity to cues predicting upcoming rewards would be positively associated with pubertal status and levels of pubertal hormones (dehydroepiandrosterone, testosterone, estradiol). Participants included 79 adolescents (10-13 year olds; 47 girls) varying in pubertal status who performed a novel reward cue processing task during fMRI. Pubertal maturation was assessed using sex-specific standardized composite measures based on Tanner staging (self-report and clinical assessment) and scores from the Pubertal Development Scale. These composite measures were computed to index overall pubertal maturation as well as maturation of the adrenal and gonadal axes separately for boys and girls. Basal levels of circulating pubertal hormones were measured using immunoassays from three samples collected weekly upon awakening across a three-week period. Results indicated greater striatal activation and functional connectivity between nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC) to reward cue (vs. no reward cue) on this task. Also, girls with higher levels of estradiol showed reduced activation in left and right caudate and greater NAcc-putamen connectivity. Girls with higher levels of testosterone showed greater NAcc connectivity with the anterior cingulate cortex and the insula. There were no significant associations in boys. Findings suggest that patterns of activation and connectivity in cortico-striatal regions are associated with reward cue processing, particularly in girls. Longitudinal follow-up neuroimaging studies are needed to fully characterize puberty-specific effects on the development of these neural regions and how such changes may contribute to pathways of risk or resilience in adolescence.

Recent studies suggested that genetics contribute to differences in dental fluorosis (DF) susceptibility among individuals having the same environmental exposure. This study evaluated if MMP2, MMP9 and MMP20 are expressed during enamel development and assessed the association between polymorphisms in these genes with DF. Mice susceptible and resistant to DF were used to evaluate if MMPs were candidate genes for DF. The animals received fluoride and their enamels were used for immunohistochemistry. Additionally, 481 subjects from a city with fluoridation of public water supplies were recruited. Genotyping was performed using real time PCR. Allele/genotype frequencies were compared between groups. MMP2, MMP9 and MMP20 immunostaining was detected in both animal groups. DF was observed in 22.4% of the subjects. A borderline association was observed in MMP2 (rs243865), MMP9 (rs17576) and in MMP20 (rs1784418) (p = 0.06, p = 0.08 and p = 0.06 respectively). Briefly, MMPs were expressed during enamel maturation and genetic polymorphisms were not associated with DF.

Chronic stressors, such as chronic isolation in social mammals, can elevate glucocorticoids, which can affect cellular mechanisms of aging, including increased levels of oxidative stress and shortened telomere lengths. Recent work in the selectively social prairie vole (Microtus ochrogaster) suggests that oxytocin and social support may mitigate some of the negative consequences of social isolation, possibly by reducing glucocorticoid levels. We investigated the influences of isolation, social support, and daily oxytocin injections in female prairie voles. Glucocorticoid levels, oxidative damage, telomere length, and anhedonia, a behavioral index of depression, were measured throughout the study. We found that six weeks of chronic isolation led to increased glucocorticoid levels, oxidative damage, telomere degradation and anhedonia. However, daily oxytocin injections in isolated voles prevented these negative consequences. These findings demonstrate that chronic social isolation in female prairie voles is a potent stressor that results in depression-like behavior and accelerated cellular aging. Importantly, oxytocin can completely prevent the negative consequences of social isolation.

Emotion dysregulation and hyperreactivity are considered central features of Borderline Personality Disorder (BPD). We assumed that such emotion dysregulation is also reflected in increased crying behavior of these patients and, consequently, hypothesized that BPD patients (N = 62), compared to Cluster C personality disorder patients (Cluster C-PD; N = 25) and non-patients (N = 54), would show higher scores on crying measures. To evaluate crying behavior, we used a set of specially designed tools. Compared to non-patients, BPD patients showed the anticipated higher crying frequency despite a similar crying proneness and ways of dealing with tears. They also reported less awareness of the influence of crying on others. However, Cluster C-PD patients showed a very similar pattern of findings. Overall, our results suggest that the increased crying of BPD patients likely results from environmental factors or the misperception of situations, rather than from stable traits. Remarkable is that the observed discrepancies in crying behavior compared to non-patients seem to be similar for Cluster-C PDs and BPD.

Although prior meta-analyses have significantly enriched the available literature on the comorbidity of substance use disorders (SUD) among individuals with eating disorders (ED), there have been few, recent, comprehensive reviews, and limited meta-analyses that include a range of SUDs.

