The structure, function and evolution of a complete human chromosome 8.

The complete assembly of each human chromosome is essential for understanding human biology and evolution1,2. Here we use complementary long-read sequencing technologies to complete the linear assembly of human chromosome 8. Our assembly resolves the sequence of five previously long-standing gaps, including a 2.08-Mb centromeric α-satellite array, a 644-kb copy number polymorphism in the ß-defensin gene cluster that is important for disease risk, and an 863-kb variable number tandem repeat at chromosome 8q21.2 that can function as a neocentromere. We show that the centromeric α-satellite array is generally methylated except for a 73-kb hypomethylated region of diverse higher-order α-satellites enriched with CENP-A nucleosomes, consistent with the location of the kinetochore. In addition, we confirm the overall organization and methylation pattern of the centromere in a diploid human genome. Using a dual long-read sequencing approach, we complete high-quality draft assemblies of the orthologous centromere from chromosome 8 in chimpanzee, orangutan and macaque to reconstruct its evolutionary history. Comparative and phylogenetic analyses show that the higher-order α-satellite structure evolved in the great ape ancestor with a layered symmetry, in which more ancient higher-order repeats locate peripherally to monomeric α-satellites. We estimate that the mutation rate of centromeric satellite DNA is accelerated by more than 2.2-fold compared to the unique portions of the genome, and this acceleration extends into the flanking sequence.

Complex interplay between FMRP and DHX9 during DNA replication stress.

Mutations in, or deficiency of, fragile X messenger ribonucleoprotein (FMRP) is responsible for the Fragile X syndrome (FXS), the most common cause for inherited intellectual disability. FMRP is a nucleocytoplasmic protein, primarily characterized as a translation repressor with poorly understood nuclear function(s). We recently reported that FXS patient cells lacking FMRP sustain higher level of DNA double-strand breaks (DSBs) than normal cells, specifically at sequences prone to forming R-loops, a phenotype further exacerbated by DNA replication stress. Moreover, expression of FMRP, and not an FMRPI304N mutant known to cause FXS, reduced R-loop-associated DSBs. We subsequently reported that recombinant FMRP directly binds R-loops, primarily through the carboxyl terminal intrinsically disordered region. Here, we show that FMRP directly interacts with an RNA helicase, DHX9. This interaction, which is mediated by the amino terminal structured domain of FMRP, is reduced with FMRPI304N. We also show that FMRP inhibits DHX9 helicase activity on RNA:DNA hybrids and the inhibition is also dependent on the amino terminus. Furthermore, the FMRPI304N mutation causes both FMRP and DHX9 to persist on the chromatin in replication stress. These results suggest an antagonistic relationship between FMRP and DHX9 at the chromatin, where their proper interaction leads to dissociation of both proteins from the fully resolved R-loop. We propose that the absence or the loss of function of FMRP leads to persistent presence of DHX9 or both proteins, respectively, on the unresolved R-loop, ultimately leading to DSBs. Our study sheds new light on our understanding of the genome functions of FMRP.

A dual-function SNF2 protein drives chromatid resolution and nascent transcripts removal in mitosis.

Mitotic chromatin is largely assumed incompatible with transcription due to changes in the transcription machinery and chromosome architecture. However, the mechanisms of mitotic transcriptional inactivation and their interplay with chromosome assembly remain largely unknown. By monitoring ongoing transcription in Drosophila early embryos, we reveal that eviction of nascent mRNAs from mitotic chromatin occurs after substantial chromosome compaction and is not promoted by condensin I. Instead, we show that the timely removal of transcripts from mitotic chromatin is driven by the SNF2 helicase-like protein Lodestar (Lds), identified here as a modulator of sister chromatid cohesion defects. In addition to the eviction of nascent transcripts, we uncover that Lds cooperates with Topoisomerase 2 to ensure efficient sister chromatid resolution and mitotic fidelity. We conclude that the removal of nascent transcripts upon mitotic entry is not a passive consequence of cell cycle progression and/or chromosome compaction but occurs via dedicated mechanisms with functional parallelisms to sister chromatid resolution.

