Imbalance between hippocampal projection cell and parvalbumin interneuron architecture increases epileptic susceptibility in mouse model of methyl CpG binding protein 2 duplication syndrome.

OBJECTIVE: Methyl CpG-binding protein 2 (MECP2) duplication syndrome is a rare X-linked genomic disorder affecting predominantly males, which is usually manifested as epilepsy and autism spectrum disorder (ASD) comorbidity. The transgenic line MeCP2Tg1 was used for mimicking MECP2 duplication syndrome and showed autism-epilepsy co-occurrence. Previous works suggested that the excitatory/inhibitory (E/I) imbalance is a potential common mechanism for both epilepsy and ASD. The projection neurons and parvalbumin (PV) interneurons account for the majority of E/I balance in the hippocampus. Therefore, we explored how structural changes of projection and PV+ neurons occur in the hippocampus of MeCP2Tg1 mice and whether these morphological changes contribute to epilepsy susceptibility. METHODS: We used the interneuron Designer receptors exclusively activated by designer drugs mouse model to inhibit inhibitory neurons in the hippocampus to verify the epilepsy susceptibility of MeCP2Tg1 (FVB, an inbred strain named as sensitivity to Friend leukemia virus) mice. Electroencephalograms were recorded for the definition of seizure. We performed retro-orbital injection of virus in MeCP2Tg1 (FVB):CaMKIIα-Cre (C57BL/6) mice or MeCP2Tg1:PV-Cre (C57BL/6) mice and their littermate controls to specifically label projection and PV+ neurons for structural analysis. RESULTS: Epilepsy susceptibility was increased in MeCP2Tg1 mice. There was a reduced number of PV neurons and reduced dendritic complexity in the hippocampus of MeCP2Tg1 mice. The dendritic complexity in MeCP2Tg1 mice was increased compared to wild-type mice, and total dendritic spine density in dentate gyrus of MeCP2Tg1 mice was also increased. Total dendritic spine density was increased in CA1 of MeCP2Tg1 mice. SIGNIFICANCE: Overexpression of MeCP2 may disrupt crucial signaling pathways, resulting in decreased dendritic complexity of PV interneurons and increased dendritic spine density of projection neurons. This reciprocal modulation of excitatory and inhibitory neuronal structures associated with MeCP2 implies its significance as a potential target in the development of epilepsy and offers a novel perspective on the co-occurrence of autism and epilepsy.

Aberrant expression of thyroidal hormone receptor α exasperating mitochondrial dysfunction induced sarcopenia in aged mice.

Disrupted mitochondrial dynamics and mitophagy contribute to functional deterioration of skeletal muscle (SM) during aging, but the regulatory mechanisms are poorly understood. Our previous study demonstrated that the expression of thyroid hormone receptor α (TRα) decreased significantly in aged mice, suggesting that the alteration of thyroidal elements, especially the decreased TRα, might attenuate local THs action thus to cause the degeneration of SM with aging, while the underlying mechanism remains to be further explored. In this study, decreased expression of myogenic regulators Myf5, MyoD1, mitophagy markers Pink1, LC3II/I, p62, as well as mitochondrial dynamic factors Mfn1 and Opa1, accompanied by increased reactive oxygen species (ROS), showed concomitant changes with reduced TRα expression in aged mice. Further TRα loss- and gain-of-function studies in C2C12 revealed that silencing of TRα not only down-regulated the expression of above-mentioned myogenic regulators, mitophagy markers and mitochondrial dynamic factors, but also led to a significant decrease in mitochondrial activity and maximum respiratory capacity, as well as more mitochondrial ROS and damaged mitochondria. Notedly, overexpression of TRα could up-regulate the expression of those myogenic regulators, mitophagy markers and mitochondrial dynamic factors, meanwhile also led to an increase in mitochondrial activity and number. These results confirmed that TRα could concertedly regulate mitochondrial dynamics, autophagy, and activity, and myogenic regulators rhythmically altered with TRα expression. Summarily, these results suggested that the decline of TRα might cause the degeneration of SM with aging by regulating mitochondrial dynamics, mitophagy and myogenesis.

