Choroid plexus mast cells drive tumor-associated hydrocephalus.

Tumor-associated hydrocephalus (TAH) is a common and lethal complication of brain metastases. Although other factors beyond mechanical obstructions have been suggested, the exact mechanisms are unknown. Using single-nucleus RNA sequencing and spatial transcriptomics, we find that a distinct population of mast cells locate in the choroid plexus and dramatically increase during TAH. Genetic fate tracing and intracranial mast-cell-specific tryptase knockout showed that choroid plexus mast cells (CPMCs) disrupt cilia of choroid plexus epithelia via the tryptase-PAR2-FoxJ1 pathway and consequently increase cerebrospinal fluid production. Mast cells are also found in the human choroid plexus. Levels of tryptase in cerebrospinal fluid are closely associated with clinical severity of TAH. BMS-262084, an inhibitor of tryptase, can cross the blood-brain barrier, inhibit TAH in vivo, and alleviate mast-cell-induced damage of epithelial cilia in a human pluripotent stem-cell-derived choroid plexus organoid model. Collectively, we uncover the function of CPMCs and provide an attractive therapy for TAH.

The evolution and diversification of oakleaf butterflies.

Oakleaf butterflies in the genus Kallima have a polymorphic wing phenotype, enabling these insects to masquerade as dead leaves. This iconic example of protective resemblance provides an interesting evolutionary paradigm that can be employed to study biodiversity. We integrated multi-omic data analyses and functional validation to infer the evolutionary history of Kallima species and investigate the genetic basis of their variable leaf wing patterns. We find that Kallima butterflies diversified in the eastern Himalayas and dispersed to East and Southeast Asia. Moreover, we find that leaf wing polymorphism is controlled by the wing patterning gene cortex, which has been maintained in Kallima by long-term balancing selection. Our results provide macroevolutionary and microevolutionary insights into a model species originating from a mountain ecosystem.

Genetic mechanisms of animal camouflage: an interdisciplinary perspective.

Camouflage is a classic example of a trait wherein animals respond to natural selection to avoid predation or attract prey. This unique phenomenon has attracted significant recent attention and the rapid development of integrative research methods is facilitating advances in our understanding of the in-depth genetic mechanisms of camouflage. In this review article, we revisit camouflage definitions and strategies and then we examine the underlying mechanisms of the two most common forms of camouflage, crypsis and masquerade, that have recently been elucidated using multiple approaches. We also discuss unresolved questions related to camouflage. Ultimately, we highlight the implications of camouflage for informing various key issues in ecology and evolution.

MAE-seq refines regulatory elements across the genome.

Proper cell fate determination relies on precise spatial and temporal genome-wide cooperation between regulatory elements (REs) and their targeted genes. However, the lengths of REs defined using different methods vary, which indicates that there is sequence redundancy and that the context of the genome may be unintelligible. We developed a method called MAE-seq (Massive Active Enhancers by Sequencing) to experimentally identify functional REs at a 25-bp scale. In this study, MAE-seq was used to identify 626879, 541617 and 554826 25-bp enhancers in mouse embryonic stem cells (mESCs), C2C12 and HEK 293T, respectively. Using ∼1.6 trillion 25 bp DNA fragments and screening 12 billion cells, we identified 626879 as active enhancers in mESCs as an example. Comparative analysis revealed that most of the histone modification datasets were annotated by MAE-Seq loci. Furthermore, 33.85% (212195) of the identified enhancers were identified as de novo ones with no epigenetic modification. Intriguingly, distinct chromatin states dictate the requirement for dissimilar cofactors in governing novel and known enhancers. Validation results show that these 25-bp sequences could act as a functional unit, which shows identical or similar expression patterns as the previously defined larger elements, Enhanced resolution facilitated the identification of numerous cell-specific enhancers and their accurate annotation as super enhancers. Moreover, we characterized novel elements capable of augmenting gene activity. By integrating with high-resolution Hi-C data, over 55.64% of novel elements may have a distal association with different targeted genes. For example, we found that the Cdh1 gene interacts with one novel and two known REs in mESCs. The biological effects of these interactions were investigated using CRISPR-Cas9, revealing their role in coordinating Cdh1 gene expression and mESC proliferation. Our study presents an experimental approach to refine the REs at 25-bp resolution, advancing the precision of genome annotation and unveiling the underlying genome context. This novel approach not only advances our understanding of gene regulation but also opens avenues for comprehensive exploration of the genomic landscape.

