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Background: Mandibular second premolar agenesis is a common problem in orthodontics and is often treated in conjunction with maxillary counterbalancing extractions. However, in cases without maxillary crowding or dental protrusion, space closure may pose challenges leading to compromised occlusal results or patient profile. Multiple techniques have been described to treat these patients; nevertheless, there is a paucity of data comparing effectiveness of space closure utilizing various anchorage techniques. The goal of this study is to assess the effectiveness of the Herbst device during mandibular molar protraction and compare it to the use of temporary anchorage device (TADs) in patients with mandibular second premolar agenesis. Materials and methods: This retrospective study included 33 patients with mandibular premolar agenesis treated without maxillary extractions. Of these patients, 21 were treated with protraction Herbst devices and 12 with TADs. Changes in molar and incisor positions, skeletal base positions and occlusal plane angulations were assessed on pretreatment (T0) and post-treatment (T1) lateral cephalograms. Scans/photographs at T0 and T1 were used to evaluate canine relationship changes representing anchorage control. Space closure and breakage/failure rates were also compared. Data was analyzed with paired and unpaired t-tests at the significance level of 0.05. Results: Within the Herbst group, changes in mandibular central incisor uprighting and mandibular molar crown angulations were statistically significant. However, no significant differences were noted between the Herbst and TAD groups. Protraction rates as well as overall treatment times were comparable (0.77 mm/month vs. 0.55 mm/month and 3.02 years vs. 2.67 years, respectively). Canine relationships were maintained or improved toward a class I in 82.85% of the Herbst sample, compared to in 66.7% of the TAD sample. Emergency visits occurred in 80.1% of the Herbst group, with cementation failures or appliance breakages as the most common reasons. Conclusion: The Herbst device could be a viable modality in cases with missing mandibular premolars where maximum anterior anchorage is desired, or if patients/parents are resistant to TADs. Furthermore, they could be beneficial in skeletal class II patients with mandibular deficiency who also need molar protraction. However, the increased incidence of emergency visits must be considered when treatment is planned. [ABSTRACT FROM AUTHOR]

Abstract Background Mandibular second premolar agenesis is a common problem in orthodontics and is often treated in conjunction with maxillary counterbalancing extractions. However, in cases without maxillary crowding or dental protrusion, space closure may pose challenges leading to compromised occlusal results or patient profile. Multiple techniques have been described to treat these patients; nevertheless, there is a paucity of data comparing effectiveness of space closure utilizing various anchorage techniques. The goal of this study is to assess the effectiveness of the Herbst device during mandibular molar protraction and compare it to the use of temporary anchorage device (TADs) in patients with mandibular second premolar agenesis. Materials and methods This retrospective study included 33 patients with mandibular premolar agenesis treated without maxillary extractions. Of these patients, 21 were treated with protraction Herbst devices and 12 with TADs. Changes in molar and incisor positions, skeletal base positions and occlusal plane angulations were assessed on pretreatment (T0) and post-treatment (T1) lateral cephalograms. Scans/photographs at T0 and T1 were used to evaluate canine relationship changes representing anchorage control. Space closure and breakage/failure rates were also compared. Data was analyzed with paired and unpaired t-tests at the significance level of 0.05. Results Within the Herbst group, changes in mandibular central incisor uprighting and mandibular molar crown angulations were statistically significant. However, no significant differences were noted between the Herbst and TAD groups. Protraction rates as well as overall treatment times were comparable (0.77 mm/month vs. 0.55 mm/month and 3.02 years vs. 2.67 years, respectively). Canine relationships were maintained or improved toward a class I in 82.85% of the Herbst sample, compared to in 66.7% of the TAD sample. Emergency visits occurred in 80.1% of the Herbst group, with cementation failures or appliance breakages as the most common reasons. Conclusion The Herbst device could be a viable modality in cases with missing mandibular premolars where maximum anterior anchorage is desired, or if patients/parents are resistant to TADs. Furthermore, they could be beneficial in skeletal class II patients with mandibular deficiency who also need molar protraction. However, the increased incidence of emergency visits must be considered when treatment is planned.

The objective was to explore if the regression of phenotypic performance for six milk production traits on the respective estimate of genetic merit for that trait differed by herd milking frequency; variance components for each trait in the two milking frequency environments were also estimated as well as the genetic correlation between the same trait in both environments. The data used included 12,581 lactations from 5,456 cows in 32 spring-calving once-a-day (OAD) milking herds. Each OAD herd was matched with three contemporary twice-a-day (TAD)-milking herds; 35,823 lactations from 15,188 cows in 96 TAD herds were used. Mean yield was 20% (fat yield) to 31% (milk yield) lower in OAD herds. Milk protein concentration was 11% higher in OAD herds, while milk fat concentration was 16% higher in OAD herds. The mean back-transformed somatic cell score (SCS) was 100,390 cells/mL in OAD herds and 72,493 cells/mL in TAD herds. The association between each milk production trait and its respective estimate of genetic merit differed by herd milking frequency; the estimated regression coefficients were larger in TAD for just milk yield and SCS. The genetic correlation between the same trait in OAD versus TAD was all ≥0.73 with the exception of SCS (genetic correlation of 0.48) which suggests some re-ranking of sires between environments. In conclusion, differences in the scale of the genetic variance were evident for both milking frequencies and possible re-ranking was evident for SCS.

Aims: Proximal femur fractures treatment can involve anterograde nailing with a single or double cephalic screw. An undesirable failure for this fixation is screw cut-out. In a single-screw nail, a tip-apex distance (TAD) greater than 25 mm has been associated with an increased risk of cut-out. The aim of the study was to examine the role of TAD as a risk factor in a cephalic double-screw nail. Methods: A retrospective study was conducted on 112 patients treated for intertrochanteric femur fracture with a double proximal screw nail (Endovis BA2; EBA2) from January to September 2021. The analyzed variables were age, sex, BMI, comorbidities, fracture type, side, time of surgery, quality of reduction, pre-existing therapy with bisphosphonate for osteoporosis, screw placement in two different views, and TAD. The last follow-up was at 12 months. Logistic regression was used to study the potential factors of screw cut-out, and receiver operating characteristic curve to identify the threshold value. Results: A total of 98 of the 112 patients met the inclusion criteria. Overall, 65 patients were female (66.3%), the mean age was 83.23 years (SD 7.07), and the mean follow-up was 378 days (SD 36). Cut-out was observed in five patients (5.10%). The variables identified by univariate analysis with p < 0.05 were included in the multivariate logistic regression model were screw placement and TAD. The TAD was significant with an odds ratio (OR) 5.03 (p = 0.012) as the screw placement with an OR 4.35 (p = 0.043) in the anteroposterior view, and OR 10.61 (p = 0.037) in the lateral view. The TAD threshold value identified was 29.50 mm. Conclusion: Our study confirmed the risk factors for cut-out in the double-screw nail are comparable to those in the single screw. We found a TAD value of 29.50 mm to be associated with a risk of cut-out in double-screw nails, when good fracture reduction is granted. This value is higher than the one reported with single-screw nails. Therefore, we suggest the role of TAD should be reconsidered in well-reduced fractures treated with double-screw intramedullary nail. Cite this article: Bone Jt Open 2024;5(6):457–463.