Characterizing unstructured data with the nearest neighbor permutation entropy.

Permutation entropy and its associated frameworks are remarkable examples of physics-inspired techniques adept at processing complex and extensive datasets. Despite substantial progress in developing and applying these tools, their use has been predominantly limited to structured datasets such as time series or images. Here, we introduce the k-nearest neighbor permutation entropy, an innovative extension of the permutation entropy tailored for unstructured data, irrespective of their spatial or temporal configuration and dimensionality. Our approach builds upon nearest neighbor graphs to establish neighborhood relations and uses random walks to extract ordinal patterns and their distribution, thereby defining the k-nearest neighbor permutation entropy. This tool not only adeptly identifies variations in patterns of unstructured data but also does so with a precision that significantly surpasses conventional measures such as spatial autocorrelation. Additionally, it provides a natural approach for incorporating amplitude information and time gaps when analyzing time series or images, thus significantly enhancing its noise resilience and predictive capabilities compared to the usual permutation entropy. Our research substantially expands the applicability of ordinal methods to more general data types, opening promising research avenues for extending the permutation entropy toolkit for unstructured data.

A new active packaging system based on chickpea-based edible coatings added with microcapsules of Cosmos sulphureus Cav. flower extract.

BACKGROUND: The Cosmos sulphureus Cav. plant is studied for its high polyphenolic content with antioxidant properties. Its flowers, rich in phenolic acids, flavonoids, and tannins, hold promise as antioxidants in food preservation. The inclusion of these compounds in chickpea-based coatings with a previously studied preservative effect would be an excellent option as a food preservation method and microencapsulation addresses challenges like dispersion and degradation of polyphenols in the coating. The objective of this research was to evaluate the in vitro antioxidant activity of Cosmos sulphureus leaves, seed, and flower extracts and explore the protective effects of chickpea-based coatings containing microcapsules of flower polyphenolic extract on the chemical quality of stored roasted sunflower seeds during storage. RESULTS: The ethanolic leaf extract exhibited the highest antiradical activity, followed by the aqueous flower extract. After a storage period of 15 days, at 40 °C, the chickpea-based coatings effectively delayed lipid oxidation in the roasted sunflowers seeds, and the inclusion of polyphenolic microcapsules with 0.01% extract (SMC 0.01%) in the coating significantly improved the protective effect. By day 15 of storage, SMC 0.01% showed comparable peroxide value, conjugated dienes, and linoleic acid content to samples containing the synthetic antioxidant BHT (butylated hydroxytoluene). Samples that only contained chickpea-based coating and coating with polyphenolic microcapsules with 0.005% extract exhibited significantly greater reduction in fatty acid content compared to the 0.01% SMC treatment. CONCLUSION: The chickpea-based coating with polyphenolic microcapsules demonstrated antioxidant activity akin to synthetic BHT, offering a promising biopackaging solution for lipid-rich foods like roasted sunflower seeds. © 2024 Society of Chemical Industry.

Initiation of speciation across multiple dimensions in a rock-restricted, tropical lizard.

Population isolation and concomitant genetic divergence, resulting in strong phylogeographical structure, is a core aspect of speciation initiation. If and how speciation then proceeds and ultimately completes depends on multiple factors that mediate reproductive isolation, including divergence in genomes, ecology and mating traits. Here we explored these multiple dimensions in two young (Plio-Pleistocene) species complexes of gekkonid lizards (Heteronotia) from the Kimberley-Victoria River regions of tropical Australia. Using mitochondrial DNA screening and exon capture phylogenomics, we show that the rock-restricted Heteronotia planiceps exhibits exceptional fine-scale phylogeographical structure compared to the codistributed habitat generalist Heteronotia binoei. This indicates pervasive population isolation and persistence in the rock-specialist, and thus a high rate of speciation initiation across this geographically complex region, with levels of genomic divergence spanning the "grey zone" of speciation. Proximal lineages of H. planiceps were often separated by different rock substrates, suggesting a potential role for ecological isolation; however, phylogenetic incongruence and historical introgression were inferred between one such pair. Ecomorphological divergence among lineages within both H. planiceps and H. binoei was limited, except that limestone-restricted lineages of H. planiceps tended to be larger than rock-generalists. By contrast, among-lineage divergence in the chemical composition of epidermal pore secretions (putative mating trait) exceeded ecomorphology in both complexes, but with less trait overlap among lineages in H. planiceps. This system-particularly the rock-specialist H. planiceps-highlights the role of multidimensional divergence during incipient speciation, with divergence in genomes, ecomorphology and chemical signals all at play at very fine spatial scales.