Dissection of 3D chromosome organization in Streptomyces coelicolor A3(2) leads to biosynthetic gene cluster overexpression.

The soil-dwelling filamentous bacteria, Streptomyces, is widely known for its ability to produce numerous bioactive natural products. Despite many efforts toward their overproduction and reconstitution, our limited understanding of the relationship between the host's chromosome three dimension (3D) structure and the yield of the natural products escaped notice. Here, we report the 3D chromosome organization and its dynamics of the model strain, Streptomyces coelicolor, during the different growth phases. The chromosome undergoes a dramatic global structural change from primary to secondary metabolism, while some biosynthetic gene clusters (BGCs) form special local structures when highly expressed. Strikingly, transcription levels of endogenous genes are found to be highly correlated to the local chromosomal interaction frequency as defined by the value of the frequently interacting regions (FIREs). Following the criterion, an exogenous single reporter gene and even complex BGC can achieve a higher expression after being integrated into the chosen loci, which may represent a unique strategy to activate or enhance the production of natural products based on the local chromosomal 3D organization.

Fusang: a framework for phylogenetic tree inference via deep learning.

Phylogenetic tree inference is a classic fundamental task in evolutionary biology that entails inferring the evolutionary relationship of targets based on multiple sequence alignment (MSA). Maximum likelihood (ML) and Bayesian inference (BI) methods have dominated phylogenetic tree inference for many years, but BI is too slow to handle a large number of sequences. Recently, deep learning (DL) has been successfully applied to quartet phylogenetic tree inference and tentatively extended into more sequences with the quartet puzzling algorithm. However, no DL-based tools are immediately available for practical real-world applications. In this paper, we propose Fusang (http://fusang.cibr.ac.cn), a DL-based framework that achieves comparable performance to that of ML-based tools with both simulated and real datasets. More importantly, with continuous optimization, e.g. through the use of customized training datasets for real-world scenarios, Fusang has great potential to outperform ML-based tools.

The Arabidopsis DREAM complex antagonizes WDR5A to modulate histone H3K4me2/3 deposition for a subset of genome repression.

The master transcriptional repressor DREAM (dimerization partner, RB-like, E2F and multivulval class B) complex regulates the cell cycle in eukaryotes, but much remains unknown about how it transmits repressive signals on chromatin to the primary transcriptional machinery (e.g., RNA polymerase II [Pol II]). Through a forward genetic screen, we identified BTE1 (barrier of transcription elongation 1), a plant-specific component of the DREAM complex. The subsequent characterization demonstrated that DREAM complex containing BTE1 antagonizes the activity of Complex Proteins Associated with Set1 (COMPASS)-like complex to repress H3K4me3 occupancy and inhibits Pol II elongation at DREAM target genes. We showed that BTE1 is recruited to chromatin at the promoter-proximal regions of target genes by E2F transcription factors. DREAM target genes exhibit characteristic enrichment of H2A.Z and H3K4me2 modification on chromatin. We further showed that BTE1 directly interacts with WDR5A, a core component of COMPASS-like complex, repressing WDR5A chromatin binding and the elongation of transcription on DREAM target genes. H3K4me3 is known to correlate with the Pol II transcription activation and promotes efficient elongation. Thus, our study illustrates a transcriptional repression mechanism by which the DREAM complex dampens H3K4me3 deposition at a set of genes through its interaction with WDR5A.

Genomic Consequences of and Demographic Response to Pervasive Hybridization Over Time in Climate-Sensitive Pikas.