Development and validation of a deep learning-based approach to predict the Mayo endoscopic score of ulcerative colitis.

Background: The ulcerative colitis (UC) Mayo endoscopy score is a useful tool for evaluating the severity of UC in patients in clinical practice. Objectives: We aimed to develop and validate a deep learning-based approach to automatically predict the Mayo endoscopic score using UC endoscopic images. Design: A multicenter, diagnostic retrospective study. Methods: We collected 15120 colonoscopy images of 768 UC patients from two hospitals in China and developed a deep model based on a vision transformer named the UC-former. The performance of the UC-former was compared with that of six endoscopists on the internal test set. Furthermore, multicenter validation from three hospitals was also carried out to evaluate UC-former's generalization performance. Results: On the internal test set, the areas under the curve of Mayo 0, Mayo 1, Mayo 2, and Mayo 3 achieved by the UC-former were 0.998, 0.984, 0.973, and 0.990, respectively. The accuracy (ACC) achieved by the UC-former was 90.8%, which is higher than that achieved by the best senior endoscopist. For three multicenter external validations, the ACC was 82.4%, 85.0%, and 83.6%, respectively. Conclusions: The developed UC-former could achieve high ACC, fidelity, and stability to evaluate the severity of UC, which may provide potential application in clinical practice. Registration: This clinical trial was registered at the ClinicalTrials.gov (trial registration number: NCT05336773).

Why was this study done? The development of an auxiliary diagnostic tool can reduce the workload of endoscopists and achieve rapid assessment of ulcerative colitis (UC) severity. What did the researchers do? We developed and validated a deep learning-based approach to automatically predict the Mayo endoscopic score using UC endoscopic images. What did the researchers find? The model that was developed in this study achieved high accuracy, fidelity, and stability, and demonstrated potential application in clinical practice. What do the findings mean? Deep learning could effectively assist endoscopists in evaluating the severity of UC in patients using endoscopic images.

Common and rare variant associations with clonal haematopoiesis phenotypes.

Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes1-5. Here we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal haematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 24 loci (21 of which are novel) where germline genetic variation influences predisposition to CHIP, including missense variants in the lymphocytic antigen coding gene LY75, which are associated with reduced incidence of CHIP. We also identify novel rare variant associations with clonal haematopoiesis and telomere length. Analysis of 5,041 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID-19 outcomes, cardiovascular disease, haematologic traits, malignancy, smoking, obesity, infection and all-cause mortality. Longitudinal and Mendelian randomization analyses revealed that CHIP is associated with solid cancers, including non-melanoma skin cancer and lung cancer, and that CHIP linked to DNMT3A is associated with the subsequent development of myeloid but not lymphoid leukaemias. Additionally, contrary to previous findings from the initial 50,000 UKB exomes6, our results in the full sample do not support a role for IL-6 inhibition in reducing the risk of cardiovascular disease among CHIP carriers. Our findings demonstrate that CHIP represents a complex set of heterogeneous phenotypes with shared and unique germline genetic causes and varied clinical implications.

[The effectiveness of different respiration models to the amplitude of waveform information in arterial blood gas].

