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Objectives: Subtrochanteric fractures have anatomic characteristics distinct from intertrochanteric fractures that may affect the positioning of the spiral blade during surgical treatment. Tip‐apex distance (TAD) and calcar‐referenced tip‐apex distance (Cal‐TAD) were measured to determine if these measures are reliable indicators to assist in the accurate placement of intramedullary nails and minimize postoperative complications. Methods: For patients treated with proximal femoral nail antirotation (PFNA) internal fixation between 2016 and 2020, we analyzed the TAD, Cal‐TAD, and postoperative complications. Fracture healing was assessed radiographically at 6‐week intervals until union. The incidences of axial cut‐off, cephalad cut‐off, and non‐union were also examined. Analysis of variance and Fisher's exact test were performed to evaluate differences in complications between the TAD and Cal‐TAD groups. Results: Data from 104 patients (58 males, 46 females) with a mean age of 56.9 years were analyzed. Fracture healing was observed in 90 (86.5%) patients at an average time of 14.92 ± 1.81 weeks. The healing rate was significantly higher when the TAD and Cal‐TAD were controlled within the 20–25 mm range (p < 0.05). Postoperative complications occurred in 14 (13.5%) cases [cephalad cut‐off, n = 5 (4.8%); axial cut‐off, n = 4 (3.8%); non‐union, n = 5 (4.8%)]. Five (4.8%) complications occurred without internal fixation failure. The fracture healing time and incidence of complications differed among groups defined by TAD and Cal‐TAD measurements, and were shortest and lowest, respectively, in the 20 mm < TAD/Cal‐TAD < 25 mm group. Conclusions: In our cohort, use of PFNA internal fixation for treatment of unstable femoral subtrochanteric fractures and placement of the spiral blade in the middle or lower 1/3 of the femoral neck did not increase the incidence of complications. Therefore, we propose that the TAD rule of 20–30 mm should not apply to subtrochanteric fractures, and TAD and Cal‐TAD should be controlled within the range of 20–25 mm to reduce the incidence of complications.

DEEP LEARNING FOR THE EARTH SCIENCES Explore this insightful treatment of deep learning in the field of earth sciences, from four leading voices Deep learning is a fundamental technique in modern Artificial Intelligence and is being applied to disciplines across the scientific spectrum; earth science is no exception.

Background Topologically associating domains (TADs) are genomic regions of self-interaction. Additionally, it is known that TAD boundaries are enriched in CTCF binding sites. In turn, CTCF sites are known to be asymmetric, whereby the convergent configuration of a pair of CTCF sites leads to the formation of a chromatin loop in vivo. However, to date, it has been unclear how to reconcile TAD structure with CTCF-based chromatin loops. Results We approach this problem by analysing CTCF binding site strengths and classifying clusters of CTCF sites along the genome on the basis of their relative orientation. Analysis of CTCF site orientation classes as a function of their spatial distribution along the human genome reveals that convergent CTCF site clusters are depleted while divergent CTCF clusters are enriched in the 5- to 100-kb range. We then analyse the distribution of CTCF binding sites as a function of TAD boundary conservation across seven primary human blood cell types. This reveals divergent CTCF site enrichment at TAD boundaries. Furthermore, convergent arrays of CTCF sites separate the left and right sections of TADs that harbour internal CTCF sites, resulting in unequal TAD ‘halves’. Conclusions The orientation-based CTCF binding site cluster classification that we present reconciles TAD boundaries and CTCF site clusters in a mechanistically elegant fashion. This model suggests that the emergent structure of nuclear chromatin in the form of TADs relies on the obligate alternation of divergent and convergent CTCF site clusters that occur at different length scales along the genome. Graphical abstract

Background Topologically associating domains (TADs) are important building blocks of three-dimensional genome architectures. The formation of TADs has been shown to depend on cohesin in a loop-extrusion mechanism. Recently, advances in an image-based spatial genomics technique known as chromatin tracing lead to the discovery of cohesin-independent TAD-like structures, also known as single-cell domains, which are highly variant self-interacting chromatin domains with boundaries that occasionally overlap with TAD boundaries but tend to differ among single cells and among single chromosome copies. Recent computational modeling studies suggest that epigenetic interactions may underlie the formation of the single-cell domains. Results Here we use chromatin tracing to visualize in female human cells the fine-scale chromatin folding of inactive and active X chromosomes, which are known to have distinct global epigenetic landscapes and distinct population-averaged TAD profiles, with inactive X chromosomes largely devoid of TADs and cohesin. We show that both inactive and active X chromosomes possess highly variant single-cell domains across the same genomic region despite the fact that only active X chromosomes show clear TAD structures at the population level. These X chromosome single-cell domains exist in distinct cell lines. Perturbations of major epigenetic components and transcription mostly do not affect the frequency or strength of the single-cell domains. Increased chromatin compaction of inactive X chromosomes occurs at a length scale above that of the single-cell domains. Conclusions In sum, this study suggests that single-cell domains are genome architecture building blocks independent of the tested major epigenetic components.

Chromosome conformation capture data, particularly from high-throughput approaches such as Hi-C, are typically very complex to analyse. Existing analysis tools are often single-purpose, or limited in compatibility to a small number of data formats, frequently making Hi-C analyses tedious and time-consuming. Here, we present FAN-C, an easy-to-use command-line tool and powerful Python API with a broad feature set covering matrix generation, analysis, and visualisation for C-like data ( https://github.com/vaquerizaslab/fanc ). Due to its compatibility with the most prevalent Hi-C storage formats, FAN-C can be used in combination with a large number of existing analysis tools, thus greatly simplifying Hi-C matrix analysis.