Rare and geographically restricted species may be vulnerable to genetic effects from inbreeding depression in small populations or from genetic swamping through hybridization with common species, but a third possibility is that selective gene flow can restore fitness (genetic rescue). Climate-sensitive pikas (Ochotona spp.) of the Qinghai-Tibetan Plateau (QHTP) and its vicinity have been reduced to residual populations through the movement of climatic zones during the Pleistocene and recent anthropogenic disturbance, whereas the plateau pika (O. curzoniae) remains common. Population-level whole-genome sequencing (n = 142) of six closely related species in the subgenus Ochotona revealed several phases of ancient introgression, lineage replacement, and bidirectional introgression. The strength of gene flow was the greatest from the dominant O. curzoniae to ecologically distinct species in areas peripheral to the QHTP. Genetic analyses were consistent with environmental reconstructions of past population movements. Recurrent periods of introgression throughout the Pleistocene revealed an increase in genetic variation at first but subsequent loss of genetic variation in later phases. Enhanced dispersion of introgressed genomic regions apparently contributed to demographic recovery in three peripheral species that underwent range shifts following climate oscillations on the QHTP, although it failed to drive recovery of northeastern O. dauurica and geographically isolated O. sikimaria. Our findings highlight differences in timescale and environmental background to determine the consequence of hybridization and the unique role of the QHTP in conserving key evolutionary processes of sky island species.

Inferring Historical Introgression with Deep Learning.

Resolving phylogenetic relationships among taxa remains a challenge in the era of big data due to the presence of genetic admixture in a wide range of organisms. Rapidly developing sequencing technologies and statistical tests enable evolutionary relationships to be disentangled at a genome-wide level, yet many of these tests are computationally intensive and rely on phased genotypes, large sample sizes, restricted phylogenetic topologies, or hypothesis testing. To overcome these difficulties, we developed a deep learning-based approach, named ERICA, for inferring genome-wide evolutionary relationships and local introgressed regions from sequence data. ERICA accepts sequence alignments of both population genomic data and multiple genome assemblies, and efficiently identifies discordant genealogy patterns and exchanged regions across genomes when compared with other methods. We further tested ERICA using real population genomic data from Heliconius butterflies that have undergone adaptive radiation and frequent hybridization. Finally, we applied ERICA to characterize hybridization and introgression in wild and cultivated rice, revealing the important role of introgression in rice domestication and adaptation. Taken together, our findings demonstrate that ERICA provides an effective method for teasing apart evolutionary relationships using whole genome data, which can ultimately facilitate evolutionary studies on hybridization and introgression.

Immunotherapy for Ovarian Cancer: Disappointing or Promising?

Ovarian cancer, one of the deadliest malignancies, lacks effective treatment, despite advancements in surgical techniques and chemotherapy. Thus, new therapeutic approaches are imperative to improving treatment outcomes. Immunotherapy, which has demonstrated considerable success in managing various cancers, has already found its place in clinical practice. This review aims to provide an overview of ovarian tumor immunotherapy, including its basics, key strategies, and clinical research data supporting its potential. In particular, this discussion highlights promising strategies such as checkpoint inhibitors, vaccines, and pericyte transfer, both individually and in combination. However, the advancement of new immunotherapies necessitates large controlled randomized trials, which will undoubtedly shape the future of ovarian cancer treatment.

Challenges for density functional theory in simulating metal-metal singlet bonding: A case study of dimerized VO2.

VO2 is renowned for its electric transition from an insulating monoclinic (M1) phase, characterized by V-V dimerized structures, to a metallic rutile (R) phase above 340 K. This transition is accompanied by a magnetic change: the M1 phase exhibits a non-magnetic spin-singlet state, while the R phase exhibits a state with local magnetic moments. Simultaneous simulation of the structural, electric, and magnetic properties of this compound is of fundamental importance, but the M1 phase alone has posed a significant challenge to the density functional theory (DFT). In this study, we show none of the commonly used DFT functionals, including those combined with on-site Hubbard U to treat 3d electrons better, can accurately predict the V-V dimer length. The spin-restricted method tends to overestimate the strength of the V-V bonds, resulting in a small V-V bond length. Conversely, the spin-symmetry-breaking method exhibits the opposite trends. Each of these two bond-calculation methods underscores one of the two contentious mechanisms, i.e., Peierls lattice distortion or Mott localization due to electron-electron repulsion, involved in the metal-insulator transition in VO2. To elucidate the challenges encountered in DFT, we also employ an effective Hamiltonian that integrates one-dimensional magnetic sites, thereby revealing the inherent difficulties linked with the DFT computations.

