bluuebunny/crossref_metadata_2025 huggingface dataset:
Câncer e políticas de saúde pública: Estratégias para reduzir a incidência e mortalidade
Authors: José Antonio da Silva  , Thamyres Maria Silva Barbosa  , Amanda Gonçalves Barreto  , Andre Paschoa  , Laura Cristina Alves de Sousa  , Túlio Döerner Steiner  , Leticia Silva Victor  , Milckea Hellene Araújo Barbosa Costa  , Dayara Carvalho de Jesus  , Talila de Assis Santana  , Rafael Leituga De Carvalho Cavalcante
Published: August 2024

O câncer é uma das principais causas de morbidade e mortalidade global, representando um desafio significativo para a saúde pública. Esta revisão narrativa tem como objetivo analisar as políticas de saúde pública voltadas para a prevenção, detecção precoce, tratamento e cuidados paliativos do câncer. A pesquisa utilizou fontes variadas, incluindo artigos científicos, relatórios governamentais e documentos de organizações internacionais, com foco em intervenções implementadas nas últimas duas décadas. Os resultados destacam a eficácia das políticas de prevenção, como o controle do tabaco e a promoção de estilos de vida saudáveis, na redução dos fatores de risco associados ao câncer. No entanto, persistem desigualdades significativas no acesso a programas de triagem e tratamento, especialmente em países de baixa e média renda. A integração dos cuidados paliativos nas políticas de saúde pública mostrou-se crucial para garantir cuidados dignos aos pacientes com câncer avançado. A coleta de dados epidemiológicos robustos e a colaboração internacional foram identificadas como componentes essenciais para o desenvolvimento de políticas baseadas em evidências. A conclusão ressalta a necessidade de uma abordagem colaborativa e dinâmica para enfrentar o câncer, com políticas adaptadas às realidades locais e um forte compromisso político e social. Somente através de esforços coletivos e sustentados será possível reduzir a carga do câncer e melhorar os resultados de saúde para todas as populações.
MISLEADING OR BENEFICIAL? ASSESSING THE EXPLOITATION POTENTIAL OF STOCK BUYBACK ANNOUNCEMENTS IN THE MALAYSIAN STOCK MARKET
Authors: Junlin He , Xiyun Zhang , Ping Gong
Published: August 2024

In the traditional sense, stock buyback announcements are generally perceived as advantageous news. However, with the evolution of the capital market, some scholars argue that such declarations possess the potential for exploitation as a means to artificially inflate stock prices, thereby deceiving investors. Consequently, within the framework of the Efficient Market Hypothesis and the Theory of Asymmetric Information, we employed an event study approach to empirically investigate 30 listed companies in Malaysia that announced stock buybacks in the before June 2022. To fortify the robustness of our research findings, we employed Market Model and the Fama-French Three-Factor Model to estimate Average Abnormal Returns and Cumulative Average Abnormal Returns. The outcomes indicate that stock buyback announcements are still regarded as favorable news in the Malaysian stock market, bestowing investors with significant positive average cumulative abnormal returns. Nevertheless, the Malaysian capital market may witness premature leakage of stock buyback information, thereby accentuating the existence of information asymmetry. We contend that corporate leadership can harness stock buyback announcements as a mechanism to stabilize stock prices and infuse confidence in investors. Concurrently, market regulators should augment transparency and regulatory measures to ensure fairness among all market participants.
Semantic plasticity across timescales in the human brain
Authors: Solomon Sarah H , Kay Kendrick , Schapiro Anna C
Published: August 2024

Our representations of the world need to be stable enough to support general knowledge but flexible enough to incorporate new information as our environment changes. How does the human brain manage this stability-plasticity trade-off? We analyzed a large dataset in which participants viewed objects embedded in thousands of natural scenes across many fMRI sessions. Semantic item representations were located by jointly leveraging a voxelwise encoding model to find reliable item representations and a word-embedding model to evaluate semantic content. Within the medial temporal lobe, semantic item representations in hippocampal subfield CA1, parahippocampal cortex, and perirhinal cortex gradually drifted across a period of multiple months. Whole-brain analyses revealed a gradient of plasticity in the temporal lobe, with drift more evident in anterior than posterior areas. On short timescales, rapid plasticity was observed only in parahippocampal cortex, such that item co-occurrence statistics warped item representations within a single session. Together, the results suggest that the brain solves the stability-plasticity trade-off through a gradient of plasticity across semantic regions.
Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome
Authors: Cozzolino Kira A , Sanford Lynn , Hunter Samuel , Molison Kayla , Erickson Benjamin , Courvan Meaghan CS , Jones Taylor , Ajit Deepa , Galbraith Matthew D , Espinosa Joaquín M , Bentley David , Allen Mary Ann , Dowell Robin D , Taatjes Dylan J
Published: August 2024