Background: The targeted axillary dissection (TAD) procedure is used in clinically positive lymph node (cN+) breast cancer to assess whether pathological complete response (pCR) is achieved after neoadjuvant systemic therapy (NST) to decide on de-escalation of axillary lymph node dissection (ALND). In this study, we review the implementation of the TAD procedure in a large regional breast cancer center. Methods: All TAD procedures between 2016 and 2022 were reviewed. The TAD procedure consists of marking pre-NST the largest suspected metastatic lymph node(s) using a radioactive I-125 seed. During surgery, the marked node was excised together with a sentinel node procedure. Axillary therapy (ALND, axillary radiotherapy, or nothing) recommendations were based on the amount of suspected positive axillary lymph nodes (ALNs < 4 or ≥ 4) pre-NST and if pCR was achieved after NST. Results: A total of 312 TAD procedures were successfully performed in 309 patients. In 134 (43%) cases, pCR of the TAD lymph nodes were achieved. Per treatment protocol, 43 cases (14%) did not receive any axillary treatment, 218 cases (70%) received adjuvant axillary radiotherapy, and 51 cases (16%) underwent an ALND. During a median follow-up of 2.8 years, 46 patients (14%) developed recurrence, of which 11 patients (3.5%) had axillary recurrence. Conclusions: Introduction of the TAD procedure has resulted in a reduction of 84% of previously indicated ALNDs. Moreover, 18% of cases did not receive adjuvant axillary radiotherapy. These data show that implementation of de-escalation axillary treatment with the TAD procedure appeared to be successful. [ABSTRACT FROM AUTHOR]

Within the three‐dimensional (3D) nuclear space, the genome organizes into a series of orderly structures that impose important influences on gene regulation. T lymphocytes, crucial players in adaptive immune responses, undergo intricate transcriptional remodeling upon activation, leading to differentiation into specific effector and memory T cell subsets. Recent evidence suggests that T cell activation is accompanied by dynamic changes in genome architecture at multiple levels, providing a unique biological context to explore the functional relevance and molecular mechanisms of 3D genome organization. Here, we summarize recent advances that link the reorganization of genome architecture to the remodeling of transcriptional programs and conversion of cell fates during T cell activation and differentiation. We further discuss how various chromatin architecture regulators, including CCCTC‐binding factor and several transcription factors, collectively modulate the genome architecture during this process. [ABSTRACT FROM AUTHOR]

IntroductionFollicle development is a critical process in the female reproductive system, with significant implications for fertility and reproductive health. Germinal vesicle (GV) oocytes are primary oocytes that are arrested in the dictyate stage, also known as the diplotene stage of meiotic prophase I. Metaphase II (MII) is the stage at which the oocyte is typically retrieved for assisted reproductive technologies such as in vitro fertilization (IVF). The granulosa cells play a pivotal role in follicle development processes. 3D chromatin organization is a fundamental aspect of cellular biology that has significant implications for gene regulation and cellular function.MethodsIn this study, we investigated 3D chromatin organization in granulosacells from GV and MII follicles, which is essential for understanding the regulatory mechanisms governing oocyte development.ResultsThe results revealed distinct compartmentalization patterns,including stable genomic regions and transitions during oocyte maturation. Notably, there was a significant shift in functional gene activation, particularly in processes related to hormone metabolic pathways. Furthermore, alterations in topologically associating domains (TADs) were observed, with differential expression observed in genes that are involved in crucial biological processes. The analysis also identified a subset of genes with altered promoter-enhancer interactions (PEIs), reflecting a regulatory shift in gene expression related to reproductive processes.DiscussionThese findings provide valuable insights into 3D genome organization in granulosa cells with implications for reproductive health and the development of assisted reproductive technologies. Understanding spatial genome organization at different stages of follicular development may help realize novel strategies for enhancing success rates in assisted reproductive technologies.

Abstract Background Cotton is a major world cash crop and an important source of natural fiber, oil, and protein. Drought stress is becoming a restrictive factor affecting cotton production. To facilitate the development of drought-tolerant cotton varieties, it is necessary to study the molecular mechanism of drought stress response by exploring key drought-resistant genes and related regulatory factors. Results In this study, two cotton varieties, ZY007 (drought-sensitive) and ZY168 (drought-tolerant), showing obvious phenotypic differences under drought stress, were selected. A total of 25,898 drought-induced genes were identified, exhibiting significant enrichment in pathways related to plant stress responses. Under drought induction, At subgenome expression bias was observed at the whole-genome level, which may be due to stronger inhibition of Dt subgenome expression. A gene co-expression module that was significantly associated with drought resistance was identified. About 90% of topologically associating domain (TAD) boundaries were stable, and 6613 TAD variation events were identified between the two varieties under drought. We identified 92 genes in ZY007 and 98 in ZY168 related to chromatin 3D structural variation and induced by drought stress. These genes are closely linked to the cotton response to drought stress through canonical hormone-responsive pathways, modulation of kinase and phosphatase activities, facilitation of calcium ion transport, and other related molecular mechanisms. Conclusions These results lay a foundation for elucidating the molecular mechanism of the cotton drought response and provide important regulatory locus and gene resources for the future molecular breeding of drought-resistant cotton varieties.

Abstract Background Multiple studies have demonstrated a negative correlation between gene expression and positioning of genes at the nuclear envelope (NE) lined by nuclear lamina, but the exact relationship remains unclear, especially in light of the highly stochastic, transient nature of the gene association with the NE. Results In this paper, we ask whether there is a causal, systematic, genome-wide relationship between the expression levels of the groups of genes in topologically associating domains (TADs) of Drosophila nuclei and the probabilities of TADs to be found at the NE. To investigate the nature of this possible relationship, we combine a coarse-grained dynamic model of the entire Drosophila nucleus with genome-wide gene expression data; we analyze the TAD averaged transcription levels of genes against the probabilities of individual TADs to be in contact with the NE in the control and lamins-depleted nuclei. Our findings demonstrate that, within the statistical error margin, the stochastic positioning of Drosophila melanogaster TADs at the NE does not, by itself, systematically affect the mean level of gene expression in these TADs, while the expected negative correlation is confirmed. The correlation is weak and disappears completely for TADs not containing lamina-associated domains (LADs) or TADs containing LADs, considered separately. Verifiable hypotheses regarding the underlying mechanism for the presence of the correlation without causality are discussed. These include the possibility that the epigenetic marks and affinity to the NE of a TAD are determined by various non-mutually exclusive mechanisms and remain relatively stable during interphase. Conclusions At the level of TADs, the probability of chromatin being in contact with the nuclear envelope has no systematic, causal effect on the transcription level in Drosophila. The conclusion is reached by combining model-derived time-evolution of TAD locations within the nucleus with their experimental gene expression levels.