NGOME-Lite: Proteome-wide prediction of spontaneous protein deamidation highlights differences between taxa.

Asparagines in proteins deamidate spontaneously, which changes the chemical structure of a protein and often affects its function. Current prediction algorithms for asparagine deamidation require a structure as an input or are too slow to be applied at a proteomic scale. We present NGOME-Lite, a new version of our sequence-based predictor for spontaneous asparagine deamidation that is faster by over two orders of magnitude at a similar degree of accuracy. The algorithm takes into account intrinsic sequence propensities and slowing down of deamidation by local structure. NGOME-Lite can run in a proteomic analysis mode that provides the half-time of the intact form of each protein, predicted by taking into account sequence propensities and structural protection or sequence propensities only, and a structure protection factor. The detailed analysis mode also provides graphical output for all Asn residues in the query sequence. We applied NGOME-Lite to over 257,000 sequences in 38 proteomes and found that different taxa differ in their predicted deamidation dynamics. Spontaneous protein deamidation is faster in Eukarya than in Bacteria because of a higher degree of structural protection in the latter. Predicted protein deamidation half-lifes correlate with protein turnover in human, mouse, rat, C. elegans and budding yeast but not in two plants and two bacteria. NGOME-Lite is implemented in a docker container available at https://ngome.proteinphysiologylab.org.

What are the correlates of intention to be physically active in Brazilian adolescents? A network analysis.

OBJECTIVE: The current study aimed to explore the association of individual characteristics, social and environmental factors - school and region - in the intention to be physically active in Brazilian adolescents. METHODS: This is a cross sectional study based on the third edition of the National School Health Survey. The study included a total of 53,937 adolescents. To assess the intention to be physically active, only who engaged in less than 300 min of physical activity per week were included. Participants were asked: "If you had the opportunity to practice physical activity most days of the week, what would your attitude be?" Individual characteristics, physical activity domains, social factors, school, and regional environments were used as exposures. Network analysis was utilized to evaluate the associations. RESULTS: We observed that boys had higher intentions to be physically active compared to their peers, as did adolescents who perceived themselves as fat. In addition, students from private schools show a higher intention to regularly engage in physical activities, and in general, private schools offer more extracurricular physical activities. CONCLUSION: In conclusion, individual factors such as sex and body image perception, and environmental factors such as school administrative dependency and availability of extracurricular activities had a significant contribution to the intention to be physically active among Brazilian adolescents.

Stochastic Particle Creation: From the Dynamical Casimir Effect to Cosmology.

We study a stochastic version of the dynamical Casimir effect, computing the particle creation inside a cavity produced by a random motion of one of its walls. We first present a calculation perturbative in the amplitude of the motion. We compare the stochastic particle creation with the deterministic counterpart. Then, we go beyond the perturbative evaluation using a stochastic version of the multiple scale analysis, that takes into account stochastic parametric resonance. We stress the relevance of the coupling between the different modes induced by the stochastic motion. In the single-mode approximation, the equations are formally analogous to those that describe the stochastic particle creation in a cosmological context, that we rederive using multiple scale analysis.

Deamidation drives molecular aging of the SARS-CoV-2 spike protein receptor-binding motif.

