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Background The ring-shaped cohesin complex is an important factor for the formation of chromatin loops and topologically associating domains (TADs) by loop extrusion. However, the regulation of association between cohesin and chromatin is poorly understood. In this study, we use super-resolution imaging to reveal the unique role of cohesin subunit RAD21 in cohesin loading and chromatin structure regulation. Results We directly visualize that up-regulation of RAD21 leads to excessive chromatin loop extrusion into a vermicelli-like morphology with RAD21 clustered into foci and excessively loaded cohesin bow-tying a TAD to form a beads-on-a-string-type pattern. In contrast, up-regulation of the other four cohesin subunits results in even distributions. Mechanistically, we identify that the essential role of RAD21 is attributed to the RAD21-loader interaction, which facilitates the cohesin loading process rather than increasing the abundance of cohesin complex upon up-regulation of RAD21. Furthermore, Hi-C and genomic analysis reveal how RAD21 up-regulation affects genome-wide higher-order chromatin structure. Accumulated contacts are shown at TAD corners while inter-TAD interactions increase after vermicelli formation. Importantly, we find that in breast cancer cells, the expression of RAD21 is aberrantly high with poor patient survival and RAD21 forms beads in the nucleus. Up-regulated RAD21 in HeLa cells leads to compartment switching and up-regulation of cancer-related genes. Conclusions Our results provide key insights into the molecular mechanism by which RAD21 facilitates the cohesin loading process and provide an explanation to how cohesin and loader work cooperatively to promote chromatin extrusion, which has important implications in construction of three-dimensional genome organization.

With the development of global clean energy and the implementation of carbon emission reduction policies, the direct purchase of electricity by large consumers has been increasingly promoted as a special form of electricity trading. Therefore, on the basis of the completion of low-carbon emission reduction targets in each country, how to rationalize the electricity purchase by large consumers in the electricity market so as to reduce their electricity purchase costs has become the main target of attention in each country. Currently, there are fewer studies in existing research on the direct electricity purchase strategy of large consumers under the consideration of the weight of consumption responsibility and risk. Based on this, this paper constructs a dual-game model for direct electricity purchase by large consumers based on the Stackelberg game and non-cooperative game theory. The concept of value at risk is further introduced, and the optimal strategy of direct electricity purchase by large consumers is proposed. The results of this study show that when market players make decisions on the purchase and sale of electricity, power suppliers will increase their biddings to obtain the highest returns, and large consumers can reduce the transaction costs by combining the medium- and long-term market with the spot market to purchase electricity. In the choice of electricity purchase market, with the increasing risk factor, large consumers shift from the risky spot market to the less risky medium- and long-term market and option market. This paper provides a reference for the issues of power suppliers’ contract bidding and large consumers’ electricity purchase strategy in the medium- and long-term contract transactions.

Food has a massive influence on the gut microbiota and is one of the most useful therapeutic levers in disease. Recent developments have highlighted how macronutrient balance, food format, and functional ingredients can regulate microbial diversity, metabolism, and host physiology in companion animals such as dogs and cats. This narrative review condenses evidence on the bidirectional gut microbiota–diet connection and on nutritional therapy for gastrointestinal, metabolic, renal, hepatic, and immune-mediated disorders. Protein-based diets including high or hydrolyzed protein, omega-3 acids, fermentative fiber, and probiotics can positively affect microbial composition, stimulate short-chain fatty acid synthesis, and enhance intestinal barrier functions. Conversely, excess fats or refined carbohydrates may cause dysbiosis, inflammation, and metabolic imbalances. Numerous studies have shown that therapeutic nutrition—e.g., low-protein renoprotective, hepatoprotective antioxidants, and allergen-elimination diets—holds enormous potential for treatment. In addition, fecal microbiota transplantation (FMT) can be used as an additive therapy for resistant gastrointestinal illnesses. Despite these developments, constraints remain in terms of standardization, study duration, and species-specific data, especially for cats. This review underscores dietary modification as a clinically actionable tool for microbiota-targeted therapy and calls for integrative, multi-omics research to translate microbiome modulation into precision nutrition for companion animals.

