Somatosensory System Deficits in Schizophrenia Revealed by MEG during a Median-Nerve Oddball Task

Although impairments related to somatosensory perception are common in schizophrenia, they have rarely been examined in functional imaging studies. In the present study, magnetoencephalography (MEG) was used to identify neural networks that support attention to somatosensory stimuli in healthy adults and abnormalities in these networks in patient with schizophrenia. A median-nerve oddball task was used to probe attention to somatosensory stimuli, and an advanced, high-resolution MEG source-imaging method was applied to assess activity throughout the brain. In nineteen healthy subjects, attention-related activation was seen in a sensorimotor network involving primary somatosensory (S1), secondary somatosensory (S2), primary motor (M1), pre-motor (PMA), and paracentral lobule (PCL) areas. A frontal–parietal–temporal “attention network”, containing dorsal- and ventral–lateral prefrontal cortex (DLPFC and VLPFC), orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), superior parietal lobule (SPL), inferior parietal lobule (IPL)/supramarginal gyrus (SMG), and temporal lobe areas, was also activated. Seventeen individuals with schizophrenia showed early attention-related hyperactivations in S1 and M1 but hypo-activation in S1, S2, M1, and PMA at later latency in the sensorimotor network. Within this attention network, hypoactivation was found in SPL, DLPFC, orbitofrontal cortex, and the dorsal aspect of ACC. Hyperactivation was seen in SMG/IPL, frontal pole, and the ventral aspect of ACC in patients. These findings link attention-related somatosensory deficits to dysfunction in both sensorimotor and frontal–parietal–temporal networks in schizophrenia

Source and extent of the felsic volcanic ashes at the Permian-Triassic boundary in South China

Highly correlated with the Permian-Triassic Boundary (PTB) Mass Extinction in stratigraphy, volcanic ashes around the PTB in South China have been suggested to be a likely cause of the PTB Mass Extinction. So the nature, source and extent of the volcanic ashes are significant in figuring out the cause of the PTB Mass Extinction. In this study, we attempt to constrain the source and extent of the PTB volcanic ashes in South China by studying pyroclastic sedimentary rocks and the spatial distribution of tuffs and ashes in South China. The detrital zircons of tuffaceous sandstones from the Penglaitan section yield an age spectrum peaked at 252 Ma, with 80% of zircons U-Pb ages in 235 +/- 2.7 Ma similar to 258 +/- 4.8 Ma, 11% in 260 +/- 3.2 Ma similar to 276 +/- 3.6 Ma, six in 294 +/- 5.8 Ma similar to 561 +/- 6.9 Ma, five from Proterozoic, and the oldest age is 2063 +/- 13.4 Ma. The results of epsilon(Hf) (i) values varying from -16.5 similar to 5. 0, and Nb/Hf, Th/Nb and Hf/Th ratios of detrital zircons from the Penglaitan section are similar to those from arc/orogenic-related settings. Coarse tuffaceous sandstones (0. 5 similar to 2 mm) imply that their source is in limited distance. Those pyroclastic sedimentary rocks in Penglaitan are well correlated with the PTB volcanic ashes in Meishan GSSP section in stratigraphy. In the spatial distribution, pyroclastic sedimentary rocks and tuffs distribute only in southwest of South China, while finer volcanic ashes (< 0.3 mm) are mainly in the northern part. This spatial distribution suggests the source of tuffs and ashes was to the south or southwest of South China. Former studies, especially that of Permian-Triassic magmatism in Hainan Island and Early Mesozoic acid volcanic rocks in Southwest Guangxi have supported the existence of a continental arc related to the subduction and closure of Palaeo-Tethys on the southwestern margin of South China during Permian. It is suggested that the PTB ashes possibly derived from this Paleo-Tethys continental arc. The fact that contemporaneous volcanic ashes haven't been reported or found in North China or Northwest China implies a limited extent of the volcanism, which thus is too small to cause the PTB Mass Extinction

Evaluation of the Effect of Concurrent Chronic Total Occlusion and Successful Staged Revascularization on Long-Term Mortality in Patients with ST-Elevation Myocardial Infarction