Objective: The objective is to find the characteristics of arterial blood sample waveform in different respiration models. Methods: Six post-operative patients with normal heart function and negative Allen test, were 4 male and 2 female, (59.00±16.64)year, (71.67±0.37)kg, left ventricular ejection fraction(LVEF) (61.33±2.16)%, had been placed the arterial catheterization and central venous catheterization for continuous collecting arterial in 3 different kinds of respiration models: normal breathing, no breathing and deep breathing. We selected two breaths cycles of waveform from each patient for data calculations of magnitudes and time interval. Compare the adjacent highest and lowest values of patients to verify whether there are periodic wave-like signal changes in arterial and venous blood gas in the three breathing states. In addition, statistical t-test analysis was performed on the change amplitude of the periodic wave-like signal of the patient's arterial and venous blood gas to compare whether there is a difference. Results: The heart beat numbers for drawing blood into pipe were 15-16, and all covered more than 2 breathing cycles. There were significant changes of arterial PaO2 (i.e. the highest high values compare to the next lowest values, P<0.05) in three different breathing models(normal, no breathing and high breathing), the magnitudes of which were (9.96±5.18)mmHg, (5.33±1.55)mmHg and (13.13±7.55)mmHg, with (8.09±2.43)%, (5.29±2.19)% and (10.40±2.68)% from their mean respectively. PO2 in venous blood gas did not show wavy changes under normal breathing, 20 s breath holding and high tidal volume ventilation. The amplitudes were (1.63 ± 0.41) mmHg, (1.13 ± 0.41) mmHg and (1.31 ± 0.67) mmHg, which were (3.91 ± 1.22)%, (2.92 ± 1.12)%, (3.33 ± 1.81)%, respectively, which were significantly lower than that of arterial blood gas under the same state, but there was no significant difference between groups. Conclusion: With continuous beat-by-beat arterial blood sampling and ABG analyzing method in three different breathing models, We obtain a clear evidence of the biggest periodic parameters ABG waveform in high breathing models, which followed by normal breathing models, no breathing was the smallest, and the wave variation amplitude of venous oxygen partial pressure was not obvious in the three respiratory states, which implies the oscillatory information of the arterial blood with comes from the gas exchanging in the lung.

[The experimental evidence of waveform information in arterial blood gas by beat-by-beat sampling method in human body-the differences of waveform information between arterial and venous blood samples].

Objective: The arterial blood with the oscillatory information comes from the right heart system after gas exchanging in the lung. However, the evidence of the waveform of venous ABG is lack. The objectives of this article are to compare the different information between arterial and venous beat-by-beat blood sample at the same time. Methods: Six post-operative patients with normal heart function and negative Allen test, had been placed the arterial catheterization and central venous catheterization directly connected to pre-heparin plasticpipes for continuous collecting arterial and venous blood. We twisted the 2 pipes into helix formation. After drawing arterial and venous blood with syringes in one heart beat with one helix at the same time, totally 15 heart beats, clipping the pipes with forceps, we put the helix pipe into icedwater at once and analyses PaO2, PaCO2, pH and SaO2 as soon as possible. We selected two breathscycles of waveform from each patient for data calculations of magnitudes and time interval. Results: The heart beat numbers for drawing blood into pipe were 15~16, and all covered more than 2 breathing cycles. There were significant changes of arterial PaO2(i.e. the highest high values compare to the next lowestvalues, P<0.05), but no significant changes in venous blood(P>0.05). The magnitudes of changing PaO2 in arterial and venous blood sample were (9.96±5.18)mmHg and (1.63±0.41)mmHg with significant variance(P=0.010), and they were (8.09±2.43)% and (3.91±1.22)%from their mean with significant variance(P=0.009) respectively. Conclusion: With continuous beat-by-beat arterial and venous blood sampling and ABG analyzing method at the same time, we obtain a clear evidence of periodic parameters ABG waveform, which following breathing cycle, but no clear ABG waveform of the periodic parameters in the venous blood samples, which implies the oscillatory information of the arterial blood with comes from the gas exchanging in the lung.

[Primary clinical investigation of cardiopulmonary exercise gas exchange in pulmonary hypertension patients with and without right-to-left shunt].