As one of the most essential genome guardians, p53 and its mutants have been suggested associated with many types of cancers. Many p53 mutants function induce unique phenotypes, including carcinogenesis, metastasis, and drug resistance. The p53(R249S) mutation is the most prevalent and specific mutation associated with liver cancer development. Here, we demonstrate the generation of a heterozygous p53(R249S) mutation in the H9 human embryonic stem cell line using TALEN-mediated genome editing. The generated cell line maintains a normal karyotype, a pluripotent state and the in vivo capacity to develop a teratoma containing all three germ layer tissues.

Epigenome-wide DNA methylation has not been studied in men perinatally exposed to PCBs and dioxins. Therefore, we examined whether perinatal exposure to polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs) induces sustained methylation changes lasting to early adulthood. We used the Illumina HumanMethylation450 BeadChip to assess DNA methylation in whole blood among Yucheng second generation (people perinatal exposed to high PCBs and PCDFs) compared with referents. Thirty male offspring from the Yucheng cohort were randomly selected and matched with 30 male offspring from the Yucheng' neighborhood referents with similar backgrounds. Methylation differences between the Yucheng second generation and non-exposed referents were identified using a P value < 1.06 × 10-7. Differential DNA methylation with epigenome-wide statistical significance was observed for 20 CpGs mapped to 11 genes, and 19 CpGs were correlated with gestational levels of PCBs or PCDF toxic equivalency (PCDF-TEQ) with the same direction of effect. Among the 11 genes, AHRR and CYP1A1 are involved in the aryl hydrocarbon receptor signaling pathway known to mediate dioxin toxicity. MYO1G, FRMD4A, ARL4C, OLFM1, and WWC3 were previously reported to be related to carcinogenesis. This is the first study examining genome-wide DNA methylation among people perinatally exposed to high concentrations of PCBs and PCDFs. We observed novel differential methylation of several genes, indicating that modifications of DNA methylation associated with perinatal PCB and PCDF exposure may persist in exposed offspring for more than 20 years. Furthermore, involvement of several carcinogesis-related genes suggested a potential in utero epigenetic mechanisms.

Reducing doses of antiretroviral drugs, including stavudine (d4T), may lower toxicity, while preserving efficacy. There are substantial concerns about renal and bone toxicities of tenofovir disoproxil fumarate (TDF).

Recent literature suggests that alterations in both neural and structural components of the neuromuscular system are major determinants of knee extensor muscle weakness after total knee arthroplasty (TKA). Therefore, the goal of this study was to investigate the maximal voluntary strength (MVS), voluntary muscle activation (VMA), and the cross-sectional area (CSA) of the muscle, up to 33 months after the TKA.  We searched relevant scientific databases and literature for outcomes of interest, including quadriceps MVS, VMA, and CSA. Ten studies met the inclusion criteria and involved a total of 289 patients. The quality of the studies was evaluated by Methodological Index for Non-Randomized Studies (MINORS). Results showed that quadriceps MVS markedly declines in the early postoperative period, after which it slowly and linearly recovers over time. However, the same phenomenon was not observed for VMA and CSA, which were not significantly altered after the TKA. Furthermore, a meta-regression analysis revealed that the change in VMA accounted for 39% of the relative change in quadriceps strength (R2=0.39; p=0.015) in the early postoperative period. Patients treated with TKA had considerable weakness of the quadriceps muscle, which was detectable up to 3 months after surgery. Although the change in VMA largely explains quadriceps weakness, this change and CSA differences were not significant, suggesting that other neural correlates, such as hamstrings coactivation, might alter quadriceps muscle function. Thus, more attention should be paid to address VMA failure and coactivation of antagonist muscles.  More comprehensive rehabilitation approaches may be required to target the whole neural circuit controlling the motor action.