Background: Multiple studies have demonstrated a negative correlation between gene expression and positioning of genes at the nuclear envelope (NE) lined by nuclear lamina, but the exact relationship remains unclear, especially in light of the highly stochastic, transient nature of the gene association with the NE. Results: In this paper, we ask whether there is a causal, systematic, genome-wide relationship between the expression levels of the groups of genes in topologically associating domains (TADs) of Drosophila nuclei and the probabilities of TADs to be found at the NE. To investigate the nature of this possible relationship, we combine a coarse-grained dynamic model of the entire Drosophila nucleus with genome-wide gene expression data; we analyze the TAD averaged transcription levels of genes against the probabilities of individual TADs to be in contact with the NE in the control and lamins-depleted nuclei. Our findings demonstrate that, within the statistical error margin, the stochastic positioning of Drosophila melanogaster TADs at the NE does not, by itself, systematically affect the mean level of gene expression in these TADs, while the expected negative correlation is confirmed. The correlation is weak and disappears completely for TADs not containing lamina-associated domains (LADs) or TADs containing LADs, considered separately. Verifiable hypotheses regarding the underlying mechanism for the presence of the correlation without causality are discussed. These include the possibility that the epigenetic marks and affinity to the NE of a TAD are determined by various non-mutually exclusive mechanisms and remain relatively stable during interphase. Conclusions: At the level of TADs, the probability of chromatin being in contact with the nuclear envelope has no systematic, causal effect on the transcription level in Drosophila. The conclusion is reached by combining model-derived time-evolution of TAD locations within the nucleus with their experimental gene expression levels. [ABSTRACT FROM AUTHOR]

Eukaryotic genomes are structurally organized via the formation of multiple loops that create gene expression regulatory units called topologically associating domains (TADs). Here we revealed the KSHV TAD structure at 500 bp resolution and constructed a 3D KSHV genomic structural model with 2 kb binning. The latent KSHV genome formed very similar genomic architectures in three different naturally infected PEL cell lines and in an experimentally infected epithelial cell line. The majority of the TAD boundaries were occupied by structural maintenance of chromosomes (SMC1) cohesin complex and CCCTC-binding factor (CTCF), and the KSHV transactivator was recruited to those sites during reactivation. Triggering KSHV gene expression decreased prewired genomic loops within the regulatory unit, while contacts extending outside of regulatory borders increased, leading to formation of a larger regulatory unit with a shift from repressive to active compartments (B to A). The 3D genomic structural model proposes that the immediate early promoter region is localized on the periphery of the 3D viral genome during latency, while highly inducible noncoding RNA regions moved toward the inner space of the structure, resembling the configuration of a "bird cage" during reactivation. The compartment-like properties of viral episomal chromatin structure and its reorganization during the transition from latency may help facilitate viral gene transcription. IMPORTANCE The 3D architecture of chromatin allows for efficient arrangement, expression, and replication of genetic material. The genomes of all organisms studied to date have been found to be organized through some form of tiered domain structures. However, the architectural framework of the genomes of large double-stranded DNA viruses such as the herpesvirus family has not been reported. Prior studies with Kaposi's sarcoma-associated herpesvirus (KSHV) have indicated that the viral chromatin shares many biological properties exhibited by the host cell genome, essentially behaving as a mini human chromosome. Thus, we hypothesized that the KSHV genome may be organized in a similar manner. In this report, we describe the domain structure of the latent and lytic KSHV genome at 500 bp resolution and present a 3D genomic structural model for KSHV under each condition. These results add new insights into the complex regulation of the viral life cycle.

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State-of-the-art manufacturing of tissue paper by Through Air Drying provides excellent product performance, although at a high production cost and energy use. In this work, a laboratory scale vacuum suction box was used to mimic the initial dewatering and the Through Air Drying molding, together with a pilot-scale trial. The purpose was to investigate both how the laboratory scale corresponds to pilot scale testing and investigate how fabric design, basis weight, beating, and fibers affect dewatering and sheet caliper. This study reevaluates dewatering mechanisms during molding, challenging the previous hypothesis of pure air displacement dewatering. Results show a parallel mechanism of compression dewatering and air displacement. The influence of rush transfer is examined, impacting the sheets’ visual appearance, thickness, and solids content. Correlations between molding box solids content and headbox freeness emphasize significance of fibers and beating levels. Pilot results confirm the link between former solids and molding box solids. Pilot trials validate the laboratory results, facilitating comprehensive simulation of full-scale manufacturing. This research reveals dewatering mechanisms, highlights operational parameters, and enables effective Through Air Drying process design and refinement.

Orthodontic miniscrews (MSs) are used for enhancing orthodontic anchorage either by supporting the teeth of the reactive unit or by obviating the need for the reactive unit altogether. Despite MSs’ popularity, their clinical application is not lacking in complications. The limited space of the insertion site (inter-radicular space), temporary use (limiting osseointegration) and the necessity to minimize the biological cost of insertion (bone incision) required the size of this auxiliary to be reduced, making it susceptible to mechanical failure. This review aimed to investigate factors influencing MS plastic deformation and fracture. The search applied five engines: PubMed, PMC, Web of Science, Scopus, Embase, and Ebsco. Quality assessment was performed according to the QUIN tool. After a thorough search process, 22 articles were included in this review. The most important factor influencing miniscrews’ plastic deformation and fracture was the screw diameter. The MS length and metal alloy did not influence its plastic deformation or fracture. The cylindrical design of the screw is preferable. If the cortical bone thickness in the insertion site exceeds 3 mm, pre-drilling upon insertion is recommended. Orthodontic MSs should not be reused. There is a need for high-quality clinical studies on the subject of MS deformation and fracture. The PROSPERO number is CRD42024509895.

Heterochromatin and euchromatin form different spatial compartments in the interphase nucleus, with heterochromatin being localized mainly at the nuclear periphery. The mechanisms responsible for peripheral localization of heterochromatin are still not fully understood. The nuclear lamina and nuclear pore complexes were obvious candidates for the role of heterochromatin binders. This review is focused on recent studies showing that heterochromatin interactions with the nuclear lamina and nuclear pore complexes maintain its peripheral localization. Differences in chromatin interactions with the nuclear envelope in cell populations and in individual cells are also discussed. [ABSTRACT FROM AUTHOR]

State-of-the-art manufacturing of tissue paper by Through Air Drying provides excellent product performance, although at a high production cost and energy use. In this work, a laboratory scale vacuum suction box was used to mimic the initial dewatering and the Through Air Drying molding, together with a pilot-scale trial. The purpose was to investigate both how the laboratory scale corresponds to pilot scale testing and investigate how fabric design, basis weight, beating, and fibers affect dewatering and sheet caliper. This study reevaluates dewatering mechanisms during molding, challenging the previous hypothesis of pure air displacement dewatering. Results show a parallel mechanism of compression dewatering and air displacement. The influence of rush transfer is examined, impacting the sheets' visual appearance, thickness, and solids content. Correlations between molding box solids content and headbox freeness emphasize significance of fibers and beating levels. Pilot results confirm the link between former solids and molding box solids. Pilot trials validate the laboratory results, facilitating comprehensive simulation of full-scale manufacturing. This research reveals dewatering mechanisms, highlights operational parameters, and enables effective Through Air Drying process design and refinement. [ABSTRACT FROM AUTHOR]