Objective: The aim of this study is to determine the changes of gas exchange parameters during ramp incremental cardiopulmonary exercise test (CPET) in patients with pulmonary hypertension (PH) could identify the right to left shunt (R-L Shunt). Methods: We did a retrospective analysis of exercise gas exchange parameters for 73 PH patients and 14 normal subjects as control, in Fuwai Hospital from October 2016 to August 2017, who did CPET with signature on content form. The gas exchange data of CPET were double-blindly independently interpreted by four export-doctors. According to the reading results of CPET, the PH patients were divided into four groups: ① R-L shunt positive group, ② R-L shunt suspicious group, ③R-L shunt negative group, ④late open R-L Shunt positive group. Results: Minute ventilation (VE), ventilatory equivalents for carbon dioxide and oxygen (VE/VCO2, VE/VO2), end-tidal partial pressure of oxygen (PETO2)in R-L shunt positive group were significantly increased ((7.36 ± 2.72) L/min, (1.84± 3.59), (5.02 ±4.34), (3.75±2.64) mmHg) at the beginning of exercise, and were also significantly higher than the control ((4.26 ± 2.59) L/min, (2.22± 2.08), (1.46 ±4.68), (3.96 ± 2.82) mmHg); Partial pressure of carbon dioxide in end expiratory gas (PETCO2) was decreased (-1.63 ±1.66) mmHg, and was significantly lower than control (2.22 ± 2.08) mmHg (P<0.01). Respiratory quotient (RER), carbon dioxide, VE/VCO2, VE/VO2, PETO2 in late open R-L Shunt positive group were suddenly increased ((0.40 ± 0.08), (11.07 ± 5.60),(30.55 ±7.89), (13.72 ±2.21) mmHg) at the end of exercise near the peak, significantly higher than control too ((0.38± 0.12), (5.67± 4.60), (4.54 ± 3.83), (5.51± 4.24) mmHg); PETCO2 was suddenly decreased at the end of the exercise compared to the resting stage (-6.82 ± 1.96) mmHg, and was significantly different from the control (5.67 ±4.60) mmHg. Carbon dioxide ventilatory efficiency, oxygen uptake ventilatory efficiency relative to the peak power (-8.38 ±3.24, -13.14 ± 6.47) at the recovery stage in late open R-L shunt positive group are significantly lower than control (6.22 ±2.87, 16.56± 4.20) (P<0.01). Conclusion: Cardiopulmonary function and ventilation efficiency of patients withpulmonary hypertension are significantly decreased; pulmonary hypertension and right to left shunt in patients not only resting ventilation efficiency is limited more serious; The characteristics of R-L shunt are the sudden increase of PETO2, VE/ VCO2, VE, RER and sudden decrease of PETCO2 and VO2/ VE at the beginning of exercise, and commonly companied with decreased SpO2. For the delay open R-L shunt, these changes occurred near the peak exercise rather than the beginning, and these characteristic changes quickly reversed after stopping exercise.

Genetic analyses support the contribution of mRNA N6-methyladenosine (m6A) modification to human disease heritability.

N6-methyladenosine (m6A) plays important roles in regulating messenger RNA processing. Despite rapid progress in this field, little is known about the genetic determinants of m6A modification and their role in common diseases. In this study, we mapped the quantitative trait loci (QTLs) of m6A peaks in 60 Yoruba (YRI) lymphoblastoid cell lines. We found that m6A QTLs are largely independent of expression and splicing QTLs and are enriched with binding sites of RNA-binding proteins, RNA structure-changing variants and transcriptional features. Joint analysis of the QTLs of m6A and related molecular traits suggests that the downstream effects of m6A are heterogeneous and context dependent. We identified proteins that mediate m6A effects on translation. Through integration with data from genome-wide association studies, we show that m6A QTLs contribute to the heritability of various immune and blood-related traits at levels comparable to splicing QTLs and roughly half of expression QTLs. By leveraging m6A QTLs in a transcriptome-wide association study framework, we identified putative risk genes of these traits.

[Development of a Software for Automatically Generated Contours in Eclipse TPS].

OBJECTIVE: The automatic generation of planning targets and auxiliary contours have achieved in Eclipse TPS 11.0. METHODS: The scripting language autohotkey was used to develop a software for automatically generated contours in Eclipse TPS. This software is named Contour Auto Margin (CAM), which is composed of operational functions of contours, script generated visualization and script file operations. RESULTS Ten cases in different cancers have separately selected, in Eclipse TPS 11.0 scripts generated by the software could not only automatically generate contours but also do contour post-processing. For different cancers, there was no difference between automatically generated contours and manually created contours. CONCLUSION: The CAM is a user-friendly and powerful software, and can automatically generated contours fast in Eclipse TPS 11.0. With the help of CAM, it greatly save plan preparation time and improve working efficiency of radiation therapy physicists.