Automated analysis of fetal heart rate baseline/acceleration/deceleration using MTU-Net3 + model.

In clinical practice, obstetricians use visual interpretation of fetal heart rate (FHR) to diagnose fetal conditions, but inconsistencies among interpretations can hinder accuracy. This study introduces MTU-Net3+, a deep learning model designed for automated, multi-task FHR analysis, aiming to improve diagnostic accuracy and efficiency. The proposed MTU-Net3 + was built upon the UNet3 + architecture, incorporating an encoder, a decoder, full-scale skip connections, and a deep supervision module, and further integrates a self-attention mechanism and bidirectional Long Short-Term Memory layers to enhance its performance. The MTU-Net3 + model accepts the preprocessed 20-minute FHR signals as input, outputting categorical probabilities and baseline values for each time point. The proposed MTU-Net3 + model was trained on a subset of a public database, and was tested on the remaining data of the public database and a private database. In the remaining public datasets, this model achieved F1 scores of 84.21% for deceleration (F1.Dec) and 61.33% for acceleration (F1.Acc), with a Root Mean Square Baseline Difference (RMSD.BL) of 3.46 bpm, 0% of points with an absolute difference exceeding 15 bpm(D15bpm), a Synthetic Inconsistency Coefficient (SI) of 44.82%, and a Morphological Analysis Discordance Index (MADI) of 7.00%. On the private dataset, the model recorded an RMSD.BL of 1.37 bpm, 0% D15bpm, F1.Dec of 100%, F1.Acc of 87.50%, an SI of 12.20% and a MADI of 2.79%. The MTU-Net3 + model proposed in this study performed well in automated FHR analysis, demonstrating its potential as an effective tool in the field of fetal health assessment.

Drinking severity mediates the relationship between hypothalamic connectivity and rule-breaking/intrusive behavior differently in young women and men: an exploratory study.

Background: The hypothalamus is a key hub of the neural circuits of motivated behavior. Alcohol misuse may lead to hypothalamic dysfunction. Here, we investigated how resting-state hypothalamic functional connectivities are altered in association with the severity of drinking and clinical comorbidities and how men and women differ in this association. Methods: We employed the data of the Human Connectome Project. A total of 870 subjects were included in data analyses. The severity of alcohol use was quantified for individual subjects with the first principal component (PC1) identified from principal component analyses of all drinking measures. Rule-breaking and intrusive scores were evaluated with the Achenbach Adult Self-Report Scale. We performed a whole-brain regression of hypothalamic connectivities on drinking PC1 in all subjects and men/women separately and evaluated the results at a corrected threshold. Results: Higher drinking PC1 was associated with greater hypothalamic connectivity with the paracentral lobule (PCL). Hypothalamic PCL connectivity was positively correlated with rule-breaking score in men (r=0.152, P=0.002) but not in women. In women but not men, hypothalamic connectivity with the left temporo-parietal junction (LTPJ) was negatively correlated with drinking PC1 (r=-0.246, P<0.001) and with intrusiveness score (r=-0.127, P=0.006). Mediation analyses showed that drinking PC1 mediated the relationship between hypothalamic PCL connectivity and rule-breaking score in men and between hypothalamic LTPJ connectivity and intrusiveness score bidirectionally in women. Conclusions: We characterized sex-specific hypothalamic connectivities in link with the severity of alcohol misuse and its comorbidities. These findings extend the literature by elucidating the potential impact of problem drinking on the motivation circuits.

The inter-related effects of alcohol use severity and sleep deficiency on semantic processing in young adults.