Resistance to endocrine therapy remains a clinical challenge in the treatment of estrogen receptor-positive (ER+) breast cancer. We investigated if adding a traditional Asian herbal mixture consisting of 12 herbs, called Jaeumkanghwa-tang (JEKHT), to tamoxifen (TAM) therapy might prevent resistance and recurrence in the ER+ breast cancer model of 7,12-dimethylbenz[a]anthracene (DMBA)-exposed Sprague-Dawley rats. Rats were divided into four groups treated as follows: 15 mg/kg TAM administered via diet as TAM citrate (TAM only); 500 mg/kg JEKHT administered via drinking water (JEKHT only group); TAM + JEKHT and no treatment control group. The study was replicated using two different batches of JEKHT. In both studies, a significantly higher proportion of ER+ mammary tumors responded to TAM if animals also were treated with JEKHT (experiment 1: 47% vs 65%, P = 0.015; experiment 2: 43% vs 77%, P < 0.001). The risk of local recurrence also was reduced (31% vs 12%, P = 0.002). JEKHT alone was mostly ineffective. In addition, JEKHT prevented the development of premalignant endometrial lesions in TAM-treated rats (20% in TAM only vs 0% in TAM + JEKHT). Co-treatment of antiestrogen-resistant LCC9 human breast cancer cells with 1.6 mg/mL JEKHT reversed their TAM resistance in dose-response studies in vitro. Several traditional herbal medicine preparations can exhibit anti-inflammatory properties and may increase anti-tumor immune activities in the tumor microenvironment. In the tumors of rats treated with both JEKHT and TAM, expression of Il-6 (P = 0.03), Foxp3/T regulatory cell (Treg) marker (P = 0.033) and Tgfβ1 that activates Tregs (P < 0.001) were significantly downregulated compared with TAM only group. These findings indicate that JEKHT may prevent TAM-induced evasion of tumor immune responses.

Lung cancer is the most common adult malignancy accounting for the largest proportion of cancer related deaths. Iron (Fe) is an essential trace element and is a component of several major metabolic pathways playing an important role in many physiological processes. In this study we evaluated the association between Fe concentration in serum, iron metabolism parameters and genetic variaton in 7 genes involved in iron metabolism and anti-oxidative processes with the incidence of lung cancer in Poland.

Multiple studies have revealed that adolescent AIDS orphans have more psychosocial problems than healthy adolescents. However, little is known about whether and how the brain structures of adolescent AIDS orphans differ from those of healthy adolescents. Here, we used magnetic resonance imaging to compare adolescent AIDS orphans reared in institutions (N = 20) with a sex- and age-matched group of healthy adolescents reared in families (N = 20) in China using a voxel-based morphometry analysis. First, we found that both total gray- and white-matter volumes did not differ between groups. Second, after correcting for age, sex, and total gray-matter volume, the AIDS orphan group demonstrated smaller hippocampal volumes, larger anterior cingulate cortex (ACC) volumes, and no differences in the amygdala. Third, a whole-brain analysis identified higher gray-matter volume of the ACC in the AIDS orphan group than in the control group. The preliminary findings of this study highlight the need for future research to confirm the sensitivity of the hippocampus and ACC to early adversity.

Reducing the number of influenza A virus (IAV) infected pigs at weaning is critical to minimize IAV spread to other farms. Sow vaccination is a common measure to reduce influenza levels at weaning. However, the impact of maternally-derived antibodies on IAV infection dynamics in growing pigs is poorly understood. We evaluated the effect of maternally-derived antibodies at weaning on IAV prevalence at weaning, time of influenza infection, number of weeks that pigs tested IAV positive, and estimated quantity of IAV in nursery pigs. We evaluated 301 pigs within 10 cohorts for their influenza serological (seroprevalence estimated by hemagglutination inhibition (HI) test) and virological (prevalence) status. Nasal swabs were collected weekly and pigs were bled 3 times throughout the nursery period. There was significant variability in influenza seroprevalence, HI titers and influenza prevalence after weaning. Increase in influenza seroprevalence at weaning was associated with low influenza prevalence at weaning and delayed time to IAV infection throughout the nursery. Piglets with IAV HI titers of 40 or higher at weaning were also less likely to test IAV positive at weaning, took longer to become infected, tested IAV RT-PCR positive for fewer weeks, and had higher IAV RT-PCR cycle threshold values compared to piglets with HI titers less than 40. Our findings suggest that sow vaccination or infection status that results in high levels of IAV strain-specific maternally-derived antibodies may help to reduce IAV circulation in both suckling and nursery pigs.