The spike protein is the main protein component of the SARS-CoV-2 virion surface. The spike receptor-binding motif mediates recognition of the human angiotensin-converting enzyme 2 receptor, a critical step in infection, and is the preferential target for spike-neutralizing antibodies. Posttranslational modifications of the spike receptor-binding motif have been shown to modulate viral infectivity and host immune response, but these modifications are still being explored. Here we studied asparagine deamidation of the spike protein, a spontaneous event that leads to the appearance of aspartic and isoaspartic residues, which affect both the protein backbone and its charge. We used computational prediction and biochemical experiments to identify five deamidation hotspots in the SARS-CoV-2 spike protein. Asparagine residues 481 and 501 in the receptor-binding motif deamidate with a half-life of 16.5 and 123 days at 37 °C, respectively. Deamidation is significantly slowed at 4 °C, indicating a strong dependence of spike protein molecular aging on environmental conditions. Deamidation of the spike receptor-binding motif decreases the equilibrium constant for binding to the human angiotensin-converting enzyme 2 receptor more than 3.5-fold, yet its high conservation pattern suggests some positive effect on viral fitness. We propose a model for deamidation of the full SARS-CoV-2 virion illustrating how deamidation of the spike receptor-binding motif could lead to the accumulation on the virion surface of a nonnegligible chemically diverse spike population in a timescale of days. Our findings provide a potential mechanism for molecular aging of the spike protein with significant consequences for understanding virus infectivity and vaccine development.

Induced aneuploidy in neural stem cells triggers a delayed stress response and impairs adult life span in flies.

Studying aneuploidy during organism development has strong limitations because chronic mitotic perturbations used to generate aneuploidy usually result in lethality. We developed a genetic tool to induce aneuploidy in an acute and time-controlled manner during Drosophila development. This is achieved by reversible depletion of cohesin, a key molecule controlling mitotic fidelity. Larvae challenged with aneuploidy hatch into adults with severe motor defects shortening their life span. Neural stem cells, despite being aneuploid, display a delayed stress response and continue proliferating, resulting in the rapid appearance of chromosomal instability, a complex array of karyotypes, and cellular abnormalities. Notably, when other brain-cell lineages are forced to self-renew, aneuploidy-associated stress response is significantly delayed. Protecting only the developing brain from induced aneuploidy is sufficient to rescue motor defects and adult life span, suggesting that neural tissue is the most ill-equipped to deal with developmental aneuploidy.

Clusters of obesogenic behaviors and metabolic risk according to somatic maturity status among adolescents.

OBJECTIVE: This study aimed to identify the clusters of obesogenic behaviors, and verify the association with metabolic risk according to the categories of somatic maturity status of adolescents. METHODS: This is a cross-sectional study conducted with 1159 (55.1% girls) Brazilian adolescents aged between 10 and 16 years (mean age: 12.9 years). Measurements of waist circumference, blood pressure, blood glucose, HDL-C, and triglycerides were combined to calculate a metabolic risk score. Somatic maturity was assessed by estimating the peak of height velocity. The obesogenic behaviors analyzed were physical activity (Baecke questionnaire), sedentary behavior (screen-based behaviors) and dietary habits (consumption of healthy and unhealthy food). The Two Step clustering algorithm using the log-likelihood measure was employed to cluster formation and regression models were adopted to the main analysis. RESULTS: We observed a complex co-existence of obesogenic behaviors. Differences regarding the metabolic risk between clusters was only observed among the early-maturing adolescents, where the cluster with higher number of healthy behaviors but lower physical activity presented higher metabolic risk score. CONCLUSIONS: We conclude that physical activity has an important role on the association of clusters of obesogenic behaviors and metabolic risk in early-maturing adolescents.

Sensitivity of South America Climate to Positive Extremes of Antarctic Sea Ice.