Rooted in self-determination theory (Deci and Ryan), our study focuses on students' perceived teacher support (TS) in different disciplines and on variables related to TS in PE. Data was collected through a questionnaire completed by 640 secondary school students. Results reveald an academic discipline effect and links between TS in PE and need of competence, grade level, enrolment in school sports association (SA). These results highlight the ability of PE teachers to create social links with their students and confirm the positive impact on the satisfaction of students' need for competence. Furthermore, the impact of the SA on perceived teacher support in PE suggests that school sport associations and other school clubs may have a positive impact on the social bond between students and their teachers. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Temporary anchorage devices (TADs) are skeletal anchorage devices. They are minimally invasive and placed by the orthodontist to prevent unwanted tooth movement. This study evaluated the survival rate of orthodontic TADs at 6 months. This study also assessed the effect of age, gender, side, site, dental arch of placement, and length of the TADs on its survival rate. MATERIALS AND METHODS: Ethical approval was obtained from the Health Research Ethics Committee of the hospital. The study sample comprised orthodontic patients who required the placement of TADs during treatment at a private dental facility in Lagos. Data for the study were obtained from the case files of the study subjects and included the subjects’ age, gender, date of placement of the TADs, the site, side and arch of placement, the length of the TADs, and the survival rate of 6 months after placement. RESULTS: We reviewed 90 placed TADs and observed a survival rate of 88.9%. Most TAD failures occurred in the first month of placement (p = 001). There was no observable statistically significant effect of all other variables assessed (age, gender, arch, site, side, or implant length) on the survival rate of the TADs. CONCLUSIONS: The survival rate of TADs was high. Most TAD failures significantly occurred within one month of placement. There was no significant association between all other clinical variables and orthodontic mini‑implant survival. [ABSTRACT FROM AUTHOR]

Energy use, together with consumption of raw materials, machine clothing, and wet end chemicals, are some of the most critical aspects in successful tissue making today. This work was aimed at developing a laboratory-scale method of estimating dewatering mechanisms, vacuum efficiency, and energy use of Through Air Drying (TAD) of tissue. When compared to pilot data, the results of the new laboratory method for investigating dewatering during TAD were in the same magnitude, around 24 to 26% dryness after vacuum dewatering, and 27 to 29% dryness after TAD molding. Sheet properties, such as caliper and surface profile, were evaluated and compared to commercial tissue sheets. The results indicate that it will be possible to precisely measure accurate dryness development and penetrated air volume for tissue sheet forming and TAD molding at a laboratory scale. This can contribute to the efforts of implementing a circular forest-based bioeconomy by increasing the fundamental understanding of dewatering of tissue paper materials, which is facilitated by improvements in energy use. The new method developed in this work will make it easier to assess ideas that are difficult to bring to pilot scale or full scale before learning more of the dewatering capabilities. The authors are convinced that improved knowledge of tissue dewatering mechanisms, forming, and material transport during and after TAD dewatering can increase the efficiency of the industrial manufacturing processes.

Background: Methylation quantitative trait loci (meQTLs) associate with different levels of local DNA methylation in cancers. Here, we investigated whether the distribution of cancer meQTLs reflected functional organization of the genome in the form of chromatin topologically associated domains (TADs) and evaluated whether cancer meQTLs near known driver genes have the potential to influence cancer risk or progression. Methods: Published cancer meQTLs were analyzed according to their location in transcriptionally active or inactive TADs and TAD boundary regions. Cancer meQTLs near known cancer genes were analyzed for association with cancer risk in the UKBioBank , and prognosis in The Cancer Genome Atlas (TCGA). Results: In TAD boundary regions, the density of cancer meQTLs was higher near inactive TADs. Furthermore, we observed an enrichment of cancer meQTLs in active TADs near tumor suppressors, whereas there was a depletion of such meQTLs near oncogenes. Several meQTLs were associated with cancer risk in the UKBioBank, and we were able to reproduce breast cancer risk associations in the DRIVE cohort. Survival analysis in TCGA implicated a number of meQTLs in 13 tumor types. In 10 of these, polygenic cancer meQTL scores were associated with increased hazard in a CoxPH analysis. Risk and survival-associated meQTLs tended to affect cancer genes involved in DNA damage repair and cellular adhesion and reproduced cancer-specific associations reported in prior literature. Conclusions: This study provides evidence that genetic variants that influence local DNA methylation are affected by chromatin structure and can impact tumor evolution.

A 9,10‐dihydro‐9‐oxa‐10 phosphophenanthrene‐10‐oxide based derivative tris‐(3‐dopo‐propyl)‐triazine trione (TAD) is applied to polyethylene terephthalate (PET). The melting and blending process of the composite is carried out through twin screws. The flame retardancy, thermostability, and mechanical property have elevated with slight load agent. The limiting oxygen index (LOI), vertical burning test (UL 94), and cone calorimeter test are proceeded to sustain the flame retardancy of PET/TAD‐x. The 30.2% LOI value and UL 94V‐1 rating will be attained with 5 wt% load, the peak of heat release rate show 33.4% decrease, concurrently. The thermogravimetric analysis is performed to characterized the constancy of flame retardant composites during the heating process. Relevant evidence express that TAD provided appreciable assistance in improving carbon‐forming capacity and postponing initial decomposition temperature. The Raman spectra, TG‐Fourier transform infrared, Hot‐Stage FTIR are used to explain the connection about the optimization of performance and the alteration of products in pyrolyzing or after pyrolyzation. In addition, the mechanical properties are supported via tensile and impact test. This study confirms TAD has great potential competitiveness in future halogen‐free flame retardant applications as viable and environmentally friendly to polyester material. [ABSTRACT FROM AUTHOR]

Topologically associating domains (TADs) are functional chromatin units with hierarchical structure. However, the existence, prevalence, and dynamics of such hierarchy in single cells remain unexplored. Here, a new generation TAD‐like domain (TLD) detection algorithm, named deDoc2, to decode the hierarchy of TLDs in single cells, is reported. With dynamic programming, deDoc2 seeks genome partitions with global minimal structure entropy for both whole and local contact matrix. Notably, deDoc2 outperforms state‐of‐the‐art tools and is one of only two tools able to identify the hierarchy of TLDs in single cells. By applying deDoc2, it is showed that the hierarchy of TLDs in single cells is highly dynamic during cell cycle, as well as among human brain cortex cells, and that it is associated with cellular identity and functions. Thus, the results demonstrate the abundance of information potentially encoded by TLD hierarchy for functional regulation. The deDoc2 can be freely accessed at https://github.com/zengguangjie/deDoc2. [ABSTRACT FROM AUTHOR]

An 18.7-year-old female patient with an anterior open bite and an ankylosed left maxillary central incisor was referred from a private orthodontic clinic. Canine relationships were Class II and molar relationships were Class I. The open bite was closed with the multiloop edgewise archwire and up-and-down elastics. The maxillary left central incisor was extruded by dentoalveolar distraction assisted with mini-implants. Active treatment took 2 years and 1 month, and the treatment result remained stable 14 months after debonding. [ABSTRACT FROM AUTHOR]

Whereas folding of genomes at the large scale of epigenomic compartments and topologically associating domains (TADs) is now relatively well understood, how chromatin is folded at finer scales remains largely unexplored in mammals. Here, we overcome some limitations of conventional 3C-based methods by using high-resolution Micro-C to probe links between 3D genome organization and transcriptional regulation in mouse stem cells. Combinatorial binding of transcription factors, cofactors, and chromatin modifiers spatially segregates TAD regions into various finer-scale structures with distinct regulatory features including stripes, dots, and domains linking promoters-to-promoters (P-P) or enhancers-to-promoters (E-P) and bundle contacts between Polycomb regions. E-P stripes extending from the edge of domains predominantly link co-expressed loci, often in the absence of CTCF and cohesin occupancy. Acute inhibition of transcription disrupts these gene-related folding features without altering higher-order chromatin structures. Our study uncovers previously obscured finer-scale genome organization, establishing functional links between chromatin folding and gene regulation.

