Repression and 3D-restructuring resolves regulatory conflicts in evolutionarily rearranged genomes.

Regulatory landscapes drive complex developmental gene expression, but it remains unclear how their integrity is maintained when incorporating novel genes and functions during evolution. Here, we investigated how a placental mammal-specific gene, Zfp42, emerged in an ancient vertebrate topologically associated domain (TAD) without adopting or disrupting the conserved expression of its gene, Fat1. In ESCs, physical TAD partitioning separates Zfp42 and Fat1 with distinct local enhancers that drive their independent expression. This separation is driven by chromatin activity and not CTCF/cohesin. In contrast, in embryonic limbs, inactive Zfp42 shares Fat1's intact TAD without responding to active Fat1 enhancers. However, neither Fat1 enhancer-incompatibility nor nuclear envelope-attachment account for Zfp42's unresponsiveness. Rather, Zfp42's promoter is rendered inert to enhancers by context-dependent DNA methylation. Thus, diverse mechanisms enabled the integration of independent Zfp42 regulation in the Fat1 locus. Critically, such regulatory complexity appears common in evolution as, genome wide, most TADs contain multiple independently expressed genes.

Structural remodeling of AAA+ ATPase p97 by adaptor protein ASPL facilitates posttranslational methylation by METTL21D.

p97 is an essential AAA+ ATPase that extracts and unfolds substrate proteins from membranes and protein complexes. Through its mode of action, p97 contributes to various cellular processes, such as membrane fusion, ER-associated protein degradation, DNA repair, and many others. Diverse p97 functions and protein interactions are regulated by a large number of adaptor proteins. Alveolar soft part sarcoma locus (ASPL) is a unique adaptor protein that regulates p97 by disassembling functional p97 hexamers to smaller entities. An alternative mechanism to regulate the activity and interactions of p97 is by posttranslational modifications (PTMs). Although more than 140 PTMs have been identified in p97, only a handful of those have been described in detail. Here we present structural and biochemical data to explain how the p97-remodeling adaptor protein ASPL enables the metastasis promoting methyltransferase METTL21D to bind and trimethylate p97 at a single lysine side chain, which is deeply buried inside functional p97 hexamers. The crystal structure of a heterotrimeric p97:ASPL:METTL21D complex in the presence of cofactors ATP and S-adenosyl homocysteine reveals how structural remodeling by ASPL exposes the crucial lysine residue of p97 to facilitate its trimethylation by METTL21D. The structure also uncovers a role of the second region of homology (SRH) present in the first ATPase domain of p97 in binding of a modifying enzyme to the AAA+ ATPase. Investigation of this interaction in the human, fish, and plant reveals fine details on the mechanism and significance of p97 trimethylation by METTL21D across different organisms.

A visual bias for falling objects.

Aristotle believed that objects fell at a constant velocity. However, Galileo Galilei showed that when an object falls, gravity causes it to accelerate. Regardless, Aristotle's claim raises the possibility that people's visual perception of falling motion might be biased away from acceleration towards constant velocity. We tested this idea by requiring participants to judge whether a ball moving in a simulated naturalistic setting appeared to accelerate or decelerate as a function of its motion direction and the amount of acceleration/deceleration. We found that the point of subjective constant velocity (PSCV) differed between up and down but not between left and right motion directions. The PSCV difference between up and down indicated that more acceleration was needed for a downward-falling object to appear at constant velocity than for an upward "falling" object. We found no significant differences in sensitivity to acceleration for the different motion directions. Generalized linear mixed modeling determined that participants relied predominantly on acceleration when making these judgments. Our results support the idea that Aristotle's belief may in part be due to a bias that reduces the perceived magnitude of acceleration for falling objects, a bias not revealed in previous studies of the perception of visual motion.

Transcranial direct current stimulation in mild cognitive impairment: Behavioral effects and neural mechanisms.

INTRODUCTION: The long preclinical phase of Alzheimer's disease provides opportunities for potential disease-modifying interventions in prodromal stages such as mild cognitive impairment (MCI). Anodal transcranial direct current stimulation (anodal-tDCS), with its potential to enhance neuroplasticity, may allow improving cognition in MCI. METHODS: In a double-blind, cross-over, sham-controlled study, anodal-tDCS was administered to the left inferior frontal cortex during task-related and resting-state functional magnetic resonance imaging (fMRI) to assess its impact on cognition and brain functions in MCI. RESULTS: During sham stimulation, MCI patients produced fewer correct semantic-word-retrieval responses than matched healthy controls, which was associated with hyperactivity in bilateral prefrontal regions. Anodal-tDCS significantly improved performance to the level of controls, reduced task-related prefrontal hyperactivity and resulted in "normalization" of abnormal network configuration during resting-state fMRI. DISCUSSION: Anodal-tDCS exerts beneficial effects on cognition and brain functions in MCI, thereby providing a framework to test whether repeated stimulation sessions may yield sustained reversal of cognitive deficits.