BACKGROUND: Both alcohol misuse and sleep deficiency are associated with deficits in semantic processing. However, alcohol misuse and sleep deficiency are frequently comorbid and their inter-related effects on semantic processing as well as the underlying neural mechanisms remain to be investigated. METHODS: We curated the Human Connectome Project data of 973 young adults (508 women) to examine the neural correlates of semantic processing in link with the severity of alcohol use and sleep deficiency. The latter were each evaluated using the first principal component (PC1) of principal component analysis of all drinking metrics and the Pittsburgh Sleep Quality Index (PSQI). We employed path modeling to elucidate the interplay among clinical, behavioral, and neural variables. RESULTS: Among women, we observed a significant negative correlation between the left precentral gyrus (PCG) and PSQI scores. Mediation analysis revealed that the left PCG activity fully mediated the relationship between PSQI scores and word comprehension in language tasks. In women alone also, the right middle frontal gyrus (MFG) exhibited a significant negative correlation with PC1. The best path model illustrated the associations among PC1, PSQI scores, PCG activity, and MFG activation during semantic processing in women. CONCLUSIONS: Alcohol misuse may lead to reduced MFG activation while sleep deficiency hinder semantic processing by suppressing PCG activity in women. The pathway model underscores the influence of sleep quality and alcohol consumption severity on semantic processing in women, suggesting that sex differences in these effects need to be further investigated.

Sex differences in dorsolateral prefrontal cortical and superior colliculus activities support the impact of alcohol use severity and sleep deficiency on two-back memory.

Background: Working memory refers to a process of temporary storage and manipulation of information to support planning, decision-making, and action. Frequently comorbid alcohol misuse and sleep deficiency have both been associated with working memory deficits. However, how alcohol misuse and sleep deficiency interact to impact working memory remains unclear. In this study, we aim to investigate the neural processes inter-relating alcohol misuse, sleep deficiency and working memory. Methods: We curated the Human Connectome Project (HCP) dataset and investigated the neural correlation of working memory in link with alcohol use severity and sleep deficiency in 991 young adults (521 women). The two were indexed by the first principal component (PC1) of principal component analysis of all drinking metrics and Pittsburgh Sleep Quality Index (PSQI) score, respectively. We processed the imaging data with published routines and evaluated the results with a corrected threshold. We used path model to characterize the inter-relationship between the clinical, behavioral, and neural measures, and explored sex differences in the findings. Results: In whole-brain regression, we identified ß estimates of dorsolateral prefrontal cortex response (DLPFC ß) to 2- vs. 0-back in correlation with PC1. The DLPFC showed higher activation in positive correlation with PC1 across men and women (r=0.16, P<0.001). Path analyses showed the model PC1 → DLPFC ß â†’ differences in reaction time (2- minus 0-back; RT2-0) of correct trials → differences in critical success index (2- minus 0-back; CSI2-0) with the best fit. In women alone, in addition to the DLPFC, a cluster in the superior colliculus (SC) showed a significant negative correlation with the PSQI score (r=-0.23, P<0.001), and the path model showed the inter-relationship of PC1, PSQI score, DLPFC and SC ß's, and CSI2-0 in women. Conclusions: Alcohol misuse may involve higher DLPFC activation in functional compensation, whereas, in women only, sleep deficiency affects 2-back memory by depressing SC activity. In women only, path model suggests inter-related impact of drinking severity and sleep deficiency on 2-back memory. These findings suggest potential sex differences in the impact of drinking and sleep problems on working memory that need to be further investigated.

Functional Networks of Reward and Punishment Processing and Their Molecular Profiles Predicting the Severity of Young Adult Drinking.

Alcohol misuse is associated with altered punishment and reward processing. Here, we investigated neural network responses to reward and punishment and the molecular profiles of the connectivity features predicting alcohol use severity in young adults. We curated the Human Connectome Project data and employed connectome-based predictive modeling (CPM) to examine how functional connectivity (FC) features during wins and losses are associated with alcohol use severity, quantified by Semi-Structured Assessment for the Genetics of Alcoholism, in 981 young adults. We combined the CPM findings and the JuSpace toolbox to characterize the molecular profiles of the network connectivity features of alcohol use severity. The connectomics predicting alcohol use severity appeared specific, comprising less than 0.12% of all features, including medial frontal, motor/sensory, and cerebellum/brainstem networks during punishment processing and medial frontal, fronto-parietal, and motor/sensory networks during reward processing. Spatial correlation analyses showed that these networks were associated predominantly with serotonergic and GABAa signaling. To conclude, a distinct pattern of network connectivity predicted alcohol use severity in young adult drinkers. These "neural fingerprints" elucidate how alcohol misuse impacts the brain and provide evidence of new targets for future intervention.