Hyperactive interferon (IFN) signaling is a hallmark of Down syndrome (DS), a condition caused by Trisomy 21 (T21); strategies that normalize IFN signaling could benefit this population. Mediator-associated kinases CDK8 and CDK19 drive inflammatory responses through incompletely understood mechanisms. Using sibling-matched cell lines with/without T21, we investigated Mediator kinase function in the context of hyperactive IFN in DS over a 75 min to 24 hr timeframe. Activation of IFN-response genes was suppressed in cells treated with the CDK8/CDK19 inhibitor cortistatin A (CA), via rapid suppression of IFN-responsive transcription factor (TF) activity. We also discovered that CDK8/CDK19 affect splicing, a novel means by which Mediator kinases control gene expression. To further probe Mediator kinase function, we completed cytokine screens and metabolomics experiments. Cytokines are master regulators of inflammatory responses; by screening 105 different cytokine proteins, we show that Mediator kinases help drive IFN-dependent cytokine responses at least in part through transcriptional regulation of cytokine genes and receptors. Metabolomics revealed that Mediator kinase inhibition altered core metabolic pathways in cell type-specific ways, and broad upregulation of anti-inflammatory lipid mediators occurred specifically in kinase-inhibited cells during hyperactive IFNγ signaling. A subset of these lipids (e.g. oleamide, desmosterol) serve as ligands for nuclear receptors PPAR and LXR, and activation of these receptors occurred specifically during hyperactive IFN signaling in CA-treated cells, revealing mechanistic links between Mediator kinases, lipid metabolism, and nuclear receptor function. Collectively, our results establish CDK8/CDK19 as context-specific metabolic regulators, and reveal that these kinases control gene expression not only via TFs, but also through metabolic changes and splicing. Moreover, we establish that Mediator kinase inhibition antagonizes IFN signaling through transcriptional, metabolic, and cytokine responses, with implications for DS and other chronic inflammatory conditions.
Specific presynaptic functions require distinct Drosophila Cav2 splice isoforms
Authors: Bell Christopher , Kilo Lukas , Gottschalk Daniel , Arian Jashar , Deneke Lea , Kern Hanna , Rickert Christof , Kobler Oliver , Strauß Julia , Heine Martin , Duch Carsten , Ryglewski Stefanie
Published: August 2024

At many vertebrate synapses, presynaptic functions are tuned by expression of different Cav2 channels. Most invertebrate genomes contain only one Cav2 gene. The Drosophila Cav2 homolog, cacophony (cac), induces synaptic vesicle release at presynaptic active zones (AZs). We hypothesize that Drosophila cac functional diversity is enhanced by two mutually exclusive exon pairs that are not conserved in vertebrates, one in the voltage sensor and one in the loop binding Caβ and Gβγ subunits. We find that alternative splicing in the voltage sensor affects channel activation voltage. Only the isoform with the higher activation voltage localizes to AZs at the glutamatergic Drosophila larval neuromuscular junction and is imperative for normal synapse function. By contrast, alternative splicing at the other alternative exon pair tunes multiple aspects of presynaptic function. While expression of one exon yields normal transmission, expression of the other reduces channel number in the AZ and thus release probability. This also abolishes presynaptic homeostatic plasticity. Moreover, reduced channel number affects short-term plasticity, which is rescued by increasing the external calcium concentration to match release probability to control. In sum, in Drosophila alternative splicing provides a mechanism to regulate different aspects of presynaptic functions with only one Cav2 gene.
Specific presynaptic functions require distinct Drosophila Cav2 splice isoforms
Authors: Bell Christopher , Kilo Lukas , Gottschalk Daniel , Kern Hanna , Arian Jashar , Deneke Lea , Kobler Oliver , Rickert Christof , Strauß Julia , Heine Martin , Duch Carsten , Ryglewski Stefanie
Published: August 2024