Understanding whether captive-reared animals destined to reintroduction are still able to discriminate predators has important implications for conservation biology. The endangered European hamster benefits from conservation programs throughout Europe, in which several thousand individuals are released into the wild every year. Despite this, the anti-predator strategy of hamsters and their ability to maintain predator discrimination in captivity remain to be investigated. Here, we explore the predator discrimination behaviour of captive-reared European hamsters and their response to different predation cues. When first exposed to the urine of cats and goats in a Y-maze test, hamsters spent more time close to the cat scent rather than to the goat scent. In a second experiment, during which hamsters were exposed to a non-mobile European ferret (inside a cage), hamsters significantly increased the time spent close to the ferret's cage and displayed aggressive behaviour towards the ferret. Furthermore, they did not take refuge inside an anti-predation tube (APT), a device designed to upgrade wildlife underpasses and reconnect wild hamster populations. Finally, when exposed to a mobile ferret (but without physical contact), hamsters displayed mobbing and aggressive behaviours towards the ferret, before taking refuge inside the APT. Taken together, our results show that captive-reared hamsters are still able to detect and react to predation cues, but that they initially adopt an offensive strategy (grunting, spitting, mobbing) during the risk-assessment phase. After risk assessment, however, hamsters used the APT as a refuge. Our study provides important insights into the anti-predator behaviour of hamsters. Testing the efficacy of the APT, a device that will allow upgrading wildlife underpasses for the hamster and other rodents, is also of great importance and is instrumental in conservation efforts for these species.

Colorectal cancer (CRC) is the second most common cancer in women and the third most common cancer in men globally. The identification of differentially expressed genes associated to patient's clinical data may represent a useful approach to find important genes in CRC carcinogenesis. Previously, the TULP3 transcription factor was identified as a possible prognostic biomarker in pancreatic ductal adenocarcinoma. Considering that pancreatic and colorectal tissues have the same embryonic origin, we investigated the profile of TULP3 expression in CRC hypothesizing that it may have a role in its development. We comparatively analysed TULP3 gene expression in CRC and normal adjacent colonic tissue and assessed association of expression profiles with survival and clinicopathological information, using publicly available datasets. TULP3 expression levels were increased in CRC when compared to the adjacent non-tumoral tissue. In addition, higher TULP3 gene expression was associated to lymphatic and vascular invasion in colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ), respectively. In summary, our results point to a possible role of TULP3 as a diagnostic and prognostic biomarker in CRC. Additional studies are necessary to confirm these preliminary findings.

Human viral pathogens are a major public health threat. Reliable information that accurately describes and characterizes the global occurrence and transmission of human viruses is essential to support national and global priority setting, public health actions, and treatment decisions. However, large areas of the globe are currently without surveillance due to limited health care infrastructure and lack of international cooperation. We propose a novel surveillance strategy, using metagenomic analysis of toilet material from international air flights as a method for worldwide viral disease surveillance. The aim of this study was to design, implement, and evaluate a method for viral analysis of airplane toilet waste enabling simultaneous detection and quantification of a wide range of human viral pathogens. Toilet waste from 19 international airplanes was analyzed for viral content, using viral capture probes followed by high-throughput sequencing. Numerous human pathogens were detected including enteric and respiratory viruses. Several geographic trends were observed with samples originating from South Asia having significantly higher viral species richness as well as higher abundances of salivirus A, aichivirus A and enterovirus B, compared to samples originating from North Asia and North America. In addition, certain city specific trends were observed, including high numbers of rotaviruses in airplanes departing from Islamabad. Based on this study we believe that central sampling and analysis at international airports could be a useful supplement for global viral surveillance, valuable for outbreak detection and for guiding public health resources.

The whipworm Trichuris trichiura is a soil-transmitted helminth that dwells in the epithelium of the caecum and proximal colon of their hosts causing the human disease, trichuriasis. Trichuriasis is characterized by colitis attributed to the inflammatory response elicited by the parasite while tunnelling through intestinal epithelial cells (IECs). The IL-10 family of receptors, comprising combinations of subunits IL-10Rα, IL-10Rβ, IL-22Rα and IL-28Rα, modulates intestinal inflammatory responses. Here we carefully dissected the role of these subunits in the resistance of mice to infection with T. muris, a mouse model of the human whipworm T. trichiura. Our findings demonstrate that whilst IL-22Rα and IL-28Rα are dispensable in the host response to whipworms, IL-10 signalling through IL-10Rα and IL-10Rβ is essential to control caecal pathology, worm expulsion and survival during T. muris infections. We show that deficiency of IL-10, IL-10Rα and IL-10Rβ results in dysbiosis of the caecal microbiota characterised by expanded populations of opportunistic bacteria of the families Enterococcaceae and Enterobacteriaceae. Moreover, breakdown of the epithelial barrier after whipworm infection in IL-10, IL-10Rα and IL-10Rβ-deficient mice, allows the translocation of these opportunistic pathogens or their excretory products to the liver causing organ failure and lethal disease. Importantly, bone marrow chimera experiments indicate that signalling through IL-10Rα and IL-10Rβ in haematopoietic cells, but not IECs, is crucial to control worm expulsion and immunopathology. These findings are supported by worm expulsion upon infection of conditional mutant mice for the IL-10Rα on IECs. Our findings emphasize the pivotal and complex role of systemic IL-10Rα signalling on immune cells in promoting microbiota homeostasis and maintaining the intestinal epithelial barrier, thus preventing immunopathology during whipworm infections.