Transient acantholytic dermatosis (TAD) is a relatively common entity that has been also noted to occur in patients with cancer. Herein, we describe a case of transient acantholytic dermatosis occurring in a patient with a history of prostate cancer status post radiation, now being treated with combination therapy with pembrolizumab and carboplatin-pemetrexed for advanced lung adenocarcinoma. Our case emphasizes the importance of being cognizant of TAD and its associations, particularly in cancer patients.

Abstract Background Recent increasing evidence indicates that three-dimensional chromosome structure plays an important role in genomic function. Topologically associating domains (TADs) are self-interacting regions that have been shown to be a chromosomal structural unit. During evolution, these are conserved based on checking synteny block cross species. Are there common TAD patterns across species or cell lines? Results To address the above question, we propose a novel task—TAD recognition—as opposed to traditional TAD identification. Specifically, we treat Hi-C maps as images, thus re-casting TAD recognition as image pattern recognition, for which we use a convolutional neural network and a residual neural network. In addition, we propose an elegant way to generate non-TAD data for binary classification. We demonstrate deep learning performance which is quite promising, AUC > 0.80, through cross-species and cell-type validation. Conclusions TADs have been shown to be conserved during evolution. Interestingly, our results confirm that the TAD recognition model is practical across species, which indicates that TADs between human and mouse show common patterns from an image classification point of view. Our approach could be a new way to identify TAD variations or patterns among Hi-C maps. For example, TADs of two Hi-C maps are conserved if the two classification models are exchangeable.

Abstract DNA loop extrusion emerges as a key process establishing genome structure and function. We introduce MoDLE, a computational tool for fast, stochastic modeling of molecular contacts from DNA loop extrusion capable of simulating realistic contact patterns genome wide in a few minutes. MoDLE accurately simulates contact maps in concordance with existing molecular dynamics approaches and with Micro-C data and does so orders of magnitude faster than existing approaches. MoDLE runs efficiently on machines ranging from laptops to high performance computing clusters and opens up for exploratory and predictive modeling of 3D genome structure in a wide range of settings.

Energy use, together with consumption of raw materials, machine clothing, and wet end chemicals, are some of the most critical aspects in successful tissue making today. This work was aimed at developing a laboratory-scale method of estimating dewatering mechanisms, vacuum efficiency, and energy use of Through Air Drying (TAD) of tissue. When compared to pilot data, the results of the new laboratory method for investigating dewatering during TAD were in the same magnitude, around 24 to 26% dryness after vacuum dewatering, and 27 to 29% dryness after TAD molding. Sheet properties, such as caliper and surface profile, were evaluated and compared to commercial tissue sheets. The results indicate that it will be possible to precisely measure accurate dryness development and penetrated air volume for tissue sheet forming and TAD molding at a laboratory scale. This can contribute to the efforts of implementing a circular forest-based bioeconomy by increasing the fundamental understanding of dewatering of tissue paper materials, which is facilitated by improvements in energy use. The new method developed in this work will make it easier to assess ideas that are difficult to bring to pilot scale or full scale before learning more of the dewatering capabilities. The authors are convinced that improved knowledge of tissue dewatering mechanisms, forming, and material transport during and after TAD dewatering can increase the efficiency of the industrial manufacturing processes. [ABSTRACT FROM AUTHOR]

Tooth ankylosis is a disorder characterized by the fusion of tooth and alveolar bone. This case report describes the treatment of a severe open bite due to tooth ankylosis. A 14-year-old female patient with a chief complaint of masticatory dysfunction was diagnosed with skeletal Class III severe anterior open bite and tooth ankylosis. She visited our university hospital with a chief complaint of an anterior open bite. After the surgical luxation of the ankylosed maxillary right central incisor, the tooth was orthodontically retracted using a nickel-titanium wire. The right mandibular lateral incisor and canine were luxated and retracted using intermaxillary elastics from a temporary anchorage device (TAD), which was inserted in the opposite jaw. During the treatment, skeletal Class III malocclusion deteriorated due to anterior growth of the mandible. Therefore, TADs were inserted into the retromolar pad on both sides of the mandible and retracted into the mandibular dental arch. Although the mandibular right canine was luxated several times, it could not be brought to the occlusal line, and was thus extracted; the extraction space was replaced with a prosthesis. Consequently, a normal overjet and overbite with a straight profile were achieved. Extrusion of ankylosed teeth by intermaxillary elastics from a TAD is a valid treatment option for patients with severe open bites. [ABSTRACT FROM AUTHOR]

Introduction: Lateral fractures of proximal femur are the most frequent fractures in elderly people. Internal fixation using medullary nails is the gold standard of treatment (Gamma 3 nail is the most implanted device) due to reduced incidence of complications than other devices. We report our experience in treating this kind of fractures with Gamma 3 nail, between January 2015 and December 2021. Methods: We performed a retrospective cohort study of patients treated in our orthopaedic department; level of clinical care is III: 559 patients (431 females and 128 males, with an average age of 85.3 years) with lateral femoral neck fracture. All patients were surgically treated with Gamma 3 standard nail (SGN). We evaluated preliminary X-rays to classify fractures, according to AO-OTA classification and post-operative X-ray to verify cephalic screw position site, according to areas described by Cleveland in 1959: we measured tip-to-apex distance (TAD) and tip-to-apex calcar referred distance (CalTAD). Finally Chang reduction quality criteria (CRQC) for fracture reduction of trochanteric fractures were determined using preoperative or postoperative Antero-Posterior (AP) and lateral radiographs in a Picture Archiving and Communication System (PACS). Incidence of cut-out was evaluated in relation with these parameters. Patients were divided into 2 groups: first group had cephalic screw in optimal positions (5-8-9), the other group had cephalic screw in other positions. Results: In 328 patients (58.7%) screw was in positions 5-8-9, in 231 patients (41.2%) screw was in not-optimal position. Median TAD was 19.1 ± 7.0 mm (range = 0.0–50.5); in 463 patients (82.8%) TAD was ≤ 25 mm. Median CalTAD was 21.4 ± 4.7 mm (range = 5.7–39.2); in 105 patients (79.4%) CalTAD was ≤ 25 mm. Cut-out was observed in 8 cases (1.43%). Multivariate analysis showed a significant correlation (p 25 mm. Cephalic screw position did not influence incidence of cut-out. Discussion: In order to obtain fracture healing with a low risk of failure, in particular cut-out, it is necessary to obtain good reduction of fracture and optimal lag screw position in order to achieve a TAD inferior to 25 mm.

