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Whipple pneumonia is a rare, chronic, multiorgan disease, with symptoms including arthritis, diarrhea, and weight loss. Diagnosis is traditionally confirmed by a histologic examination of a small bowel biopsy (1). [...]

Introduction The value of postoperative radiotherapy (PORT) for resected stage IIIA-N2 non-small-cell lung cancer (NSCLC) is controversial with few studies focusing on whether PORT always plays a part in clinical practice and generates benefits to patients across different time periods. We investigated this issue using the Surveillance, Epidemiology, and End Results Database (SEER) and assessed the temporal trends spanning 27 years. Methods Within SEER, we selected stage IIIA-N2 NSCLC patients who underwent a lobectomy or pneumonectomy and coded as receiving PORT or never receiving radiotherapy over three time periods: 1988 to 1996, 1997 to 2005, 2006 to 2014. For each period, survival analyses were performed and propensity score matching (PSM) was used in the potentially beneficial subgroup. Results 45.4% of 5568 eligible patients received PORT. The yearly PORT use rates varied largely from 27.8% to 74.4%. Overall survival (OS) was distinctly improved over the period. The application of PORT had a significant impact on survival only in period 1 and 3. In subgroup analysis, the OS benefit of PORT was significant in each period in patients with 50% or more lymph node ratio (LNR) both before (hazard ratios, and P values of 0.647, P = .002; 0.804, P = .008; 0.721, P < .001 for period 1, 2, 3, respectively) and after PSM (0.642, P = .006; 0.785, P = .004; 0.748, P = .003 for period 1, 2, 3, respectively). Conclusions The benefits of PORT are lasting and stable throughout the years in patients with LNR of 50% or more. This might provide a clue on proper patient selection for PORT application., Author(s): Wan-Qin Zeng [sup.1] , Wen Feng [sup.1] , Li Xie [sup.2] , Chen-Chen Zhang [sup.1] , Wen Yu [sup.1] , Xu-Wei Cai [sup.1] , Xiao-Long Fu [sup.1] Author Affiliations: [...]

Background: Previous studies have indicated that pain‐related diseases can result in significant functional alterations in the brain. However, differences in spontaneous brain activity in toothache (TA) patients remain unclear. Objective: To investigate altered spontaneous brain activity in patients with TA and its underlying mechanisms using the resting‐state functional magnetic resonance imaging–fractional amplitude of low‐frequency fluctuation (rsfMRI–fALFF) technique. Methods: Twelve patients with TA and 12 non‐toothache controls (NTCs) (matched for sex, age, and level of education) were enrolled. Spontaneous cerebral activity variations were investigated using the rsfMRI–fALFF technique in all individuals. The mean fALFF values of the TA patients and NTCs were classified using receiver operating characteristic (ROC) curves. The correlations between fALFF signals of distinct brain regions and clinical manifestations of TA patients were evaluated using Pearson's correlation analysis. Results: TA patients showed lower fALFF values in the left superior frontal gyrus, medial; right superior frontal gyrus, dorsolateral; and left median cingulate and paracingulate gyri (LDCG) than the NTCs. Moreover, ROC curve analysis indicated that the area under the curve of each cerebral region studied had high accuracy. Besides, in the TA group, the visual analog scale score was negatively correlated with fALFF signal values of the LDCG (r =.962, p <.001). Conclusion: Abnormal spontaneous activity was detected in numerous brain regions in patients with TA, which may be valuable for understanding the brain processing mechanism underlying TA. These regional changes in brain activity may serve as effective clinical indicators of TA. [ABSTRACT FROM AUTHOR]