Longitudinal patterns of patient-reported sleep disturbances after surgery for lung cancer.

PURPOSE: The purpose of this study was to identify longitudinal heterogeneous trajectories of sleep status, adjusted for the effect of pain over time, among patients who had surgery for lung cancer and to quantify how disturbed sleep in the hospital affects functional recovery after discharge. METHODS: We included patients from a surgical cohort (CN-PRO-Lung 1). All patients reported symptoms using the MD Anderson Symptom Inventory-Lung Cancer (MDASI-LC) daily during postoperative hospitalization. Group-based dual trajectory modeling was used to investigate trajectories of disturbed sleep and pain during the first 7 days of postoperative hospitalization. Cox regression was used to compare the recovery of walking ability between the different sleep trajectories. RESULTS: Among 421 patients, disturbed sleep trajectories comprised low (31%), moderate (52%), and high (17%) groups. The surgical approach and number of chest tubes were associated with pain, and the number of chest tubes was also associated with sleep disturbances (OR = 1.99; 95% CI: 1.08-3.67). Recovery of walking ability after discharge was significantly slower in the high (median days = 16; 95% CI: 5-NA) and moderate disturbed sleep trajectory groups (median days = 5; 95%CI: 4-6) than in the low group (median days = 3; 95% CI: 3-4). CONCLUSION: Changes in disturbed sleep among patients with lung cancer followed three distinct trajectories over the first 7 days of hospitalization after surgery. Dual trajectory analyses highlighted the high concordance between specific trajectories of disturbed sleep and pain. Patients at high sleep disturbance and high levels of pain may benefit from appropriate interventions for both symptoms in combination with the patient's surgical approach and the number of chest tubes.

Diterpenoid Alkaloids from Delphinium ajacis and Their Anti-inflammatory Activity.

Three novel diterpenoid alkaloids, comprising two C19 -diterpenoid alkaloids (1 and 2) and one C20 -diterpenoid alkaloid (3), were isolated from Delphinium ajacis, alongside the six known compounds (4-9). Their structures were elucidated by spectroscopic methods (MS, UV, IR, 1D and 2D NMR) and chemical properties. Simultaneously, the anti-inflammatory properties of all compounds (1-9) was conducted, focusing on nitric oxide (NO) production in LPS-induced BV-2 cells. The results indicated compounds 1-3, 7, and 8 have potential anti-inflammatory activity.

Phenolic and flavonoid compounds from the fruit shell of Camellia oleifera.

A new phenolic compound oleiphenol (1), and a new dihydrochalcone oleifechalcone (2) along with seven known compounds (3-9) were isolated from the fruit shell of Camellia oleifera Abel. The planar structures of compounds 1 and 2 were determined on the basis of extensive spectroscopic analyses (IR, UV, NMR, and HR-ESI-MS) and comparison with literature data. The absolute configurations of the new structures were determined by ECD calculations and chemical methods. In addition, compounds 1-9 underwent a series of pharmacological activity tests, including cytotoxic, anti-inflammatory, anti-RSV and antioxidant activities.

Efficient benzo(a)pyrene degradation by coal gangue-based catalytic material for peroxymonosulfate activation.