Mammalian genomes are folded into topologically associating domains (TADs), consisting of chromatin loops anchored by CTCF and cohesin. Some loops are cell-type specific. Here we asked whether CTCF loops are established by a universal or locus-specific mechanism. Investigating the molecular determinants of CTCF clustering, we found that CTCF self-association in vitro is RNase sensitive and that an internal RNA-binding region (RBRi) mediates CTCF clustering and RNA interaction in vivo. Strikingly, deleting the RBRi impairs about half of all chromatin loops in mESCs and causes deregulation of gene expression. Disrupted loop formation correlates with diminished clustering and chromatin binding of RBRi mutant CTCF, which in turn results in a failure to halt cohesin-mediated extrusion. Thus, CTCF loops fall into at least two classes: RBRi-independent and RBRi-dependent loops. We speculate that evidence for RBRi-dependent loops may provide a molecular mechanism for establishing cell-specific CTCF loops, potentially regulated by RNA(s) or other RBRi-interacting partners.

Achieving a quantitative and predictive understanding of 3D genome architecture remains a major challenge, as it requires quantitative measurements of the key proteins involved. Here, we report the quantification of CTCF and cohesin, two causal regulators of topologically associating domains (TADs) in mammalian cells. Extending our previous imaging studies (Hansen et al., 2017), we estimate bounds on the density of putatively DNA loop-extruding cohesin complexes and CTCF binding site occupancy. Furthermore, co-immunoprecipitation studies of an endogenously tagged subunit (Rad21) suggest the presence of cohesin dimers and/or oligomers. Finally, based on our cell lines with accurately measured protein abundances, we report a method to conveniently determine the number of molecules of any Halo-tagged protein in the cell. We anticipate that our results and the established tool for measuring cellular protein abundances will advance a more quantitative understanding of 3D genome organization, and facilitate protein quantification, key to comprehend diverse biological processes.

Este trabajo se encuadra en un proyecto de investigación que se desarrolla en la Universidad Nacional del Comahue, Argentina. Está centrado en la enseñanza de la matemática para la formación de futuros ingenieros y tiene por objetivo el análisis de los problemas que vinculan conceptos de diversas disciplinas con el estudio de los sistemas de ecuaciones lineales en materias de primer año de carreras de ingeniería. El referencial teórico utilizado es la Teoría Antropológica de lo Didáctico. A partir de una muestra de libros de Álgebra Lineal, seleccionamos problemas relativos a circuitos eléctricos, flujo de red y mínimos cuadrados. Para el análisis de los mismos utilizamos un instrumento basado en constructos de la TAD. Estas aplicaciones de los sistemas de ecuaciones lineales promueven la ejercitación de determinadas técnicas que ya han sido explicitadas por los autores a través de ejemplos; como así también el uso de software. Asimismo, requieren un trabajo colaborativo entre especialistas y docentes que dictan asignaturas matemáticas para futuros ingenieros a fin de atender criteriosamente al contexto extramatemático de las mismas.

Background: Recent increasing evidence indicates that three-dimensional chromosome structure plays an important role in genomic function. Topologically associating domains (TADs) are self-interacting regions that have been shown to be a chromosomal structural unit. During evolution, these are conserved based on checking synteny block cross species. Are there common TAD patterns across species or cell lines? Results: To address the above question, we propose a novel task—TAD recognition—as opposed to traditional TAD identification. Specifically, we treat Hi-C maps as images, thus re-casting TAD recognition as image pattern recognition, for which we use a convolutional neural network and a residual neural network. In addition, we propose an elegant way to generate non-TAD data for binary classification. We demonstrate deep learning performance which is quite promising, AUC > 0.80, through cross-species and cell-type validation. Conclusions: TADs have been shown to be conserved during evolution. Interestingly, our results confirm that the TAD recognition model is practical across species, which indicates that TADs between human and mouse show common patterns from an image classification point of view. Our approach could be a new way to identify TAD variations or patterns among Hi-C maps. For example, TADs of two Hi-C maps are conserved if the two classification models are exchangeable. [ABSTRACT FROM AUTHOR]

Background: Despite recent advances in implants and surgical techniques, catastrophic and clinical failures in the treatment of intertrochanteric fractures continue to occur, with dire consequences in an overall frail population subset. The aim of the current study is to evaluate the effect of the factors under the surgeons' control, namely fracture reduction and implant selection, on the biomechanical behavior of fracture fixation constructs.Material-methods: An experimental protocol was conducted with the use of instrumented sawbones, in order to validate the finite element models. The implants used were the Gamma3®and DHS systems. Subsequently, a series of scenaria were considered, including various reduction and implant angle combinations. Data were retrieved concerning the peak cancellous bone stresses around the hip screw and the volume of cancellous bone in the femoral head stressed at critical levels, as well as implant stresses and stresses on the cortical bone of the distal fragment.Results: All stable fracture models displayed significantly decreased cancellous bone stresses and implant stresses compared to their unstable counterparts, regardless of implant used. The effect of increasing implant angle led to a decrease in implant stresses in all models studied, but had a beneficial effect on the stresses in the cancellous bone of the proximal fragment only in the subgroups of stable fractures with both implants and unstable fractures treated with a cephalomedullary nail (CMN). In unstable fractures anatomically reduced, the use of CMN led to significantly lower peak stresses in the cancellous bone and a smaller volume of bone stressed at critical levels. Increasing the reduction angle by 5 ° led to a significant decrease in both peak stresses and volume of bone stressed at critical levels, more prominent in the sliding hip screw (SHS) models. Decreasing the reduction angle into varus by 5 or 10 ° led to a significant increase in bone and implant stresses regardless of implant used.Conclusions: In stable two-part (AO31.A2) fractures the use of the SHS appears to be biomechanically equivalent to CMN. In unstable, anatomically reduced fractures, the use of CMN leads to significantly reduced cancellous bone stresses and decreased rotation of the proximal fragment during loading. A reduction in varus should be avoided at all costs. In unstable fractures treated with SHS a reduction in slight valgus appears to be biomechanically beneficial. The highest implant angle that allows for proper screw position and trajectory in the femoral head should be used for stable fractures with both implants and unstable fractures treated with Gamma3®. [ABSTRACT FROM AUTHOR]