Disturbed inhibitory synaptic transmission has functional impacts on neurodevelopmental and psychiatric disorders. An essential mechanism for modulating inhibitory synaptic transmission is alteration of the postsynaptic abundance of GABAARs, which are stabilized by postsynaptic scaffold proteins and recruited by presynaptic signals. However, how GABAergic neurons trigger signals to transsynaptically recruit GABAARs remains elusive. Here, we show that UNC-43/CaMKII functions at GABAergic neurons to recruit GABAARs and modulate inhibitory synaptic transmission at C. elegans neuromuscular junctions. We demonstrate that UNC-43 promotes presynaptic MADD-4B/Punctin secretion and NRX-1α/Neurexin surface delivery. Together, MADD-4B and NRX-1α recruit postsynaptic NLG-1/Neuroligin and stabilize GABAARs. Further, the excitation of GABAergic neurons potentiates the recruitment of NLG-1-stabilized-GABAARs, which depends on UNC-43, MADD-4B, and NRX-1. These data all support that UNC-43 triggers MADD-4B and NRX-1α, which act as anterograde signals to recruit postsynaptic GABAARs. Thus, our findings elucidate a mechanism for pre- and postsynaptic communication and inhibitory synaptic transmission and plasticity. The pre-and postsynaptic communication is critical for faithful synaptic transmission and induction of synaptic plasticity. Here, the authors found that CaMKII functions at GABAergic neurons to recruit GABAARs by triggering anterograde signals. [ABSTRACT FROM AUTHOR]

Because hydrogen sulfide (H2S) is classified as a gaseous signaling molecule, protein S-sulfhydration is known to be one of the mechanisms by which H2S signals are conducted. PTP1B, a negative regulator in insulin signaling, has been found to be S-sulfhydrated at Cys215-SH to form Cys215-SSH in response to endoplasmic reticulum (ER) stress. Therefore, we aimed to understand the change in PTP1B S-sulfhydration and cellular redox homeostasis in response to insulin stimulation. We demonstrated a feasible PEG-switch method to determine the levels of PTP1B S-sulfhydration. According to the results obtained from HEK293T and MDA-MB-231 cells, insulin induced a change in PTP1B S-sulfhydration that was similar to the change in Insulin receptor substrate 1 (IRS1) phosphorylation in both cell lines. However, insulin-induced PTP1B S-sulfhydration and IRS1 phosphorylation were only significantly affected by metformin in HEK293T cells. Insulin also induced an increase in reactive oxygen species (ROS) in both cell lines. However, the level of H2S, GSH, and GSSG was only significantly affected by insulin and metformin in HEK293T cells. HEK293T cells maintained high levels of H2S and cysteine, but low levels of GSSG and GSH in general compared to MDA-MB-231 cells. From these findings, we suggest that PTP1B activity is modulated by H2S and redox-regulated S-sulfhydration during insulin signaling. [ABSTRACT FROM AUTHOR]

Hedgehog (Hh) signaling pathway plays a pivotal role in embryonic development. Hh binding to Patched1 (PTCH1) derepresses Smoothened (SMO), thereby activating the downstream signal transduction. Covalent SMO modification by cholesterol in its cysteine‐rich domain (CRD) is essential for SMO function. SMO cholesterylation is a calcium‐accelerated autoprocessing reaction, and STIM1‐ORAI1‐mediated store‐operated calcium entry promotes cholesterylation and activation of endosome‐localized SMO. However, it is unknown whether the Hh‐PTCH1 interplay regulates the activity of the endoplasmic reticulum (ER)‐localized SMO. Here, we found that PTCH1 inhibited the COPII‐dependent export of SMO from the ER, whereas Hh promoted this process. The RRxWxR amino acid motif in the cytosolic tail of SMO was essential for COPII recognition, ciliary localization, and signal transduction activity. Hh and PTCH1 regulated cholesterol modification of the ER‐localized SMO, and SMO cholesterylation accelerated its exit from ER. The GRAMD1/ASTER sterol transport proteins facilitated cholesterol transfer to ER from PM, resulting in increased SMO cholesterylation and enhanced Hh signaling. Collectively, we reveal a regulatory role of GRAMD‐mediated cholesterol transport in ER‐resident SMO maturation and Hh signaling. Synopsis: Cholesterol modification of Smoothened (SMO) is essential for Hedgehog signaling pathway activation. Here, cholesterol transport proteins GRAMD1s/ASTERs are shown to promote SMO cholesterylation in the endoplasmic reticulum (ER), thus accelerating its ER exit. SMO export from the ER is increased by Hedgehog and decreased by Patched1.The RRxWxR motif in the cytosolic tail of SMO is essential for its COPII recognition, ER exit, and ciliary localization.SMO cholesterylation promotes its export from the ER.GRAMD1/ASTER proteins transfer cholesterol from plasma membrane to ER and promote SMO cholesterylation. [ABSTRACT FROM AUTHOR]