The multiplicity of neural circuits that accommodate the sheer infinite number of computations conducted by brains requires diverse synapse and neuron types. At the vertebrate presynaptic active zone functional diversity can be achieved by the expression of different voltage gated calcium channels of the Ca
v
2 family. In fact, release probability and other aspects of presynaptic function are tuned by different combinations of Ca
v
2.1, Ca
v
2.2, and Ca
v
2.3 channels. By contrast, most invertebrate genomes contain only one Ca
v
2 gene. The one
Drosophila
Ca
v
2 homolog, cacophony, localizes to presynaptic active zones to induce synaptic vesicle release. We hypothesize that Drosophila Ca
v
2 functional diversity is enhanced by two specific exon pairs that are mutually exclusively spliced and not conserved in vertebrates, one in the voltage sensor and one in the intracellular loop containing the binding site(s) for Caβ and G-protein βγ subunits. We test our hypothesis by combining opto- and electrophysiological with neuroanatomical approaches at a fast glutamatergic model synapse, the Drosophila larval neuromuscular junction. We find that alternative splicing in the voltage sensor affects channel activation voltage and is imperative for normal synapse function. Only the isoform with the higher activation voltage localizes to the presynaptic active zone and mediates evoked release. Removal of this Ca
v
2 splice isoforms renders fast glutamatergic synapses non-functional. The By contrast, alternative splicing at the other alternative exon does not affect Ca
v
2 presynaptic expression, but it tunes multiple aspects of presynaptic function. While expression of one exon yields normal transmission, expression of the other exon reduces channel number in the active zone and thus release probability. It also affects short term plasticity and abolishes presynaptic homeostatic plasticity. Thus, in
Drosophila
alternative splicing provides a mechanism to regulate different aspects of presynaptic functions with only one Ca
v
2 gene.
Linking the evolution of two prefrontal brain regions to social and foraging challenges in primates
Authors: Bouret Sebastien , Paradis Emmanuel , Prat Sandrine , Castro Laurie , Perez Pauline , Gilissen Emmanuel , Garcia Cécile
Published: August 2024

The diversity of cognitive skills across primates remains both a fascinating and a controversial issue. Recent comparative studies provided conflicting results regarding the contribution of social vs ecological constraints to the evolution of cognition. Here, we used an interdisciplinary approach combining comparative cognitive neurosciences and behavioral ecology. Using brain imaging data from 16 primate species, we measured the size of two prefrontal brain regions, the frontal pole (FP) and the dorso-lateral prefrontal cortex (DLPFC), respectively involved in metacognition and working memory, and examined their relation to a combination of socio-ecological variables. The size of these prefrontal regions, as well as the whole brain, was best explained by three variables: body mass, daily traveled distance (an index of ecological constraints) and population density (an index of social constraints). The strong influence of ecological constraints on FP and DLPFC volumes suggests that both metacognition and working memory are critical for foraging in primates. Interestingly, FP volume was much more sensitive to social constraints than DLPFC volume, in line with laboratory studies showing an implication of FP in complex social interactions. Thus, our data highlights the relative weight of social vs ecological constraints on the evolution of specific prefrontal brain regions and their associated cognitive operations in primates.
CaBP1 and 2 enable sustained CaV1.3 calcium currents and synaptic transmission in inner hair cells
Authors: Oestreicher David , Chepurwar Shashank , Kusch Kathrin , Rankovic Vladan , Jung Sangyong , Strenzke Nicola , Pangrsic Tina
Published: August 2024