The paradox of bone mineral density and fracture risk in type 2 diabetes.

Fracture risk in type 2 diabetes (T2D) patients is paradoxically increased despite no decrease in areal bone mineral density (BMD). This phenomenon, known as the "diabetic bone paradox", has been attributed to various factors including alterations in bone microarchitecture and composition, hyperinsulinemia and hyperglycemia, advanced glycation end products (AGEs), and comorbidities associated with T2D. Zhao et al. recently investigated the relationship between T2D and fracture risk using both genetic and phenotypic datasets. Their findings suggest that genetically predicted T2D is associated with higher BMD and lower fracture risk, indicating that the bone paradox is not observed when confounding factors are controlled using Mendelian randomization (MR) analysis. However, in prospective phenotypic analysis, T2D remained associated with higher BMD and higher fracture risk, even after adjusting for confounding factors. Stratified analysis revealed that the bone paradox may disappear when T2D-related risk factors are eliminated. The study also highlighted the role of obesity in the relationship between T2D and fracture risk, with BMI mediating a significant portion of the protective effect. Overall, managing T2D-related risk factors may be crucial in preventing fracture risk in T2D patients.

Deficient sleep, altered hypothalamic functional connectivity, depression and anxiety in cigarette smokers.

Background: Deficient sleep is implicated in nicotine dependence as well as depressive and anxiety disorders. The hypothalamus regulates the sleep-wake cycle and supports motivated behavior, and hypothalamic dysfunction may underpin comorbid nicotine dependence, depression and anxiety. We aimed to investigate whether and how the resting state functional connectivities (rsFCs) of the hypothalamus relate to cigarette smoking, deficient sleep, depression and anxiety. Methods: We used the data of 64 smokers and 198 age- and sex-matched adults who never smoked, curated from the Human Connectome Project. Deficient sleep and psychiatric problems were each assessed with Pittsburgh Sleep Quality Index (PSQI) and Achenbach Adult Self-Report. We processed the imaging data with published routines and evaluated the results at a corrected threshold, all with age, sex, and the severity of alcohol use as covariates. Results: Smokers vs. never smokers showed poorer sleep quality and greater severity of depression and anxiety. In smokers only, the total PSQI score, indicating more sleep deficits, was positively associated with hypothalamic rsFCs with the right inferior frontal/insula/superior temporal and postcentral (rPoCG) gyri. Stronger hypothalamus-rPoCG rsFCs were also associated with greater severity of depression and anxiety in smokers but not never smokers. Additionally, in smokers, the PSQI score completely mediated the relationships of hypothalamus-rPoCG rsFCs with depression and anxiety severity. Conclusions: These findings associate hypothalamic circuit dysfunction to sleep deficiency and severity of depression and anxiety symptoms in adults who smoke. Future studies may investigate the roles of the hypothalamic circuit in motivated behaviors to better characterize the inter-related neural markers of smoking, deficient sleep, depression and anxiety.

Deep-learning-based real-time individualization for reduce-order haemodynamic model.

The reduced-order lumped parameter model (LPM) has great computational efficiency in real-time numerical simulations of haemodynamics but is limited by the accuracy of patient-specific computation. This study proposed a method to achieve the individual LPM modeling with high accuracy to improve the practical clinical applicability of LPM. Clinical data was collected from two medical centres comprising haemodynamic indicators from 323 individuals, including brachial artery pressure waveforms, cardiac output data, and internal carotid artery flow waveforms. The data were expanded to 5000 synthesised cases that all fell within the physiological range of each indicator. LPM of the human blood circulation system was established. A double-path neural network (DPNN) was designed to input the waveforms of each haemodynamic indicator and their key features and then output the individual parameters of the LPM, which was labelled using a conventional optimization algorithm. Clinically collected data from the other 100 cases were used as the test set to verify the accuracy of the individual LPM parameters predicted by DPNN. The results show that DPNN provided good convergence in the training process. In the test set, compared with clinical measurements, the mean differences between each haemodynamic indicator and the estimate calculated by the individual LPM based on the DPNN were about 10 %. Furthermore, DPNN prediction only takes 4 s for 100 cases. The DPNN proposed in this study permits real-time and accurate individualization of LPM's. When facing medical issues involving haemodynamics, it lays the foundation for patient-specific numerical simulation, which may be beneficial for potential clinical application.