In this study, dinuclear cobalt complexes (1 and 2) featuring bis(benzimidazole)pyrazolide‐type ligands (H2L and Me2L) were prepared and evaluated as molecular electrocatalysts for water oxidation. Notably, 1 bearing a non‐innocent ligand (H2L) displayed faster catalytic turnover than 2 under alkaline conditions, and the base dependence of water oxidation and kinetic isotope effect analysis indicated that the reaction mediated by 1 proceeded by a different mechanism relative to 2. Spectroelectrochemical, cold‐spray ionization mass spectrometric and computational studies found that double deprotonation of 1 under alkaline conditions cathodically shifted the catalysis‐initiating potential and further altered the turnover‐limiting step from nucleophilic water attack on (H2L)CoIII2(superoxo) to deprotonation of (L)CoIII2(OH)2. The rate–overpotential analysis and catalytic Tafel plots showed that 1 exhibited a significantly higher rate than previously reported Ru‐based dinuclear electrocatalysts at similar overpotentials. These observations suggest that using non‐innocent ligands is a valuable strategy for designing effective metal‐based molecular water oxidation catalysts. [ABSTRACT FROM AUTHOR]

Changes in neurotransmitter receptor abundance at post-synaptic elements play a pivotal role in regulating synaptic strength. For this reason, there is significant interest in identifying and characterizing the scaffolds required for receptor localization at different synapses. Here we analyze the role of two C. elegans post-synaptic scaffolding proteins (LIN-2/CASK and FRM-3/FARP) at cholinergic neuromuscular junctions. Constitutive knockouts or muscle specific inactivation of lin-2 and frm-3 dramatically reduced spontaneous and evoked post-synaptic currents. These synaptic defects resulted from the decreased abundance of two classes of post-synaptic ionotropic acetylcholine receptors (ACR-16/CHRNA7 and levamisole-activated AChRs). LIN-2's AChR scaffolding function is mediated by its SH3 and PDZ domains, which interact with AChRs and FRM-3/FARP, respectively. Thus, our findings show that post-synaptic LIN-2/FRM-3 complexes promote cholinergic synaptic transmission by recruiting AChRs to post-synaptic elements. Author summary: Post-synaptic receptors are immobilized to form clusters at synapses. This process requires the participation of scaffolding proteins, and is thought to be of critical importance in central neurotransmission, ensuring the synaptic efficiency and fidelity. Here we report that two scaffold proteins, LIN-2/CASK and FRM-3/FARP, function as major synaptic organizers at C. elegans cholinergic neuromuscular junctions. LIN-2/CASK belongs to the MAGUK protein family and has been found to be important for cellular junctions. Knockout of lin-2 or frm-3 leads to severe defects in cholinergic synaptic transmission, with the mEPSC (miniature excitatory postsynaptic current) amplitude and synaptic localization of ionotropic acetylcholine receptors (AChRs) being dramatically reduced in lin-2 and frm-3 mutants. Conditional knockout of lin-2 or frm-3 in body wall muscles produced all phenotypes observed in the constitutive mutants, demonstrating that LIN-2/CASK and FRM-3/FARP function postsynaptically, regulating synaptic localization of AChRs. The function of LIN-2/CASK requires its SH3 and PDZ domains, which mediate interaction with AChRs and FRM-3. Collectively, our results have shown that scaffolding proteins LIN-2/CASK and FRM-3/FARP regulate postsynaptic AChRs, thereby promoting cholinergic synaptic transmission. [ABSTRACT FROM AUTHOR]