Cofilin-induced changes in F-actin detected via cross-linking with benzophenone-4-maleimide.

Cofilin is a member of the actin depolymerizing factor (ADF)/cofilin family of proteins. It plays a key role in actin dynamics by promoting disassembly and assembly of actin filaments. Upon its binding, cofilin has been shown to bridge two adjacent protomers in filamentous actin (F-actin) and promote the displacement and disordering of subdomain 2 of actin. Here, we present evidence for cofilin promoting a new structural change in the actin filament, as detected via a switch in cross-linking sites. Benzophenone-4-maleimide, which normally forms intramolecular cross-linking in F-actin, cross-links F-actin intermolecularly upon cofilin binding. We mapped the cross-linking sites and found that in the absence of cofilin intramolecular cross-linking occurred between residues Cys374 and Asp11. In contrast, cofilin shifts the cross-linking by this reagent to intermolecular, between residue Cys374, located within subdomain 1 of the upper protomer, and Met44, located in subdomain 2 of the lower protomer. The intermolecular cross-linking of F-actin slows the rate of cofilin dissociation from the filaments and decreases the effect of ionic strength on cofilin-actin binding. These results are consistent with a significant role of filament flexibility in cofilin-actin interactions.

Validity of Machine Learning in Detecting Complicated Appendicitis in a Resource-Limited Setting: Findings from Vietnam.

Background: Complicated appendicitis, a potentially life-threatening condition, is common. However, the diagnosis of this condition is mainly based on physician's experiences and advanced diagnostic equipment. This study built and validated machine learning models to facilitate the detection of complicated appendicitis. Methods: A retrospective cohort study was conducted based on medical charts of all patients undergoing a laparoscopic appendectomy at a city hospital during 2016-2020. The synthetic minority over-sampling technique (SMOTE) was used to adjust for the imbalance. Multiple classification approaches were used to train and validate models including support vector machine (SVM), decision tree (DT), K-nearest neighbor (KNN), logistic regression (LR), artificial neural network (ANN), and gradient boosting (GB). Results: Among 1,950 patients included in the data analysis, there were 483 patients identified as having complicated appendicitis (24.8%). Based on data without SMOTE adjustment for imbalance, the accuracy levels and AUCs were high in all models using different parameters, ranging from 0.687 to 0.815. After adjusting for imbalance data using SMOTE, AUC and accuracy levels in the models using imbalance adjusted data were higher. Of these, the GB had all AUC and accuracy values of approximately 0.8 or more in both adjusted and unadjusted data. Conclusions: Machine learning approaches including SVM, DT, logistic, KNN, ANN, and GB have a high level of validity in classifying patients with complicated appendicitis and patients without complicated appendicitis. Among these, GB had the highest level of validity and should be used or further validated. Our study indicates the beneficial potentials of machine learning techniques in a clinical setting in general and in the diagnosis of complicated appendicitis in particular.

Investigation on Synthesis of Hydrogel Starting from Vietnamese Pineapple Leaf Waste-Derived Carboxymethylcellulose.

Carboxymethyl cellulose (CMC) is obtained from Vietnamese pineapple leaf waste through etherification. By treating pineapple leaf powder with a solution of NaOH then with HNO3 at 90°C for an appropriate time, cellulose can be efficiently extracted. To obtain CMC, carboxymethylation was performed by reaction of the pineapple cellulose with chloroacetic acid at 60°C for 1.5 h. The optimal conditions for this reaction were established. The resulting CMC had a degree of substitution (DS) of 0.91. The hydrogel was prepared by graft copolymerization of acrylic acid and acrylamide to the synthesized CMC. During that reaction, N,N'methylenebisacrylamide (MBA) served as the crosslinking agent and ammonium persulfate (APS) as the initiator. The maximum hydrogel absorbencies for distilled water and 0.9 wt.% NaCl solution were relatively high, namely, 588.2 g/g and 79.3 g/g, respectively. Additionally, the water swelling and water retention behaviors of the hydrogel in soil were also investigated. The results showed that this hydrogel can be employed as a suitable moisture-holding additive in soil for cultivation purposes.

Antiparallel dimer and actin assembly.

The antiparallel dimer (APD) is a unique actin species, which can be detected in the early stages of actin polymerization. In this work, we introduce novel tools for examination of the effects of the APD on actin polymerization. We document that bifunctional methanothiosulfonate (MTS) reagents are an attractive alternative to the routinely used p-phenylene maleimide (pPDM) for APD detection, allowing for fast and efficient cross-linking under conditions of actin polymerization at neutral pH. We report also that pyrene-labeled yeast actin mutant A167C/C374A (C167PM) forms significant amounts of stable APD in solution, without chemical cross-linking or polymerization-affecting compounds, and that the kinetics of APD transformation and decay upon actin polymerization can be easily monitored. The dimerization of C167PM has been characterized in sedimentation equilibrium experiments (K(d) approximately 0.3 microM). This new system offers the advantage of assessing the effects of the APD under physiological conditions (pH, ionic strength, and Mg(2+) concentration) and testing for conformational transitions in the APD during nucleation-polymerization reactions or/and in the presence of actin-interacting factors. The results obtained using two different systems (C167PM actin and polylysine-induced polymerization of alpha-actin) show that the APD decays at a rate slower than that at which the filaments elongate, revealing its transient incorporation into filaments, and confirm that it inhibits the nucleation and elongation of actin filaments.