A real-time patient-specific treatment strategy for enhanced external counterpulsation.

Diastolic/systolic blood pressure ratio (D/S) ≥ 1.2 is the gold standard of enhanced external counterpulsation (EECP) treatment, but it does not show a clear clinical correspondence with the configuration of the EECP mode. As such, a single target results in different treatment effects in different individuals. The local haemodynamic effect (wall shear stress, WSS) of EECP on vascular endothelial cells is conducive to promote the growth of collateral circulation vessels and restore the blood supply distal to the stenosis lesion. Considering the haemodynamic effects of WSS on human arteries, this study developed a real-time patient-specific treatment strategy of EECP for patients with cardio-cerebrovascular diseases. Based on patient-specific haemodynamic data from 113 individuals, an optimization algorithm was developed to achieve the individualization of a 0D lumped-parameter model of the human circulatory system, thereby simulating the patient-specific global haemodynamic effects. 0D/3D coupled cardio-cerebrovascular models of two subjects were established to simulate the local WSS. We then established statistical models to evaluate clinically unmeasurable WSS based on measurable global haemodynamic indicators. With the aim of attaining appropriate area- and time-averaged WSS (ATAWSS, 4-7 Pa), as evaluated by global haemodynamic indicators, a closed-loop feedback tuning method was developed to provide patient-specific EECP treatment strategies. Results showed that for clinical data collected from 113 individuals, the individualized 0D model can accurately simulate patient-specific global haemodynamic effects (average error <5%). Based on two subjects, the statistical models can be used to evaluate local ATAWSS (error <6%) for coronary arteries and for cerebral arteries. An EECP mode planned by the patient-specific treatment strategy can promote an appropriate ATAWSS within a 16 s calculation time. The real-time patient-specific treatment strategy of EECP is expected to improve the long-term outcome for each patient and have potential clinical significance.

Sleep Deficits Inter-Link Lower Basal Forebrain-Posterior Cingulate Connectivity and Perceived Stress and Anxiety Bidirectionally in Young Men.

BACKGROUND: The basal nucleus of Meynert (BNM), a primary source of cholinergic projections to the cortex, plays key roles in regulating the sleep-wake cycle and attention. Sleep deficit is associated with impairment in cognitive and emotional functions. However, whether or how cholinergic circuit, sleep, and cognitive/emotional dysfunction are inter-related remains unclear. METHODS: We curated the Human Connectome Project data and explored BNM resting state functional connectivities (rsFC) in relation to sleep deficit, based on the Pittsburgh Sleep Quality Index (PSQI), cognitive performance, and subjective reports of emotional states in 687 young adults (342 women). Imaging data were processed with published routines and evaluated at a corrected threshold. We assessed the correlation between BNM rsFC, PSQI, and clinical measurements with Pearson regressions and their inter-relationships with mediation analyses. RESULTS: In whole-brain regressions with age and alcohol use severity as covariates, men showed lower BNM rsFC with the posterior cingulate cortex (PCC) in correlation with PSQI score. No clusters were identified in women at the same threshold. Both BNM-PCC rsFC and PSQI score were significantly correlated with anxiety, perceived stress, and neuroticism scores in men. Moreover, mediation analyses showed that PSQI score mediated the relationship between BNM-PCC rsFC and these measures of negative emotions bidirectionally in men. CONCLUSIONS: Sleep deficit is associated with negative emotions and lower BNM rsFC with the PCC. Negative emotional states and BNM-PCC rsFC are bidirectionally related through poor sleep quality. These findings are specific to men, suggesting potential sex differences in the neural circuits regulating sleep and emotional states.

The effects of cocaine use severity and abstinence on behavioral performance and neural processes of response inhibition.