Transposable element (TE) amplification has been recognized as a driving force mediating genome size expansion and evolution, but the consequences for shaping 3D genomic architecture remains largely unknown in plants. Here, we report reference-grade genome assemblies for three species of cotton ranging 3-fold in genome size, namely Gossypium rotundifolium (K2), G. arboreum (A2), and G. raimondii (D5), using Oxford Nanopore Technologies. Comparative genome analyses document the details of lineage-specific TE amplification contributing to the large genome size differences (K2, 2.44 Gb; A2, 1.62 Gb; D5, 750.19 Mb) and indicate relatively conserved gene content and synteny relationships among genomes. We found that approximately 17% of syntenic genes exhibit chromatin status change between active (“A”) and inactive (“B”) compartments, and TE amplification was associated with the increase of the proportion of A compartment in gene regions (∼7,000 genes) in K2 and A2 relative to D5. Only 42% of topologically associating domain (TAD) boundaries were conserved among the three genomes. Our data implicate recent amplification of TEs following the formation of lineage-specific TAD boundaries. This study sheds light on the role of transposon-mediated genome expansion in the evolution of higher-order chromatin structure in plants.

Animal genomes are organized into topologically associated domains (TADs). TADs are thought to contribute to gene regulation by facilitating enhancer-promoter (E-P) contacts within a TAD and preventing these contacts across TAD borders. However, the absolute difference in contact frequency across TAD boundaries is usually less than 2-fold, even though disruptions of TAD borders can change gene expression by 10-fold. Existing models fail to explain this hypersensitive response. Here, we propose a futile cycle model of enhancer-mediated regulation that can exhibit hypersensitivity through bistability and hysteresis. Consistent with recent experiments, this regulation does not exhibit strong correlation between E-P contact and promoter activity, even though regulation occurs through contact. Through mathematical analysis and stochastic simulation, we show that this system can create an illusion of E-P biochemical specificity and explain the importance of weak TAD boundaries. It also offers a mechanism to reconcile apparently contradictory results from recent global TAD disruption with local TAD boundary deletion experiments. Together, these analyses advance our understanding of cis-regulatory contacts in controlling gene expression and suggest new experimental directions.

Michael Talkowski and colleagues analyze balanced chromosomal abnormalities in 273 individuals by whole-genome sequencing. Their findings suggest that sequence-level resolution improves prediction of clinical outcomes for balanced rearrangements and provides insight into pathogenic mechanisms such as altered gene regulation due to changes in chromosome topology. Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C , a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.

Background Three-dimensional spatial organization of chromosomes is defined by highly self-interacting regions 0.1–1 Mb in size termed Topological Associating Domains (TADs). Genetic factors that explain dynamic variation in TAD structure are not understood. We hypothesize that common structural variation (SV) in the human population can disrupt regulatory sequences and thereby influence TAD formation. To determine the effects of SVs on 3D chromatin organization, we performed chromosome conformation capture sequencing (Hi-C) of lymphoblastoid cell lines from 19 subjects for which SVs had been previously characterized in the 1000 genomes project. We tested the effects of common deletion polymorphisms on TAD structure by linear regression analysis of nearby quantitative chromatin interactions (contacts) within 240 kb of the deletion, and we specifically tested the hypothesis that deletions at TAD boundaries (TBs) could result in large-scale alterations in chromatin conformation. Results Large (> 10 kb) deletions had significant effects on long-range chromatin interactions. Deletions were associated with increased contacts that span the deleted region and this effect was driven by large deletions that were not located within a TAD boundary (nonTB). Some deletions at TBs, including a 80 kb deletion of the genes CFHR1 and CFHR3, had detectable effects on chromatin contacts. However for TB deletions overall, we did not detect a pattern of effects that was consistent in magnitude or direction. Large inversions in the population had a distinguishable signature characterized by a rearrangement of contacts that span its breakpoints. Conclusions Our study demonstrates that common SVs in the population impact long-range chromatin structure, and deletions and inversions have distinct signatures. However, the effects that we observe are subtle and variable between loci. Genome-wide analysis of chromatin conformation in large cohorts will be needed to quantify the influence of common SVs on chromatin structure.

Background The three-dimensional spatial organization of the genome plays important roles in chromatin accessibility and gene expression in multiple biological processes and has been reported to be altered in response to environmental stress. However, the functional changes in spatial genome organization during environmental changes in crop plants are poorly understood. Results Here we perform Hi-C, ATAC-seq, and RNA-seq in two agronomically important rice cultivars, Nipponbare (Nip; Japonica ) and 93-11 ( Indica ), to report a comprehensive profile of nuclear dynamics during heat stress (HS). We show that heat stress affects different levels of chromosome organization, including A/B compartment transition, increase in the size of topologically associated domains, and loss of short-range interactions. The chromatin architectural changes were associated with chromatin accessibility and gene expression changes. Comparative analysis revealed that 93-11 exhibited more dynamic gene expression and chromatin accessibility changes, including HS-related genes, consistent with observed higher HS tolerance in this cultivar. Conclusions Our data uncovered higher-order chromatin architecture as a new layer in understanding transcriptional regulation in response to heat stress in rice.