Mental health among Vietnamese urban late adolescents: The association of parenting styles.

The aim of this study was to explore the correlation between parental styles and mental problems among Vietnamese high school students. In total, 16.4 percent of 757 eligible participants reported mental difficulties. Findings showed that being female and in grade 12 were risk factors to mental problems while living in Hue city was likely as a protective factor. The father's warmth reduced the risk of having mental problems among adolescents, while an overprotective mother increased the risk. There was no correlation between authoritarianism of both mother and father and mental difficulties. These results suggest that a parenting program for parents might reduce the risk of mental problems among Vietnamese youth.

Transgenerational effects of maternal and grandmaternal age on offspring viability and performance in Drosophila melanogaster.

In non-social insects, fitness is determined by relative lifetime fertility. Fertility generally declines with age as a part of senescence. For females, senescence has profound effects on fitness by decreasing viability and fertility as well as those of her offspring. However, important aspects of these maternal effects, including the cause(s) of reduced offspring performance and carry-over effects of maternal age, are poorly understood. Drosophila melanogaster is a useful system for examining potential transgenerational effects of increasing maternal age, because of their use as a model system for studying the physiology and genetic architecture of both reproduction and senescence. To test the hypothesis that female senescence has transgenerational effects on offspring viability and development, we measured the effects of maternal age on offspring survival over two generations and under two larval densities in two laboratory strains of flies (Oregon-R and Canton-S). Transgenerational effects of maternal age influence embryonic viability and embryonic to adult viability in both strains. However, the generation causing the effects, and the magnitude and direction of those effects differed by genotype. The effects of maternal age on embryonic to adult viability when larvae are stressed was also genotype-specific. Maternal effects involve provisioning: older females produced smaller eggs and larger offspring. These results show that maternal age has profound, complex, and multigenerational consequences on several components of offspring fitness and traits. This study contributes to a body of work demonstrating that female age is an important condition affecting phenotypic variation and viability across multiple generations.

Incidence and severity of retinopathy of prematurity in Vietnam, a developing middle-income country.

BACKGROUND: Although retinopathy of prematurity (ROP) is a leading cause of childhood blindness, its impact in lower income countries is not well documented. The World Health Organization has proclaimed that infants at risk for ROP should have screening eye examinations and access to treatment. PATIENTS AND METHODS: A prospective study was conducted from January 1 through December 31, 2001, at Tu Du Hospital in Ho Chi Minh City for premature infants who weighed 1,500 g or less at birth or were 33 gestational weeks or younger. Serial examinations were used to classify ROP, and treatment outcomes were noted. RESULTS: Two hundred twenty-five consecutive infants were included in the data analysis. Birth weights ranged from 900 to 2,000 g (mean, 1,512 g). Gestational ages ranged from 26 to 36 weeks (mean, 31 weeks). ROP was present in 103 (45.8%) of the 225 infants. In infants who weighed 1,250 g or less at birth, the ROP rate was 81.2% (26 of 32 infants). Threshold ROP was present in 9.3% of the 225 infants but in 25% of the 32 infants. Twenty-four eyes received treatment, whereas 16 lacked the family resources. Of the 24 treated eyes, 18 (75%) had a favorable outcome. Of the 16 untreated eyes, only 3 had a favorable outcome. CONCLUSIONS: ROP incidence is high in Vietnam, similar to that in the United States. However, larger, older infants are at risk in Vietnam and the rate of severe ROP seems to be higher. This necessitates an ROP screening paradigm different from that currently used in the United States.

The song of the old mother: reproductive senescence in female drosophila.

Among animals with multiple reproductive episodes, changes in adult condition over time can have profound effects on lifetime reproductive fitness and offspring performance. The changes in condition associated with senescence can be particularly acute for females who support reproductive processes from oogenesis through fertilization. The pomace fly Drosophila melanogaster is a well-established model system for exploring the physiology of reproduction and senescence. In this review, we describe how increasing maternal age in Drosophila affects reproductive fitness and offspring performance as well as the genetic foundation of these effects. Describing the processes underlying female reproductive senescence helps us understand diverse phenomena including population demographics, condition-dependent selection, sexual conflict, and transgenerational effects of maternal condition on offspring fitness. Understanding the genetic basis of reproductive senescence clarifies the nature of life-history trade-offs as well as potential ways to augment and/or limit female fertility in a variety of organisms.