Previous studies identified cerebral markers of response inhibition dysfunction in cocaine dependence. However, whether deficits in response inhibition vary with the severity of cocaine use or ameliorate during abstinence remain unclear. This study aimed to address these issues and the neural mechanisms supporting the individual variation. We examined the data of 67 individuals with cocaine dependence (CD) and 84 healthy controls (HC) who underwent functional magnetic resonance imaging during a stop-signal task (SST). The stop-signal reaction time (SSRT) was computed using the integration method, with a longer SSRT indicating poorer response inhibition. The results showed that, while CD and HC did not differ significantly in SSRT, years of cocaine use (YOC) and days of abstinence (DOA) were each positively and negatively correlated with the SSRT in CD. Whole-brain regressions of stop minus go success trials on SSRT revealed correlates in bilateral superior temporal gyrus (STG) in response inhibition across CD and HC. Further, mediation and path analyses revealed that YOC and DOA affected SSRT through the STG activities in CD. Together, the findings characterized the contrasting effects of cocaine use severity and abstinence on response inhibition as well as the neural processes that support these effects in cocaine dependence.

Sleep dysfunction mediates the relationship between hypothalamic-insula connectivity and anxiety-depression symptom severity bidirectionally in young adults.

BACKGROUND: The hypothalamus plays a crucial role in regulating sleep-wake cycle and motivated behavior. Sleep disturbance is associated with impairment in cognitive and affective functions. However, how hypothalamic dysfunction may contribute to inter-related sleep, cognitive, and emotional deficits remain unclear. METHODS: We curated the Human Connectome Project dataset and investigated how hypothalamic resting state functional connectivities (rsFC) were associated with sleep dysfunction, as evaluated by the Pittsburgh Sleep Quality Index (PSQI), cognitive performance, and subjective mood states in 687 young adults (342 women). Imaging data were processed with published routines and evaluated with a corrected threshold. We examined the inter-relationship amongst hypothalamic rsFC, PSQI score, and clinical measures with mediation analyses. RESULTS: In whole-brain regressions with age and drinking severity as covariates, men showed higher hypothalamic rsFC with the right insula in correlation with PSQI score. No clusters were identified in women at the same threshold. Both hypothalamic-insula rsFC and PSQI score were significantly correlated with anxiety and depression scores in men. Further, mediation analyses showed that PSQI score mediated the relationship between hypothalamic-insula rsFC and anxiety/depression symptom severity bidirectionally in men. CONCLUSIONS: Sleep dysfunction is associated with negative emotions and hypothalamic rsFC with the right insula, a core structure of the interoceptive circuits. Notably, anxiety-depression symptom severity and altered hypothalamic-insula rsFC are related bidirectionally by poor sleep quality. These findings are specific to men, suggesting potential sex differences in the neural circuits regulating sleep and emotional states that need to be further investigated.

Active learning based on similarity level histogram and adaptive-scale sampling for very high resolution image classification.

In remote sensing image classification, active learning aims to obtain an excellent classification model by selecting informative or representative training samples. However, due to the complexity of remote sensing images, the same class of ground objects usually have different spectral representations. The existing active learning methods may not take into account diverse representations of the same targets, which leads to a possible lack of intra-class diversity in the collected samples. To alleviate this problem, we propose an active learning method based on similarity level histogram (SLH) and adaptive-scale sampling to improve very high resolution remote sensing image classification. Specifically, we construct a SLH for each class of ground objects to effectively consider the intra-class diversity of the same target. To avoid the problem of sample imbalance caused by over-sampling or under-sampling, we design an adaptive-scale sampling strategy. Then, we utilize active learning to mine representative samples from each SLH warehouse according to adaptive-scale sampling strategies until the iteration condition is satisfied. Experiments show that the proposed algorithm can achieve better classification performance with limited training samples and is competitive with other methods based on four sets of publicly available data.

Suppurative Temporomandibular Arthritis Caused by Chronic Suppurative Otitis Media: A Case Report.