Postural control, especially when standing and performing cognitive “dual tasks,” requires effective regulation of cerebral blood flow (CBF) to support functional neural activation within involved brain networks. Aging from adulthood into senescence diminishes dual task performance and CBF. However, it is unknown whether CBF obtained during dual task execution correlates with performance, or if age influences the nature of this relationship. Twenty-three relatively healthy younger (26 ± 3 years) and 24 older (76 ± 6 years) adults completed the n -back task of executive function (i.e., identify X [IdX] and 2-back) while standing. CBF of the middle cerebral artery was measured using transcranial Doppler ultrasound and postural control (i.e., elliptical area, range, and path length) was recorded using a wearable motion sensor. N -back task performance was reported as the Balanced Integration Score (BIS). During the IdX task, the relationship between CBF and postural control was dependent upon age ( p  = 0.03). Within the younger group, the association between CBF velocity and path length was slightly negative, but nonsignificant. This association, however, was opposite (i.e., positive) in the older group. There was no association between CBF and BIS for the IdX task. During the higher demanding 2-back task, greater CBF was associated with longer path length irrespective of age group ( p  = 0.03), yet lower BIS (more efficiency) for the 2-back in older adults only. These results indicate that dual task postural control is reliant on CBF, yet the nature of this relationship may be dependent upon both age and difficulty of the cognitive task.

A novel geolocation architecture, termed “Multiple Transponders and Multiple Receivers for Multiple Emitters Positioning System (MTRE)” is proposed in this paper. Existing Direct Position Determination (DPD) methods take advantage of a rather simple channel assumption (line of sight channels with complex path attenuations) and a simplified MUltiple SIgnal Classification (MUSIC) algorithm cost function to avoid the high dimension searching. We point out that the simplified assumption and cost function reduce the positioning accuracy because of the singularity of the array manifold in a multi-path environment. We present a DPD model for unknown signals in the presence of Multi-path Propagation (MP-DPD) in this paper. MP-DPD adds non-negative real path attenuation constraints to avoid the mistake caused by the singularity of the array manifold. The Multi-path Propagation MUSIC (MP-MUSIC) method and the Active Set Algorithm (ASA) are designed to reduce the dimension of searching. A Multi-path Propagation Maximum Likelihood (MP-ML) method is proposed in addition to overcome the limitation of MP-MUSIC in the sense of a time-sensitive application. An iterative algorithm and an approach of initial value setting are given to make the MP-ML time consumption acceptable. Numerical results validate the performances improvement of MP-MUSIC and MP-ML. A closed form of the Cramér–Rao Lower Bound (CRLB) is derived as a benchmark to evaluate the performances of MP-MUSIC and MP-ML.

Gibberellins (GAs) promote secondary cell wall (SCW) development in plants, but the underlying molecular mechanism is still to be elucidated. Here, we employed a new system, the first internode of cotton, and the virus-induced gene silencing method to address this problem. We found that knocking down major DELLA genes via VIGS phenocopied GA treatment and significantly enhanced SCW formation in the xylem and phloem of cotton stems. Cotton DELLA proteins were found to interact with a wide range of SCW-related NAC proteins, and virus-induced gene silencing of these NAC genes inhibited SCW development with downregulated biosynthesis and deposition of lignin. The findings indicated a framework for the GA regulation of SCW formation; that is, the interactions between DELLA and NAC proteins mediated GA signaling to regulate SCW formation in cotton stems.

Major depressive disorder (MDD) is a worldwide cause of disability in older age, especially during the covid pandemic. Transcranial Direct Current Stimulation (tDCS) is a non-invasive neuromodulation technique that has shown encouraging efficacy for treatment of depression. Here, we investigate the feasibility of an innovative protocol where tDCS is administered within the homes of older adults with MDD with the help of a study companion (I.e. caregiver). We further analyze the feasibility of a remotely-hosted training program that provides the knowledge and skills to administer tDCS at home, without requiring them to visit the lab. We also employed a newly developed multi-channel tDCS system with real-time monitoring designed to guarantee the safety and efficacy of home-based tDCS. Participants underwent a total of 37 home-based tDCS sessions distributed over 12 weeks. The protocol consisted of three phases each lasting four weeks: an acute phase, containing 28 home-based tDCS sessions, a taper phase containing 9 home-based tDCS sessions, and a follow up phase, with no stimulation sessions. We found that the home-based, remotely-supervised, study companion administered, multi-channel tDCS protocol for older adults with MDD was feasible and safe. Further, the study introduces a novel training program for remote instruction of study companions in the administration of tDCS. Future research is required to determine the translatability of these findings to a larger sample.