[Display omitted] • Rice whole-genome duplication leads to alterations of phenotypes, gene transcriptions, 3D chromatin structures and DNA methylation. • Three-dimensional (3D) chromatin architectures including chromatin compartments and topologically associating domains (TADs) are uncorrelated with gene transcription upon rice genome duplication. • The first study to reveal the mechanism regarding the disconnection between 3D genome architecture and gene transcription. • Hypermethylated transposable elements (TEs) suppress the role of 3D chromatin structure in modulating gene transcription upon rice genome duplication. Polyploidy is a major force in plant evolution and the domestication of cultivated crops. The study aimed to explore the relationship and underlying mechanism between three-dimensional (3D) chromatin organization and gene transcription upon rice genome duplication. The 3D chromatin structures between diploid (2C) and autotetraploid (4C) rice were compared using high-throughput chromosome conformation capture (Hi-C) analysis. The study combined genetics, transcriptomics, whole-genome bisulfite sequencing (WGBS-seq) and 3D genomics approaches to uncover the mechanism for DNA methylation in modulating gene transcription through 3D chromatin architectures upon rice genome duplication. We found that 4C rice presents weakened intra-chromosomal interactions compared to its 2C progenitor in some chromosomes. In addition, we found that changes of 3D chromatin organizations including chromatin compartments, topologically associating domains (TADs), and loops, are uncorrelated with gene transcription. Moreover, DNA methylations in the regulatory sequences of genes in compartment A/B switched regions and TAD boundaries are unrelated to their expression. Importantly, although there was no significant difference in the methylation levels in transposable elements (TEs) in differentially expressed gene (DEG) and non-DEG promoters between 2C and 4C rice, we found that the hypermethylated TEs across genes in compartment A/B switched regions and TAD boundaries may suppress the expression of these genes. The study proposed that the rice genome doubling might modulate TE methylation to buffer the effects of chromatin architecture on gene transcription in compartment A/B switched regions and TAD boundaries, resulting in the disconnection between 3D chromatin structure alteration and gene transcription upon rice genome duplication. [ABSTRACT FROM AUTHOR]

Abstract Background A growing body of evidence has revealed that the mammalian genome is organized into hierarchical layers that are closely correlated with and may even be causally linked with variations in gene expression. Recent studies have characterized chromatin organization in various porcine tissues and cell types and compared them among species and during the early development of pigs. However, how chromatin organization differs among pig breeds is poorly understood. Results In this study, we investigated the 3D genome organization and performed transcriptome characterization of two adipose depots (upper layer of backfat [ULB] and greater omentum [GOM]) in wild boars and Bama pigs; the latter is a typical indigenous pig in China. We found that over 95% of the A/B compartments and topologically associating domains (TADs) are stable between wild boars and Bama pigs. In contrast, more than 70% of promoter-enhancer interactions (PEIs) are dynamic and widespread, involving over a thousand genes. Alterations in chromatin structure are associated with changes in the expression of genes that are involved in widespread biological functions such as basic cellular functions, endocrine function, energy metabolism and the immune response. Approximately 95% and 97% of the genes associated with reorganized A/B compartments and PEIs in the two pig breeds differed between GOM and ULB, respectively. Conclusions We reported 3D genome organization in adipose depots from different pig breeds. In a comparison of Bama pigs and wild boar, large-scale compartments and TADs were mostly conserved, while fine-scale PEIs were extensively reorganized. The chromatin architecture in these two pig breeds was reorganized in an adipose depot-specific manner. These results contribute to determining the regulatory mechanism of phenotypic differences between Bama pigs and wild boar.

Recent studies have characterized the genomic structures of many eukaryotic cells, often focusing on their relation to gene expression. However, these studies have largely investigated cells grown in 2D cultures, although the transcriptomes of 3D-cultured cells are generally closer to their in vivo phenotypes. To examine the effects of spatial constraints on chromosome conformation, we investigated the genomic architecture of mouse hepatocytes grown in 2D and 3D cultures using in situ Hi-C. Our results reveal significant differences in higher-order genomic interactions, notably in compartment identity and strength as well as in topologically associating domain (TAD)–TAD interactions, but only minor differences are found at the TAD level. Our RNA-seq analysis reveals an up-regulated expression of genes involved in physiological hepatocyte functions in the 3D-cultured cells. These genes are associated with a subset of structural changes, suggesting that differences in genomic structure are critically important for transcriptional regulation. However, there are also many structural differences that are not directly associated with changes in gene expression, whose cause remains to be determined. Overall, our results indicate that growth in 3D significantly alters higher-order genomic interactions, which may be consequential for a subset of genes that are important for the physiological functioning of the cell.

This review discusses our current understanding of chromatin biology and bioinformatics under the unifying concept of “chromatin hubs.” The first part reviews the biology of chromatin hubs, including chromatin–chromatin interaction hubs, chromatin hubs at the nuclear periphery, hubs around macromolecules such as RNA polymerase or lncRNAs, and hubs around nuclear bodies such as the nucleolus or nuclear speckles. The second part reviews existing computational methods, including enhancer–promoter interaction prediction, network analysis, chromatin domain callers, transcription factory predictors, and multi-way interaction analysis. We introduce an integrated model that makes sense of the existing evidence. Understanding chromatin hubs may allow us (i) to explain long-unsolved biological questions such as interaction specificity and redundancy of mechanisms, (ii) to develop more realistic kinetic and functional predictions, and (iii) to explain the etiology of genomic disease.

Introduction: Determination of difference between conventional and passive self-ligating brackets (SLBs) in respect of extraction space closure, patient perception and root resorption. Material and Methods: Eighty patients were divided into four groups of 20 each with age-sex-matched control using a simple randomisation technique and allocation concealment with a closed opaque envelope method. Group 1 consisted of conventional brackets with Connecticut New Archwire (CNA) wire mushroom loop, group 2 consisted of conventional brackets with TAD (AbsoAnchor, Korea) supported retraction, group 3 consisted of passive SLB with CNA archwires (Libral Traders, India) mushroom loop and group 4 consisted of passive SLB brackets with TAD (AbsoAnchor, Korea) supported retraction. The rate of retraction, root resorption and patient satisfaction were assessed. All conventional brackets (Orthox, USA) and passive SLBs (CaptainOrtho, India) had 0.018 Roth prescriptions with a slot size of 0.018 × 0.025. Results: Retraction was the fastest in group 2 with a mean of 1.266 ± 0.14 mm/4 week and a duration of 23.40 weeks. Similarly, group 4 showed the most sluggish movement with a mean of 1.182 ± 0.80 mm/4 weeks with a total duration of 25 weeks; howeverdifferencesce among groups were not statistically significant (P = 0.470). Conclusion: SLBs have advantage of better patient comfort, less pain and reduced chairside time. Though the present study found increased treatment duration with SLB along with friction mechanics, refuting the previous claims of reduced friction with SLBs, however, the difference was not statistically significant and results have to be extrapolated with caution and experience considering other advantages of SLBs.

With the development of Hi-C technology, the detection of topologically associated domains (TADs) boundaries plays an important role in exploring the relationship between gene structure and expression. However, a method that can identify accurate TAD boundaries from the Hi-C contact matrix with different resolutions is currently lacking. We proposed a method named CASPIAN that can identify chromatin TAD boundaries based on the spatial density clustering algorithm. CASPIAN requires few parameters to call TADs. This method is realized using the hierarchical density-based clustering method HDBSCAN, where the distance of pairwise bins is calculated based on three distance metrics (Euclidean, Manhattan, and Chebyshev distance metric) to adapt to the characteristics of the Hi-C contact matrix generated from simulation experiments or normalized methods. Our results show that, same as standard methods (e.g., Insulation Score, TopDom), CASPIAN can enrich factors related to promoting the gene expression, such as CTCF, H3K4me1, H3K4me3, RAD21, POLR2A, and SMC3. We also calculated the approximate proportion of various factors anchored at the TAD boundaries to observe the distribution of these factors surrounding the TAD boundaries. In conclusion, CASPIAN is an easy method to explore the relationship between transcription factors and TAD boundaries. CASPIAN is available online (https://gitee.com/ghaiyan/caspian).