A low cost and green peroxymonosulfate (PMS) activation catalyst (CG-Ca-N) was successfully prepared with coal gangue (CG), calcium chloride, and melamine as activator. Under the optimal conditions, the CG-Ca-N can remove 100 % for benzo(a)pyrene (Bap) in an aqueous solution after 20 min and 72.06 % in soil slurry medium within 60 min, which also display excellent reuse ability toward Bap after three times. The removal of Bap is significantly decreased when the initial pH value was greater than 9 and obviously inhibited in the presence of HCO3- or SO42-. The characterization results indicated that the addition of calcium chloride could stabilize and increase the content of pyridinic N during thermal annealing, resulting in the production of •OH, SO4•- and 1O2. Based on electron paramagnetic resonance (EPR) and active radical scavenging experiments, 1O2 could be identified to be the dominant role in Bap degradation. Overall, this work opened a new perspective for the low cost and green PMS catalysts and offered great promise in the practical remediation of organic pollution of groundwater and soil.

An SPRI beads-based DNA purification strategy for flexibility and cost-effectiveness.

BACKGROUND: Current solid-phase reversible immobilization (SPRI) beads technology is widely used in molecular biology due to its convenience for DNA manipulation. However, the high performance commercial SPRI beads have no price advantage over our method. Furthermore, the use of commercially available SPRI beads standards does not provide the flexibility required for a number of specific nucleic acid handling scenarios. RESULTS: We report an efficient DNA purification strategy by combining home-made beads-suspension buffer with SPRI beads. The method tests the critical concentrations of polyethylene glycol (PEG) 8000 and beads to maximise recovery. And the composition of the SPRI beads DNA purification system (SDPS) was determined at 20% PEG 8000, 2 M NaCl and 16.3 mM MgCl2, and 1.25 mg/ml beads (1/8th original concentration). Then, we tested the DNA recovery of the SDPS, and the result showed that it was comparable to the control (AMPure XP beads). In the study, we have also developed an adjustment SPRI beads DNA purification system (ASDPS), the volume of ASDPS per reaction is 0.6× reaction volume (beads/samples). The performance of ASDPS is similar to SDPS and the control. But the cost of our methods is only about 1/24th of the control. To further assess its performance, we prepare the DNA-seq libraries to evaluate the yield, library quality, capture efficiency and consistency. We have compared all these results with the performance of the control and confirmed its efficiency. CONCLUSION: We have proposed an alternative DNA purification approach with great flexibility, allowing researchers to manipulate DNA in different conditions. And ultimately, its application will benefit molecular biology research in the future.

Correlation of coagulation states with prognosis of sudden deafness.

Prognosis of sudden deafness remains a challenge in clinics because of inhomogeneity of the disease. Here we report our retrospective study aimed to explore the value of coagulative markers including activated partial thromboplastin time (APTT), prothrombin time (PT), plasma fibrinogen (FIB), and plasma D-dimer in the prognosis of patients. The study included a total of 160 patients, of whom 92 had valid responses, 68 had invalid responses, and 68 had ineffective responses. APTT, PT, and the levels of FIB and D-dimer in serum were compared between the two groups, and their prognostic values were determined in terms of area under the curve (AUC) in receiver operating curve (ROC) analysis, sensitivity, and specificity. The correlations of APTT, PT, and FIB to degree of hearing loss were also assessed. Serum APTT and PT, FIB, and D-dimer levels were lower in patients with sudden deafness who responded poorly to treatments. ROC analysis showed that APTT, PT, FIB, and D-dimer had high AUC, sensitivity, and specificity for nonresponders, particularly when used in combination (AUC = 0.91, sensitivity = 86.76%, and specificity = 82.61%). Patients with a higher degree of hearing loss (>91 dB) also demonstrated significantly lower values of APTT and PT and higher levels of serum FIB and D-dimer than those with a lower degree of hearing loss. Our study demonstrated that APTT, PT, and serum levels of FIB and D-dimer could serve as strong predictors of sudden deafness, potentiating the use of these tests to identify patients who respond poorly to treatments.NEW & NOTEWORTHY Our retrospective study indicated that lower serum APTT and PT levels and higher fibrinogen (FIB) and D-dimer levels are characteristics associated with poor treatment responses among patients with sudden deafness. A combination of these levels had a high accuracy in identifying the nonresponders. APTT, PT, and serum levels of FIB and D-dimer could serve as strong predictors of sudden deafness, potentiating the use of these tests to identify patients who respond poorly to treatments.