The clinical diagnosis and treatment, including information such as age, history, clinical symptoms, signs, audiology, imaging examination, mode of operation, and postoperative follow-up, of a patient with suppurative temporomandibular arthritis caused by chronic suppurative otitis media were analyzed. As conservative drug treatment and drainage surgery were ineffective, the patient was treated with microscopic open radical mastoidectomy, tympanoplasty, the plasty of the cavity of auricular concha, facial nerve decompression, coarctation of the mastoid cavity combined with otoendoscpic resection of the lower temporomandibular lesions, and standard anti-inflammatory treatment after surgery. The patient appeared to be cured at the 3-month follow-up. The ear canal was dry, without any preauricular swelling, purulent ear discharge, otalgia, limitation of mouth opening, or other symptoms. A clear diagnosis by defining the scope of the lesions, analysis of the transmission route of the lesions, and standard conservative treatment, local drainage, and surgical resection, if necessary, are recommended for patients with suppurative temporomandibular arthritis.

Cross-species analysis and comparison of the inner ear between chickens and mice.

The inner ear of mammals includes the cochlea and vestibule, which house specialized hair cells that are responsible for hearing and balance, respectively. While cochlear hair cells fail to regenerate following damage, those of the utricle, which is part of the vestibular apparatus, show partial regeneration. In birds, the macula lagena, a unique ear structure in this clade, has the ability to regenerate hair cells similarly to the utricle. Many studies have sought to explain regeneration in terms of evolution and species differences. However, it remains unclear what the cellular and molecular basis is behind the differences in inner ear structures and between avians and mammals. In the present study, we first investigated the anatomical structures of the inner ear of both chickens and rodents. We then performed RNA sequencing (RNA-Seq) and made cross-species analyses of the expression of homologous genes obtained from the inner ear tissue from both chickens and mice. Finally, we focused on the lagena, the basilar papilla, and the utricle in chickens and identified differentially expressed genes between tissues and determined the expression patterns of genes involved in inner ear structure formation by single-cell RNA sequencing and bulk RNA-Seq. We concluded that the cellular and molecular composition of the lagena is more similar to that of the utricle than the cochlea. Taken together, our study provides a valuable resource for the study of inner ear evolution and development.

Non-Contact Monitoring of Fetal Movement Using Abdominal Video Recording.

Fetal movement (FM) is an important indicator of fetal health. However, the current methods of FM detection are unsuitable for ambulatory or long-term observation. This paper proposes a non-contact method for monitoring FM. We recorded abdominal videos from pregnant women and then detected the maternal abdominal region within each frame. FM signals were acquired by optical flow color-coding, ensemble empirical mode decomposition, energy ratio, and correlation analysis. FM spikes, indicating the occurrence of FMs, were recognized using the differential threshold method. FM parameters including number, interval, duration, and percentage were calculated, and good agreement was found with the manual labeling performed by the professionals, achieving true detection rate, positive predictive value, sensitivity, accuracy, and F1_score of 95.75%, 95.26%, 95.75%, 91.40%, and 95.50%, respectively. The changes in FM parameters with gestational week were consistent with pregnancy progress. In general, this study provides a novel contactless FM monitoring technology for use at home.

Role of Iron Accumulation in Osteoporosis and the Underlying Mechanisms.

Osteoporosis is prevalent in postmenopausal women. The underlying reason is mainly estrogen deficiency, but recent studies have indicated that osteoporosis is also associated with iron accumulation after menopause. It has been confirmed that some methods of decreasing iron accumulation can improve the abnormal bone metabolism associated with postmenopausal osteoporosis. However, the mechanism of iron accumulation-induced osteoporosis is still unclear. Iron accumulation may inhibit the canonical Wnt/ß-catenin pathway via oxidative stress, leading to osteoporosis by decreasing bone formation and increasing bone resorption via the osteoprotegerin (OPG)/receptor activator of nuclear factor kappa-B ligand (RANKL)/receptor activator of nuclear factor kappa-B (RANK) system. In addition to oxidative stress, iron accumulation also has been reported to inhibit either osteoblastogenesis or osteoblastic function as well as to stimulate either osteoclastogenesis or osteoclastic function directly. Furthermore, serum ferritin has been widely used for the prediction of bone status, and nontraumatic measurement of iron content by magnetic resonance imaging may be a promising early indicator of postmenopausal osteoporosis.