The spatial organization of chromosomes is involved in regulating the majority of intranuclear processes in higher eukaryotes, including gene expression. Drosophila was used as a model to discover many transcription factors whose homologs play a key role in regulation of gene expression in mammals. According to modern views, a cohesin complex mostly determines the architecture of mammalian chromosomes by forming chromatin loops on anchors created by the CTCF DNA-binding architectural protein. The role of the cohesin complex in chromosome architecture is poorly understood in Drosophila, and CTCF is merely one of many Drosophila architectural proteins with a proven potential to organize specific long-range interactions between regulatory elements in the genome. The review compares the mechanisms responsible for long-range interactions and chromosome architecture between mammals and Drosophila.

The spatial organization of chromosomes is involved in regulating the majority of intranuclear processes in higher eukaryotes, including gene expression. Drosophila was used as a model to discover many transcription factors whose homologs play a key role in regulation of gene expression in mammals. According to modern views, a cohesin complex mostly determines the architecture of mammalian chromosomes by forming chromatin loops on anchors created by the CTCF DNA-binding architectural protein. The role of the cohesin complex in chromosome architecture is poorly understood in Drosophila, and CTCF is merely one of many Drosophila architectural proteins with a proven potential to organize specific longrange interactions between regulatory elements in the genome. The review compares the mechanisms responsible for long-range interactions and chromosome architecture between mammals and Drosophila. [ABSTRACT FROM AUTHOR]

Point mutations and structural variants that directly disrupt the coding sequence of MEF2C have been associated with a spectrum of neurodevelopmental disorders (NDDs). However, the impact of MEF2C haploinsufficiency on neurodevelopmental pathways and synaptic processes is not well understood, nor are the complex mechanisms that govern its regulation. To explore the functional changes associated with structural variants that alter MEF2C expression and/or regulation, we generated an allelic series of 204 isogenic human induced pluripotent stem cell (hiPSC)-derived neural stem cells and glutamatergic induced neurons. These neuronal models harbored CRISPR-engineered mutations that involved direct deletion of MEF2C or deletion of the boundary points for topologically associating domains (TADs) and chromatin loops encompassing MEF2C. Systematic profiling of mutation-specific alterations, contrasted to unedited controls that were exposed to the same guide RNAs for each edit, revealed that deletion of MEF2C caused differential expression of genes associated with neurodevelopmental pathways and synaptic function. We also discovered significant reduction in synaptic activity measured by multielectrode arrays (MEAs) in neuronal cells. By contrast, we observed robust buffering against MEF2C regulatory disruption following deletion of a distal 5q14.3 TAD and loop boundary, whereas homozygous loss of a proximal loop boundary resulted in down-regulation of MEF2C expression and reduced electrophysiological activity on MEA that was comparable to direct gene disruption. Collectively, these studies highlight the considerable functional impact of MEF2C deletion in neuronal cells and systematically characterize the complex interactions that challenge a priori predictions of regulatory consequences from structural variants that disrupt three-dimensional genome organization. [Display omitted] The authors present functional characterization of a CRISPR-engineered allelic series of deletions altering MEF2C and the 3D regulatory architecture encompassing the 5q14.3 microdeletion syndrome region. They find that direct deletion of MEF2C and some, but not all, 3D regulatory interactions result in shared transcriptional and electrophysiological deficits in early neurodevelopment. [ABSTRACT FROM AUTHOR]

Topologically associating domains (TADs) are chromatin domains in the eukaryotic genome. TADs often comprise several sub-TADs. The boundaries of TADs and sub-TADs are enriched in CTCF, an architectural protein. Deletion of CTCF-binding motifs at one boundary disrupts the domains, often resulting in a transcriptional decrease in genes inside the domains. However, it is not clear how TAD and sub-TAD affect each other in the domain formation. Unaffected gene transcription was observed in the β-globin locus when one boundary of TAD or sub-TAD was destroyed. Here, we disrupted β-globin TAD and sub-TAD by deleting CTCF motifs at both boundaries in MEL/ch11 cells. Disruption of TAD impaired sub-TAD, but sub-TAD disruption did not affect TAD. Both TAD and sub-TAD disruption compromised the β-globin transcription, accompanied by the loss of enhancer-promoter interactions. However, histone H3 occupancy and H3K27ac were largely maintained across the β-globin locus. Genome-wide analysis showed that putative enhancer-promoter interactions and gene transcription were decreased by the disruption of CTCF-mediated topological domains in neural progenitor cells. Collectively, our results indicate that there is unequal relationship between TAD and sub-TAD formation. TAD is likely not sufficient for gene transcription, and, therefore, sub-TAD appears to be required. TAD-dependently formed sub-TADs are considered to provide chromatin environments for enhancer-promoter interactions enabling gene transcription., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Long-range transcriptional activation of gene promoters by abundant enhancers in animal genomes calls for mechanisms to limit inappropriate regulation. DNA elements called insulators serve this purpose by shielding promoters from an enhancer when interposed. Unlike promoters and enhancers, insulators have not been systematically characterized due to lacking high-throughput screening assays, and questions regarding how insulators are distributed and encoded in the genome remain. Here, we establish "insulator-seq" as a plasmid-based massively parallel reporter assay in Drosophila cultured cells to perform a systematic insulator screen of selected genomic loci. Screening developmental gene loci showed that not all insulator protein binding sites effectively block enhancer-promoter communication. Deep insulator mutagenesis identified sequences flexibly positioned around the CTCF insulator protein binding motif that are critical for functionality. The ability to screen millions of DNA sequences without positional effect has enabled functional mapping of insulators and provided further insights into the determinants of insulators., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Innate anti-inflammatory mechanisms are essential for immune homeostasis and can present opportunities to intervene inflammatory diseases. In this report, we found that YAP isoform 9 (YAP9) is an essential negative regulator of the potent inflammatory stimuli such as TNFα, IL-1β, and LPS. YAP9 constitutively interacts with another anti-inflammatory regulator A20 (TNFAIP3) to suppress inflammatory responses, but A20 and YAP can function only in the presence of the other. YAP9 uses a short stretch of amino acids in the proline-rich domain (PRD) and transactivation domain (TAD) suppress the inflammatory signaling while A20 mainly uses the zinc finger domain 7 (ZF7). Cell-penetrating synthetic PRD, TAD, and ZF7 peptides act as YAP9 and A20 mimetics respectively to suppress the proinflammatory responses at the cellular level and in mice. Our data uncover a novel anti-inflammatory axis and anti-inflammatory agents that can be developed to treat acute or chronic conditions where TNFα, IL-1β, or LPS plays a key role in initiating and/or perpetuating inflammation. [ABSTRACT FROM AUTHOR]