To encode continuous sound stimuli, the inner hair cell (IHC) ribbon synapses utilize calcium-binding proteins (CaBPs), which reduce the inactivation of their Ca
V
1.3 calcium channels. Mutations in the
CABP2
gene underlie non-syndromic autosomal recessive hearing loss DFNB93. Besides CaBP2, the structurally related CaBP1 is highly abundant in the IHCs. Here, we investigated how the two CaBPs cooperatively regulate IHC synaptic function. In
Cabp1/2
double-knockout mice, we find strongly enhanced Ca
V
1.3 inactivation, slowed recovery from inactivation and impaired sustained exocytosis. Already mild IHC activation further reduces the availability of channels to trigger synaptic transmission and may effectively silence synapses. Spontaneous and sound-evoked responses of spiral ganglion neurons
in vivo
are strikingly reduced and strongly depend on stimulation rates. Transgenic expression of CaBP2 leads to substantial recovery of IHC synaptic function and hearing sensitivity. We conclude that CaBP1 and 2 act together to suppress voltage and calcium-dependent inactivation of IHC Ca
V
1.3 channels in order to support sufficient rate of exocytosis and enable fast, temporally precise and indefatigable sound encoding.
Allosteric modulation of the CXCR4:CXCL12 axis by targeting receptor nanoclustering via the TMV-TMVI domain
Authors: García-Cuesta Eva M , Martínez Pablo , Selvaraju Karthik , Ulltjärn Gabriel , Gómez Pozo Adrián Miguel , D’Agostino Gianluca , Gardeta Sofía , Quijada-Freire Adriana , Blanco Gabella Patricia , Roca Carlos , del Hoyo Daniel , Jiménez-Saiz Rodrigo , García-Rubia Alfonso , Soler-Palacios Blanca , Lucas Pilar , Ayala-Bueno Rosa , Santander Acerete Noelia , Carrasco Yolanda R , Sánchez-Sorzano Carlos O , Martínez Ana , Campillo Nuria E , Jenssen Lasse , Rodríguez-Frade José Miguel , Santiago César , Mellado Mario
Published: August 2024

CXCR4 is a ubiquitously expressed chemokine receptor that regulates leukocyte trafficking and arrest in both homeostatic and pathological states. It also participates in organogenesis, HIV-1 infection and tumor development. Despite the potential therapeutic benefit of CXCR4 antagonists, only one, plerixafor (AMD3100), which blocks the ligand-binding site, has reached the clinic. Recent advances in imaging and biophysical techniques have provided a richer understanding of the membrane organization and dynamics of this receptor. Activation of CXCR4 by CXCL12 reduces the number of CXCR4 monomers/dimers at the cell membrane and increases the formation of large nanoclusters, which are largely immobile and are required for correct cell orientation to chemoattractant gradients. Mechanistically, CXCR4 activation involves a structural motif defined by residues in TMV and TMVI. Using this structural motif as a template, we performed
in silico
molecular modeling followed by
in vitro
screening of a small compound library to identify negative allosteric modulators of CXCR4 that do not affect CXCL12 binding. We identified AGR1.137, a small molecule that abolishes CXCL12-mediated receptor nanoclustering and dynamics and blocks the ability of cells to sense CXCL12 gradients both
in vitro
and
in vivo
while preserving ligand binding and receptor internalization.
Transcriptional inhibition after irradiation occurs preferentially at highly expressed genes in a manner dependent on cell cycle progression
Authors: Chen Zulong , Wang Xin , Gao Xinlei , Arslanovic Nina , Chen Kaifu , Tyler Jessica
Published: August 2024

In response to DNA double strand damage, ongoing transcription is inhibited to facilitate accurate DNA repair while transcriptional recovery occurs after DNA repair is complete. However, the mechanisms at play and identity of the transcripts being regulated in this manner are unclear. In contrast to the situation following UV damage, we found that transcriptional recovery after ionizing radiation (IR) occurs in a manner independent of the HIRA histone chaperone. Sequencing of the nascent transcripts identified a programmed transcriptional response, where certain transcripts and pathways are rapidly downregulated after IR, while other transcripts and pathways are upregulated. Specifically, most of the loss of nascent transcripts occurring after IR is due to inhibition of transcriptional initiation of the highly transcribed histone genes and the rDNA. To identify factors responsible for transcriptional inhibition after IR in an unbiased manner, we performed a whole genome gRNA library CRISPR / Cas9 screen. Many of the top hits in our screen were factors required for protein neddylation. However, at short times after inhibition of neddylation, transcriptional inhibition still occurred after IR, even though neddylation was effectively inhibited. Persistent inhibition of neddylation blocked transcriptional inhibition after IR, and it also leads to cell cycle arrest. Indeed, we uncovered that many inhibitors and conditions that lead to cell cycle arrest in G
1
or G
2
phase also prevent transcriptional inhibition after IR. As such, it appears that transcriptional inhibition after IR occurs preferentially at highly expressed genes in cycling cells.
ImmCellTyper: an integrated computational pipeline for systematic mining of Mass Cytometry data to assist deep immune profiling
Authors: Sun Jing , Choy Desmond , Sompairac Nicolas , Jamshidi Shirin , Mishto Michele , Kordasti Shahram
Published: August 2024