Aims. To investigate the impact of chronic total occlusion (CTO) in non-infarct-related artery (IRA) on the long-term prognosis and evaluate the clinical significance of staged revascularization in patients with ST-segment elevation myocardial infarction (STEMI). Methods. 1266 STEMI patients with primary percutaneous coronary intervention (PCI) were categorized as single-vessel disease (SVD), multivessel disease (MVD) without and with CTO. We study the clinical outcomes of patients after primary PCI in the following 3 years. Additionally, patients with CTO received staged revascularization, and major adverse cardiac events (MACE) during 3-year follow-up were recorded. Results. Presence of CTO was a predictor of both early mortality [hazard ratio (HR) 3.4, 95% confidence interval (CI) 2.4–4.5, P<0.01] and late mortality (HR 1.9, 95% CI 1.4–3.6, P<0.01), whereas MVD without CTO was only a predictor of early mortality (HR 1.7, 95% CI 1.3–2.3, P<0.05). In CTO group, 100 patients had successful CTO recanalization, and 48 patients failed. During 3-year follow-up, patients with failed procedure had higher cardiac mortality (22.9% versus 9.0%, P=0.020) and lower MACE-free survival (50.0% versus 72.0%, P=0.009) compared to patients with successful procedure. Conclusion. The presence of CTO and not MVD alone is associated with long-term mortality. Successful revascularization of CTO in the non-IRA is associated with improved clinical outcomes in patients with STEMI undergoing primary PCI

Association of anaemia and all‐cause mortality in patients with ischaemic heart failure varies by renal function status

Abstract Aims The aims of the current study were to evaluate the association between anaemia and all‐cause mortality according to chronic kidney disease (CKD) status and to explore at what level of haemoglobin concentration would the all‐cause mortality risk increase prominently among CKD and non‐CKD patients, respectively. Methods and results This is a prospective cohort study, and 1559 patients with ischaemic heart failure (IHF) were included (mean age of 63.5 ± 11.0 years, 85.8% men) from December 2015 to June 2019. Patients were divided into the CKD (n = 481) and non‐CKD (n = 1078) groups based on the estimated glomerular filtration rate of 60 mL/min/1.73 m2. In the CKD group, the incidence rate of all‐cause mortality in anaemic and non‐anaemic patients was 15.4 per 100 person‐years and 10.8 per 100 person‐years, respectively, with an incidence rate ratio of 1.42 (95% confidence interval: 1.00–2.02; P‐value = 0.05). In the non‐CKD group, the incidence rate of all‐cause mortality in anaemic and non‐anaemic patients was 9.8 per 100 person‐years and 5.5 per 100 person‐years, respectively, with an incidence rate ratio of 1.78 (95% confidence interval: 1.20–2.59; P‐value = 0.005). After a median follow‐up of 2.1 years, the cumulative incidence rate of all‐cause mortality in anaemic and non‐anaemic patients was 41.5% and 44.1% (P‐value = 0.05) in the CKD group, and 30.9% and 18.1% (P‐value < 0.0001) in the non‐CKD group. In the CKD group, cumulative incidence rate of all‐cause mortality increased prominently when haemoglobin concentration was below 100 g/L, which was not observed in the non‐CKD group. Conclusions Results of the current study indicated that among IHF patients, the association between anaemia and all‐cause mortality differed by the renal function status. These findings underline the importance to assess mortality risk and manage anaemia among IHF patients according to the renal function status

A redox-responsive self-assembling COA-4-arm PEG prodrug nanosystem for dual drug delivery suppresses cancer metastasis and drug resistance by downregulating hsp90 expression