[Display omitted] Three new anthraquinones (1 – 3), together with four known analogues (4 – 7) were isolated from the twigs of Cassia auriculata Linn.. Their structures were elucidated by extensive spectroscopic analysis and comparison of spectroscopic data with those reported in literatures. All compounds were tested for their anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activity. Compounds 1 , 2 and 7 showed modest antibacterial activity against MRSA with MIC values of 4.2, 5.0, 4.7 μ g/mL, and compounds 3 , 4 , 5 and 6 showed weak antibacterial activity against MRSA with MIC valves of 9.2, 7.6, 7.1, 9.6 μ g/mL, respectively. [ABSTRACT FROM AUTHOR]

This paper presents a method that allows two wheeled, mobile robots to navigate unknown environments while cooperatively carrying an object. In the navigation method, a leader robot and a follower robot cooperatively perform either obstacle boundary following (OBF) or target seeking (TS) to reach a destination. The two robots are controlled by fuzzy controllers (FC) whose rules are learned through an adaptive fusion of continuous ant colony optimization and particle swarm optimization (AF-CACPSO), which avoids the time-consuming task of manually designing the controllers. The AF-CACPSO-based evolutionary fuzzy control approach is first applied to the control of a single robot to perform OBF. The learning approach is then applied to achieve cooperative OBF with two robots, where an auxiliary FC designed with the AF-CACPSO is used to control the follower robot. For cooperative TS, a rule for coordination of the two robots is developed. To navigate cooperatively, a cooperative behavior supervisor is introduced to select between cooperative OBF and cooperative TS. The performance of the AF-CACPSO is verified through comparisons with various population-based optimization algorithms for the OBF learning problem. Simulations and experiments verify the effectiveness of the approach for cooperative navigation of two robots. [ABSTRACT FROM PUBLISHER]

BackgroundSince December 2019, an outbreak of the coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly in Wuhan and worldwide. However, previous studies on pregnant patients were limited. ObjectiveThe aim of this study is to evaluate the clinical characteristics and outcomes of pregnant and nonpregnant women with COVID-19. MethodsThis study retrospectively collected epidemiological, clinical, laboratory, imaging, management, and outcome data of 43 childbearing-age women patients (including 17 pregnant and 26 nonpregnant patients) who presented with laboratory-confirmed COVID-19 in Tongji Hospital, Wuhan, China from January 19 to March 2, 2020. Clinical outcomes were followed up to March 28, 2020. ResultsOf the 43 childbearing-age women in this study, none developed a severe adverse illness or died. The median ages of pregnant and nonpregnant women were 33.0 and 33.5 years, respectively. Pregnant women had a markedly higher proportion of history exposure to hospitals within 2 weeks before onset compared to nonpregnant women (9/17, 53% vs 5/26, 19%, P=.02) and a lower proportion of other family members affected (4/17, 24% vs 19/26, 73%, P=.004). Fever (8/17, 47% vs 18/26, 69%) and cough (9/17, 53% vs 12/26, 46%) were common onsets of symptoms for the two groups. Abdominal pain (n=4, 24%), vaginal bleeding (n=1, 6%), reduced fetal movement (n=1, 6%), and increased fetal movement (n=2, 13%) were observed at onset in the 17 pregnant patients. Higher neutrophil and lower lymphocyte percent were observed in the pregnant group compared to the nonpregnant group (79% vs 56%, P