Global climate change is expected to increasingly affect climate-sensitive sectors of society, such as the economy and environment, with significant impacts on water, energy, agriculture and fisheries. This is the case in South America, whose economy is highly dependent on the agricultural sector. Here, we analyzed the sensitivity of South American climate to positive extremes of Antarctic sea ice (ASI) extent and volume at continental and regional scales. Sensitivity ensemble experiments were conducted with the GFDL-CM2.1 model and compared with the ERA-Interim reanalysis dataset. The results have shown significant impacts on the seasonal regime of precipitation, air temperature and humidity in South America, such as a gradual establishment of the South Atlantic Convergence Zone, the formation of the Upper Tropospheric Cyclonic Vortex, the strengthening of Bolivian High and the presence of a low level cyclonic circulation anomaly over the South Atlantic Subtropical High region which contributed, for instance, to increased precipitation over the Southeastern Brazil. A northward shift of the Intertropical Convergence Zone was initially also a response pattern to the increased ASI. Moreover, the greatest variance of the climatic signal generated from the disturbances applied on the high southern latitudes has occurred in the interseasonal timescale (110-120 days), especially over the Brazilian Amazon and the Southeastern Brazil regions.

Response of southern troposphere meridional circulation to historical maxima of Antarctic sea ice.

The variability of Antarctic sea ice (ASI) has great potential to affect atmospheric circulation, with impacts that can extend from the surface to the middle and high levels of troposphere. The present study has evaluated the response of South Atlantic tropospheric circulation to increased coverage in area and volume of ASI. Monthly data of air temperature, zonal and meridional wind and mean sea level pressure were obtained from two ensemble simulations performed with the GDFL/CM2.1 model, covering the period from July 2020 to June 2030. In general, the response of South Atlantic tropospheric circulation to increased ASI showed that the climatic signal extended up from the surface to the high levels, propagating as a South Pole-Tropics teleconnection. The results show a general cooling of the southern troposphere, which for instance lead to the strengthening and northward shift of the polar jet and the southward shift of the subtropical jet and to an inversion from the positive to negative phase of the Southern Annular Mode. This study has great relevance for understanding the global climate changes in short term, by assessing the sensitivity of South Atlantic tropospheric circulation to extreme variations in ASI.

Lagged response of Tropical Atlantic Ocean to cold and fresh water pulse from Antarctic sea ice melting.

The formation of dense water masses at polar regions has been largely influenced by climate changes arising from global warming. In this context, based on ensemble simulations with a coupled model we evaluate the meridional shift of a climate signal (i.e., a cold and fresh water input pulse generated from melting of positive Antarctic sea ice (ASI) extremes) towards the Tropical Atlantic Ocean (TAO). This oceanic signal propagated from Southern Ocean towards the equator through the upper layers due to an increase in its buoyance. Its northward shift has given by the Subantarctic Mode Water (SAMW) and Antarctic Intermediate Water (AAIW) flows, that inject cold and fresh mode/intermediate waters from into subtropical basin. The signal has reached low latitudes through the equatorial upwelling and spreads out southwards, through the upper branch of southern subtropical gyre. We concluded that 10 years of coupled simulations was enough time to propagate the climate signal generated by ASI positive extremes melting, which reached TOA around 2 year later. The oceanic connection between Southern Ocean and TAO is indeed established within the timescale analyzed in the study (10 years). Nonetheless, the period needed to completely dissipate the disturbance generated from ASI seems to be longer.

Binding Properties of Photosynthetic Herbicides: Photosynthetic Activity and Molecular Docking Approach towards 1,4-Dihydropyridines Derivatives.

In the current work, we describe the synthesis of 1,4-dihydropyridine (1,4-DHP) derivatives via Hantzsch multicomponent reaction and their evaluation as photosystem II (PSII) inhibitors through chlorophyll a fluorescence bioassay. Among all the compounds tested, 1,1'-(2,4,6-trimethyl-1,4-dihydropyridine-3,5-diyl)bis(ethan-1-one) (4b) showed best results, reducing the parameters performance index on absorption basis (PIabs ) and electron transport per reaction center by 61 % and 49 %, respectively, as compared to the control. These results indicate the inhibitory activity of PSII over the electron transport chain. Additionally, a molecular docking approach using the protein D1 (PDB code 4V82) was performed in order to assess the structure-activity relationship among the 1,4-DHP derivatives over the PSII, which revealed that both, size of the group at position 4 and the carbonyl groups at the dihydropyridine ring are important for the ligand's interaction, particularly for the hydrogen-bonding interaction with the residues His215, Ser264, and Phe265. Thus, the optimization of these molecular features is the aim of our research group to extend the knowledge of PSII electron chain inhibitors and the establishment of new potent bioactive molecular scaffolds.