Metastasis and resistance are main causes to affect the outcome of the current anticancer therapies. Heat shock protein 90 (Hsp90) as an ATP-dependent molecular chaperone takes important role in the tumor metastasis and resistance. Targeting Hsp90 and downregulating its expression show promising in inhibiting tumor metastasis and resistance. In this study, a redox-responsive dual-drug nanocarrier was constructed for the effective delivery of a commonly used chemotherapeutic drug PTX, and a COA-modified 4-arm PEG polymer (4PSC) was synthesized. COA, an active component in oleanolic acid that exerts strong antitumor activity by downregulating Hsp90 expression, was used as a structural and functional element to endow 4PSC with redox responsiveness and Hsp90 inhibitory activity. Our results showed that 4PSC/PTX nanomicelles efficiently delivered PTX and COA to tumor locations without inducing systemic toxicity. By blocking the Hsp90 signaling pathway, 4PSC significantly enhanced the antitumor effect of PTX, inhibiting tumor proliferation and invasiveness as well as chemotherapy-induced resistance in vitro. Remarkable results were further confirmed in vivo with two preclinical tumor models. These findings demonstrate that the COA-modified 4PSC drug delivery nanosystem provides a potential platform for enhancing the efficacy of chemotherapies

Activation of Autophagic Flux Maintains Mitochondrial Homeostasis during Cardiac Ischemia/Reperfusion Injury

Reperfusion injury after extended ischemia accounts for approximately 50% of myocardial infarct size, and there is no standard therapy. HDAC inhibition reduces infarct size and enhances cardiomyocyte autophagy and PGC1α-mediated mitochondrial biogenesis when administered at the time of reperfusion. Furthermore, a specific autophagy-inducing peptide, Tat-Beclin 1 (TB), reduces infarct size when administered at the time of reperfusion. However, since SAHA affects multiple pathways in addition to inducing autophagy, whether autophagic flux induced by TB maintains mitochondrial homeostasis during ischemia/reperfusion (I/R) injury is unknown. We tested whether the augmentation of autophagic flux by TB has cardioprotection by preserving mitochondrial homeostasis both in vitro and in vivo. Wild-type mice were randomized into two groups: Tat-Scrambled (TS) peptide as the control and TB as the experimental group. Mice were subjected to I/R surgery (45 min coronary ligation, 24 h reperfusion). Autophagic flux, mitochondrial DNA (mtDNA), mitochondrial morphology, and mitochondrial dynamic genes were assayed. Cultured neonatal rat ventricular myocytes (NRVMs) were treated with a simulated I/R injury to verify cardiomyocyte specificity. The essential autophagy gene, ATG7, conditional cardiomyocyte-specific knockout (ATG7 cKO) mice, and isolated adult mouse ventricular myocytes (AMVMs) were used to evaluate the dependency of autophagy in adult cardiomyocytes. In NRVMs subjected to I/R, TB increased autophagic flux, mtDNA content, mitochondrial function, reduced reactive oxygen species (ROS), and mtDNA damage. Similarly, in the infarct border zone of the mouse heart, TB induced autophagy, increased mitochondrial size and mtDNA content, and promoted the expression of PGC1α and mitochondrial dynamic genes. Conversely, loss of ATG7 in AMVMs and in the myocardium of ATG7 cKO mice abolished the beneficial effects of TB on mitochondrial homeostasis. Thus, autophagic flux is a sufficient and essential process to mitigate myocardial reperfusion injury by maintaining mitochondrial homeostasis and partly by inducing PGC1α-mediated mitochondrial biogenesis

Discovery of Potent Small-Molecule Inhibitors of WDR5-MYC Interaction

WD repeat domain 5 (WDR5) is a member of the WD40-repeat protein family that plays a critical role in multiple processes and is also a prominent target for pharmacological inhibition in multiple disease such as cancer, aging and neurodegenerative disorders. Interaction between WDR5 and its various partners are essential for sustaining its function. Most drug-discovery efforts center on the WIN site of WDR5 that is responsible for the recruitment of WDR5 to chromatin. Here, we describe the discovery of novel WDR5 inhibitors for the other WBM pocket on this scaffold protein, to disrupt WDR5 interaction with its binding partner MYC by high-throughput biochemical screening, subsequent molecule optimization and biological assessment. These new WDR5 inhibitors provide useful probes for future investigations of WDR5 and an avenue for targeting WDR5 as a therapeutic strategy