266 nm ultraviolet communication under unknown interference using UVC micro-LED.

Ultraviolet C (UVC) micro light-emitting diode (LED) can achieve symbol communication rate up to 100Msps at distance 40 meters without transmitter-side lens to guarantee certain communication mobility. We consider what we believe to be a new scenario where high speed UV communciation is realized under unknown low-rate interference. The signal amplitude properties are characterized, and the interference intensity is categorized into three cases, namely weak, medium and high interference intensity. The achievable transmission rates for the three cases are derived, where the achievable transmission rate for medium interference intensity can approach those in weak interference intensity and strong interference intensity cases. We provide Gaussian approximation and related log-likelihood ratio (LLR) calculation, which are fed into the subsequent message-passing decoder. In the experiment, the data is transmitted with symbol rate 20 Msps under unknown interference with symbol rate 1 Msps, received by one photomultiplier tube (PMT). Experimental results show that the proposed interference symbol estimation approach shows negligibly higher bit error rate (BER) compared with those with perfect knowledge on the interference symbols.

Risk stratification and molecular heterogeneity of endometrial cancer and expression profile of TIM-3: A retrospective cohort study.

OBJECTIVE: The present study aimed to implement ProMisE classification and risk grouping on a retrospective cohort of 628 patients with endometrial cancer (EC) and determine the molecular heterogeneity across subtypes and subgroups, as well as to investigate the potential beneficiary for TIM-3 checkpoint inhibition in ECs. METHODS: Protein expressions of p53, MMR, TIM-3 and CD8 were measured by immunohistochemistry, and massively parallel sequencing was conducted for 128 cancer-related genes. Patients were categorized into four ProMisE subtypes: MMR-deficient (MMRd), POLE-ultramutated (POLEmut), p53-wild type (p53wt), and p53-abnormal (p53abn), and were subjected to risk classification. RESULTS: 43 (6.9%) patients belonged to POLEmut, 118 (18.8%) to MMRd, 69 (11%) to p53abn, and 398 (63.3%) to p53wt. Compared to the 2016 stratification system, the 2021 ESGO/ESTRO/ESP risk stratification integrated with molecular classification revealed that 11 patients (11/628, 1.8%) were upgraded due to the p53abn signature, whereas 23 patients (23/628, 3.7%) were downgraded due to the POLEmut signature. JAK1 and RAD50 mutations showed higher frequencies in patients with aggressive phenotypes. RAD51B mutation was significantly related to poor RFS of the p53wt subtype but not of the other three molecular subgroups. TIM-3 expression was detected in 30.9% immune cells (ICs) and 29.0% tumor cells (TCs) in ECs, respectively. It was frequently expressed in POLEmut and MMRd ECs as compared to that in the other two molecular subtypes in TCs and ICs. CONCLUSIONS: Our study revealed the molecular heterogeneity across subtypes and subgroups. The new risk stratification system changed the risk grouping of some patients due to the integration of molecular features. RAD51B mutation can further stratify the recurrence risk in the p53wt subtype. Patients with MMRd or POLEmut may benefit most from immunotherapy against TIM-3.

Application of interface treatment at different positionp-nc-Si:H hole collector of silicon heterojunction cells.

The hole collector in silicon heterojunction cells serves not only as an integral component of thep/njunction, determining the strength of the built-in electric field, but also as a layer responsible for hole transport, thereby affecting carrier transport capacity. To enhance carrier extraction and transport properties of the hole collector, various interface treatments have been employed onp-type nanocrystalline (p-nc-Si:H) hole collectors. Through an examination of characteristics such as dark conductivity, crystallinity, and contact resistance, the impact of interface treatment onp-nc-Si:H hole collectors is clarified. Furthermore, considering distinct requirements for the hole collector at different locations, interface treatment processes are optimized accordingly. The introduction of interface treatment onp-nc-Si:H hole collectors has demonstrated significant enhancement of both front and rear junction cell efficiencies, which increased from 17.74% to 21.61% and from 16.83% to 20.92%, respectively.