The study of drug toxicity in human organs is complicated by their complex inter-relations and by the obvious difficulty to testing drug effects on biologically relevant material. Animal models and human cell cultures offer alternatives for systematic and large-scale profiling of drug effects on gene expression level, as typically found in the so-called toxicogenomics datasets. However, the complexity of these data, which includes variable drug doses, time points, and experimental setups, makes it difficult to choose and integrate the data, and to evaluate the appropriateness of one or another model system to study drug toxicity (of particular drugs) of particular human organs. Here, we define a protocol to integrate drug-wise rankings of gene expression changes in toxicogenomics data, which we apply to the TG-GATEs dataset, to prioritize genes for association to drug toxicity in liver or kidney. Contrast of the results with sets of known human genes associated to drug toxicity in the literature allows to compare different rank aggregation approaches for the task at hand. Collectively, ranks from multiple models point to genes not previously associated to toxicity, notably, the PCNA clamp associated factor (PCLAF), and genes regulated by the master regulator of the antioxidant response NFE2L2, such as NQO1 and SRXN1. In addition, comparing gene ranks from different models allowed us to evaluate striking differences in terms of toxicity-associated genes between human and rat hepatocytes or between rat liver and rat hepatocytes. We interpret these results to point to the different molecular functions associated to organ toxicity that are best described by each model. We conclude that the expected production of toxicogenomics panels with larger numbers of drugs and models, in combination with the ongoing increase of the experimental literature in organ toxicity, will lead to increasingly better associations of genes for organism toxicity.

During Xenopus fertilization, the initial intracellular calcium ((Ca2+)i) release at the sperm-egg binding site (hot spot) has not been described without the use of inhibitors, nor related to underlying ER structure. Without inhibitors, we now report that sperm induce an initial hot spot after sperm addition to Xenopus eggs that was ~25 µm. This area is consistent with the size of ER patches and clusters of IP3 receptors that have enhanced activity. Furthermore, we find a new mechanism for the fertilization (Ca2+)i wave; instead of outward diffusion of inositol 1,4,5-trisphosphate (IP3), we find that the wave was generated by an outward, clockwise rotation of a ~63 µm disk of elevated (Ca2+)i moving very rapidly at ~65 µm/s. We also suggest a new mechanism for the acceleration of the fertilization (Ca2+)i wave as the disk accelerated and was joined by other rotating disks (some rotating counterclockwise) at a time when the speed of the (Ca2+)i wave increases. To examine the role of phosphatidic acid (PA) in the release of (Ca2+)i during Xenopus fertilization, we find that two inhibitors of PA production delayed the appearance of fertilization hot spots by ~9-12 min but did not reduce the size of hot spots and actually accelerated the later (Ca2+)i wave. Surprisingly, global addition of PA to Xenopus eggs induced localized hot spots at a time and size that was similar to those induced after sperm addition. In contrast, sperm induce a rapid (Ca2+)i wave (~4 µm/s) within ~30 s after hot spot appearance, whereas hot spots induced by PA required an ~32 min to induce a very slow (~1 µm/s) (Ca2+)i wave with a lower peak of (Ca2+)i. Thus, PA may not be required for the initial release of (Ca2+)i at the sperm-egg binding site, but mimics sperm by inducing a similarly sized localized (Ca2+)i release. As compared with sperm, PA may induce a weak, slow (Ca2+)i wave by slowly increasing IP3 receptor clustering. Addition of PA to Xenopus oocytes, or Ca2+ ionophore to either Xenopus oocytes or eggs, did not induce hot spots but a global (Ca2+)i wave that rapidly moved at ~12 µm/s.