Presentation of fatal stroke due to SARS-CoV-2 and dengue virus coinfection.

Herein, we report a case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and dengue coinfection, presented as a fatal stroke in our hospital, in São José do Rio Preto, São Paulo State, a Brazilian city hyperendemic for dengue viruses and other arthropod-borne viruses (arboviruses) and currently facing a surge of SARS-CoV-2 cases. This case is the first described in the literature and contributes to the better understanding of clinical presentations of two important diseases in a tropical setting.

Predictors of phylogeographic structure among codistributed taxa across the complex Australian monsoonal tropics.

Differences in the geographic scale and depth of phylogeographic structure across codistributed taxa can reveal how microevolutionary processes such as population isolation and persistence drive diversification. In turn, environmental heterogeneity, species' traits, and historical biogeographic barriers may influence the potential for isolation and persistence. Using extensive SNP data and a combination of population genetic summary statistics and landscape genomic analyses, we explored predictors of the scale and depth of phylogeographic structure in codistributed lizard taxa from the topographically and climatically complex monsoonal tropics (AMT) of Australia. We first resolved intraspecific lineages and then tested whether genetic divergence across space within lineages is related to isolation by distance, resistance and/or environment and whether these factors differ across genera or between rock-related versus habitat generalist taxa. We then tested whether microevolutionary processes within lineages explain differences in the geographic scale and depth of intraspecific phylogeographic lineages. The results indicated that landscape predictors of phylogeographic structure differ between taxa. Within lineages, there was prevalent isolation by distance, but the strength of isolation by distance is independent of the taxonomic family, habitat specialization, and climate. Isolation by environment is the strongest predictor of landscape-scale genetic divergence for all taxa, with both temperature and precipitation acting as limiting factors. The strength of isolation by distance does not predict the geographic scale of the phylogeographic structure. However, more localized lineages had higher mean individual heterozygosity and less negative Tajima's D. This result implies that finer-scale phylogeographic structuring within species is associated with larger and more stable populations and, hence, persistence.

[18F]-FDG PET/CT in oncologic patients with unsuspected asymptomatic infection with SARS-CoV-2.

PURPOSE: Spain has been one of the most affected countries by the COVID-19 pandemic, being among the countries with worse numbers, including the death rate. However, most patients are asymptomatic, although they are very contagious. The objective of this study was to investigate the incidence in oncological patients infected with SARS-CoV-2 that are asymptomatic for COVID-19 and at home and that undergo PET/CT for oncologic indications, nonrelated to COVID-19, finding in the PET/CT lung alterations that are suggestive of SARS-CoV-2 infection. METHODS: During the period of maximum incidence of the global pandemic in one of the most affected regions of Spain, there were 145 patients that met inclusion and exclusion criteria and were included in the study. Imaging findings previously described such as ground-glass opacities with low [18F]-FDG uptake were considered images suspicious for SARS-CoV-2 infection. Patients with these findings were referred to RT-PCR testing and close follow-up to confirm the presence or absence of COVID-19. RESULTS: Suspicious lung imaging findings were present in 7 of 145 patients (4.8%). Five of these 7 patients were confirmed as presenting SARS-CoV-2 infection, this is, COVID-19. In the remaining two, it was not possible to confirm the presence of COVID-19 with RT-PCR, although in one of them, PET/CT allowed an early diagnosis of a lung infection related to a bacterial pneumonic infection that was promptly and adequately treated with antibiotics. CONCLUSION: These results confirm that the prevalence of SARS-CoV-2 infection is higher than suspected and that there are asymptomatic patients that are attending imaging departments to be explored for their baseline oncologic processes. In these patients, PET/CT allows an early diagnosis of COVID-19.

Correction: Brain-Computer Interface-Based Communication in the Completely Locked-In State.

[This corrects the article DOI: 10.1371/journal.pbio.1002593.].