Antenatal depression might cause adverse pregnancy outcomes. However, previous study results were inconsistent, especially in the low- and middle- income countries. We aimed to study the association between antenatal depression and adverse perinatal outcomes in a Chinese population. We performed a prospective cohort study and enrolled pregnant women from January 2020 to January 2021. Antenatal depressive symptoms in the third trimester of pregnancy were evaluated by the Edinburgh Postpartum Depression Scale (EPDS). Baseline characteristics and pregnancy outcomes were recorded. After adjusting for confounding factors (age, occupation, education level, and annual income), multivariate logistic regression analysis was applied to evaluate the associations between antenatal depression and pregnancy outcomes. Among the 5209 participants, 1448 (27.7 %) pregnant women were positive for depression. After adjusting for potential confounders, women with antenatal depressive symptoms were significantly more likely to deliver prematurely [Odds ratio (OR) = 1.404, 95 % confidence interval (CI) = 1.020–1.933, P = 0.037] and receive cesarean section (OR = 1.154, 95 % CI = 1.002–1.331, P = 0.048). EPDS, not a structured diagnostic interview, was used for psychological assessment. In addition, we only screened the women in their third trimester in a single research center. The association between the duration of antenatal depression and perinatal outcomes was not evaluated. Depressive symptoms were common among Chinese women in their third trimester of pregnancy. Women with antenatal depressive symptoms had increased cesarean section and preterm delivery risks. Screening and treatment for antenatal depression are needed during the prenatal care. [ABSTRACT FROM AUTHOR]

Background: Cognitive deficits are prevalent in bipolar disorder and are a significant contributor to negative patient-reported outcomes. Herein we conducted a pilot study of repetitive transcranial magnetic stimulation (rTMS) to improve cognitive function in adults with bipolar disorder.Methods: The study was a triple-blinded, randomized, placebo-control trial. Participants (aged 18 to 60) with a diagnosis of DSM-5-defined bipolar disorder (I or II) were recruited and randomized (N=36) to receive either a sham treatment (n=20) or an active rTMS treatment (n=16). Patients completed the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) at baseline and 1-2 weeks after the rTMS intervention.Results: A significant group by time interaction was observed in the Hopkins Verbal Learning Test-Revised (HVLT-R), (F (1, 34) = 17.0, p < 0.001, partial η2 = 0.33). Post-hoc analysis revealed that although both groups did not significantly differ at baseline (p = 0.58), patients in the active rTMS group significantly improved following neurostimulation (p = 0.02) for HVLT-R. Moreover, within-subject analysis indicated that the active rTMS group significantly improved in score from pre-treatment to post-treatment (p < 0.001), while the sham group did not improve (p = 0.94) for HVLT-R. No significant differences were seen in the other cognitive measures.Limitations: The study was conducted in a small sample .Conclusion: This pilot study, which was intended to establish feasibility, suggests that rTMS may offer benefit in select domains of cognitive functioning in bipolar disorder. None of the measures across subdomains revealed a dyscognitive effect. [ABSTRACT FROM AUTHOR]

• Research is needed to identify possible predictive factors for PORT in pN2 NSCLC patients. • The effect of PORT differs in subgroups of pN2 NSCLC patients. • PORT improves OS in patients at a high risk of LRR. This study aimed to evaluate the effect of postoperative radiotherapy (PORT) in patients with resected pathologic N2 (pN2) non–small cell lung cancer (NSCLC) with different locoregional recurrence (LRR) risks. The primary cohort and validation cohort were retrieved from two independent medical centres. Data for all consecutive patients with completely resected pathologic stage T1-3N2M0 NSCLC were analysed. Patients without PORT in the primary cohort were identified as a training set. Significant prognostic factors for LRR were identified by the Fine-Gray model to develop a prognostic index (PI) in the training set. The primary cohort consisted of 357 patients who met the eligibility criteria (training set, 287 patients without PORT). The external validation cohort consisted of 1044 patients who met the eligibility criteria (validation set, 711 patients without PORT). Heavy cigarette smoking history, clinical N2 status (cN2), and the number of positive lymph nodes >4 were identified as independent risk factors. The PI was computed as follows: PI＝0.8*smoking history＋0.5*cN2＋0.7*the number of involved lymph nodes (reference level was assigned the value 1 and risk level the value 2). In the low-risk group (PI score< = 3), PORT showed a trend towards decreased LRR rates but not significantly improved overall survival (OS). In the high-risk group (PI score>3), PORT significantly reduced the risk of LRR and improved OS. We constructed and validated a PI to predict individually the effect of PORT in patients with completely resected pN2 NSCLC. Patients with a higher PI score can benefit from PORT in terms of OS. [ABSTRACT FROM AUTHOR]