Sex differences in externalizing and internalizing traits and ventral striatal responses to monetary loss.

Ventral striatum (VS) processes rewarding and punishing stimuli. Women and men vary in externalizing and internalizing traits, which may influence neural responses to reward and punishment. To investigate sex differences in how individual traits influence VS responses to reward and punishment, we curated the data of the Human Connectome Project and identified 981 (473 men) subjects evaluated by the Achenbach Adult Self-Report Syndrome Scales. We processed the imaging data with published routines and extracted VS response (ß) to win and to loss vs. baseline in a gambling task for correlation with externalizing and internalizing symptom severity. Men vs. women showed more severe externalizing symptoms and higher VS response to monetary losses (VS-loss ß) but not to wins. Men but not women showed a significant, positive correlation between VS-loss ß and externalizing traits, and the sex difference was confirmed by a slope test. The correlations of VS-loss vs. externalizing and of VS-win vs. externalizing and those of VS-loss vs. externalizing and of VS-loss vs. internalizing traits both differed significantly in slope, confirming its specificity, in men. Further, the sex-specific relationship between VS-loss ß and externalizing trait did not extend to activities during exposure to negative emotion in the face matching task. To conclude, VS responses to loss but not to win and their correlation with externalizing rather than internalizing symptom severity showed sex differences in young adults. The findings highlight the relationship of externalizing traits and VS response to monetary loss and may have implications for psychological models of externalizing behaviors in men.

Tuning charge density of chimeric antigen receptor optimizes tonic signaling and CAR-T cell fitness.

Tonic signaling of chimeric antigen receptor (CAR), i.e., the spontaneous CAR activation in the absence of tumor antigen stimulation, is considered to be a pivotal event controlling CAR-T efficacy. However, the molecular mechanism underlying the spontaneous CAR signals remains elusive. Here, we unveil that positively charged patches (PCPs) on the surface of the CAR antigen-binding domain mediate CAR clustering and result in CAR tonic signaling. For CARs with high tonic signaling (e.g., GD2.CAR and CSPG4.CAR), reducing PCPs on CARs or boosting ionic strength in the culture medium during ex vivo CAR-T cell expansion minimizes spontaneous CAR activation and alleviates CAR-T cell exhaustion. In contrast, introducing PCPs into the CAR with weak tonic signaling, such as CD19.CAR, results in improved in vivo persistence and superior antitumor function. These results demonstrate that CAR tonic signaling is induced and maintained by PCP-mediated CAR clustering. Notably, the mutations we generated to alter the PCPs maintain the antigen-binding affinity and specificity of the CAR. Therefore, our findings suggest that the rational tuning of PCPs to optimize tonic signaling and in vivo fitness of CAR-T cells is a promising design strategy for the next-generation CAR.

Osteoporotic bone loss from excess iron accumulation is driven by NOX4-triggered ferroptosis in osteoblasts.

Excess iron accumulation is a risk factor for osteopenia and osteoporosis, and ferroptosis is becoming well understood as iron-dependent form of cell death resulting from lipid peroxide accumulation. However, any pathological impacts of ferroptosis on osteoporosis remain unknown. Here, we show that ferroptosis is involved in excess-iron-induced bone loss and demonstrate that osteoporotic mice and humans have elevated skeletal accumulation of the NADPH oxidase 4 (NOX4) enzyme. Mechanistically, we found that the NOX4 locus contains iron-response element-like (IRE-like) sequences that are normally bound (and repressed) by the iron regulatory protein 1 (IRP1) protein. Binding with iron induces dissociation of IRP1 from the IRE-like sequences and thereby activates NOX4 transcription. Elevated NOX4 increases lipid peroxide accumulation and causes obvious dysregulation of mitochondrial morphology and function in osteoblasts. Excitingly, the osteoporotic bone loss which we initially observed in an excessive-iron accumulating mouse line (Hepc1-/-) was blocked upon treatment with the ferroptosis-inhibitor ferrostatin-1 (Ferr-1) and with the iron chelator deferoxamine (DFO), suggesting a potential therapeutic strategy for preventing osteoporotic bone loss based on disruption of ferroptosis.