Over 55 million people worldwide are currently diagnosed with Alzheimer's disease (AD) and live with debilitating episodic memory deficits. Current pharmacological treatments have limited efficacy. Recently, transcranial alternating current stimulation (tACS) has shown memory improvement in AD by normalizing high-frequency neuronal activity. Here we investigate the feasibility, safety, and preliminary effects on episodic memory of an innovative protocol where tACS is administered within the homes of older adults with AD with the help of a study companion (HB-tACS). Eight participants diagnosed with AD underwent multiple consecutive sessions of high-definition HB-tACS (40 Hz, 20-min) targeting the left angular gyrus (AG), a key node of the memory network. The Acute Phase comprised 14-weeks of HB-tACS with at least five sessions per week. Three participants underwent resting state electroencephalography (EEG) before and after the 14-week Acute Phase. Subsequently, participants completed a 2-3-month Hiatus Phase not receiving HB-tACS. Finally, in the Taper phase, participants received 2-3 sessions per week over 3-months. Primary outcomes were safety, as determined by the reporting of side effects and adverse events, and feasibility, as determined by adherence and compliance with the study protocol. Primary clinical outcomes were memory and global cognition, measured with the Memory Index Score (MIS) and Montreal Cognitive Assessment (MoCA), respectively. Secondary outcome was EEG theta/gamma ratio. Results reported as mean ± SD. All participants completed the study, with an average of 97 HB-tACS sessions completed by each participant; reporting mild side effects during 25% of sessions, moderate during 5%, and severe during 1%. Acute Phase adherence was 98 ± 6.8% and Taper phase was 125 ± 22.3% (rates over 100% indicates participants completed more than the minimum of 2/week). After the Acute Phase, all participants showed memory improvement, MIS of 7.25 ± 3.77, sustained during Hiatus 7.00 ± 4.90 and Taper 4.63 ± 2.39 Phases compared to baseline. For the three participants that underwent EEG, a decreased theta/gamma ratio in AG was observed. Conversely, participants did not show improvement in the MoCA, 1.13 ± 3.80 after the Acute Phase, and there was a modest decrease during the Hiatus -0.64 ± 3.28 and Taper -2.56 ± 5.03 Phases. This pilot study shows that the home-based, remotely-supervised, study companion administered, multi-channel tACS protocol for older adults with AD was feasible and safe. Further, targeting the left AG, memory in this sample was improved. These are preliminary results that warrant larger more definite trials to further elucidate tolerability and efficacy of the HB-tACS intervention. NCT04783350. https://clinicaltrials.gov/ct2/show/NCT04783350?term=NCT04783350&draw=2&rank=1, identifier NCT04783350.

Cotton exhibits indeterminate growth potential at its apical meristem. In field cultivation, it is often necessary to restrict plant height by the foliar application of plant growth regulators or artificial topping. The genetic engineering of cotton architecture offers an efficient, environmentally friendly, and low-cost alternative to current field management. Our study aimed to improve the plant architecture of transgenic cotton by the suppression of GhSP, a key flowering repressor, via the RNA interference method. Sixteen independent transgenic lines were generated and classified as mildly, moderately, and severely suppressed, according to GhSP expression levels. Field evaluation revealed the dose-dependent effects of GhSP silencing on plant height. The mildly suppressed line GhSPi-#5 exhibited a semi-dwarf phenotype of approximately 70~100 cm in height. Negative phenotypes, including excessive dwarf plant architecture and inferior fiber quality and yield traits, were observed in severely GhSP-suppressed transgenic lines. Notably, the mild silencing of GhSP in GhSPi-#5 did not negatively affect leaf and flower organ growth, pollen fertility, major agronomic traits, or fiber quality compared with the wild type. These observations demonstrate the feasibility of manipulating the architecture of transgenic cotton via GhSP silencing.

Background Organophosphate pesticides (OPs) have been found to have reproductive toxicity with overt endocrine disruption potential, yet the relationships between OPs with reproductive lifespan remain unexplored. Objective We aimed to investigate associations between urinary OP concentrations with reproductive lifespan. Method This study included 1,356 postmenopausal women who participated in the National Health and Nutrition Examination Survey from 1999 to 2018 to evaluate the relationship between OP exposure and reproductive lifespan. Urine was analysed using gas chromatography coupled with mass spectrometry for concentrations of six dialkyl phosphate (DAP) metabolites of OPs. Result Multivariate linear regression and Bayesian kernel machine regression (BKMR) models revealed that total urinary DAP metabolite concentrations ( β  = 0.10, 95% CI: 0.03–0.17, p  = 0.006) were positively associated with age at menopause. Urinary dimethyl phosphate (DMP) concentration was positively associated with age at menopause ( β  = 0.67, 95% CI: 0.30–1.03, p  = 0.001) and reproductive lifespan ( β  = 0.64, 95% CI: 0.26–1.02, p  = 0.001). Furthermore, BKMR and weighted quantile sum models identified DMP as the primary risk contributor amongst the six detected DAP metabolites (weight = 0.573 for age at menopause and weight = 0.634 for reproductive lifespan). Conclusion For the mixed analysis, the overall exposure to DAP metabolites was associated with delayed age at menopause. For the individual analysis, DMP exposure was associated with delayed age at menopause and longer reproductive lifespan, and DMP was identified as the major risk factor amongst the six detected DAP metabolites. Future research should prioritise DMP to further elucidate impacts of OPs exposure on female reproductive health.