Mass cytometry, also known as Cytometry by time-of-flight (CyTOF), is a cutting-edge high-dimensional technology for profiling marker expression at the single-cell level. This technology significantly advances clinical research in immune monitoring and the interrogation of immune cell populations. Nevertheless, the vast amount of data generated by CyTOF poses a daunting challenge for analysis. To address this, we describe ImmCellTyper (https://github.com/JingAnyaSun/ImmCellTyper), a novel and robust toolkit designed for CyTOF data analysis. The analytical framework incorporates an in-house developed semi-supervised clustering tool named BinaryClust, which first characterises main cell lineages, followed by in-depth interrogation for population of interest using unsupervised methods.BinaryClust was benchmarked with existing clustering tools and demonstrated superior accuracy and speed across two datasets comprising around 4 million cells, performing as good as manual gating by human experts. Furthermore, this computational pipeline provides a variety of visualization and analytical tools spanning from quality control to differential analysis, which can be tailored to user’s specific needs, aiming to provide a one-stop solution for CyTOF data analysis. The general workflow consists of five key steps: 1) Batch effect evaluation and correction, 2) Data quality control and pre-processing, 3) Main cell lineage characterisation and quantification, 4) Extraction and in-depth investigation of cell type of interest; 5) Differential analysis of cell abundance and functional marker expression (supporting multiple study groups). Overall, ImmCellTyper integrates expert’s biological knowledge in a semi-supervised fashion to accurately deconvolute well-defined main cell lineages, while also preserving the potential of unsupervised approaches to discover novel cell subsets and providing a user-friendly toolset to remove the analytical barrier for high-dimensional immune profiling.
A Modified BPaL Regimen for Tuberculosis Treatment replaces Linezolid with Inhaled Spectinamides
Authors: Ali Malik Zohaib , Dutt Taru S , MacNeill Amy , Walz Amanda , Pearce Camron , Lam Ha , Philp Jamie , Patterson Johnathan , Henao-Tamayo Marcela , Lee Richard E , Liu Jiuyu , Robertson Gregory T , Hickey Anthony J , Meibohm Bernd , Gonzalez-Juarrero Mercedes
Published: August 2024

The Nix-TB clinical trial evaluated a new 6-month regimen containing three-oral- drugs; bedaquiline (B), pretomanid (Pa) and linezolid (L) (BPaL regimen) for treatment of tuberculosis (TB). This regimen achieved remarkable results as almost 90% of the multidrug resistant (MDR) or extensively drug resistant (XDR) TB participants were cured but many patients also developed severe adverse events (AEs). The AEs were associated with the long-term administration of the protein synthesis inhibitor linezolid. Spectinamide 1599 is also a protein synthesis inhibitor of Mycobacterium tuberculosis with an excellent safety profile but which lacks oral bioavailability. Here, we propose to replace L in the BPaL regimen with spectinamide (S) administered via inhalation and we demonstrate that inhaled spectinamide 1599, combined with BPa ––BPaS regimen––has similar efficacy to that of BPaL regimen while simultaneously avoiding the L-associated AEs. The BPaL and BPaS regimens were compared in the BALB/c and C3HeB/FeJ murine chronic TB efficacy models. After 4-weeks of treatment, both regimens promoted equivalent bactericidal effect in both TB murine models. However, treatment with BPaL resulted in significant weight loss and the complete blood count suggested development of anemia. These effects were not similarly observed in mice treated with BPaS. BPaL and BPa, but no the BPaS treatment, also decreased myeloid to erythroid ratio suggesting the S in the BPaS regimen was able to recover this effect. Moreover, the BPaL also increased concentration of proinflammatory cytokines in bone marrow compared to mice receiving BPaS regimen. During therapy both regimens improved the lung lesion burden, reduced neutrophil and cytotoxic T cells counts while increased the number of B and helper and regulatory T cells. These combined data suggest that inhaled spectinamide 1599 combined with BPa is an effective TB regimen that avoids L-associated AEs.
Hosts Manipulate Lifestyle Switch and Pathogenicity Heterogeneity of Opportunistic Pathogens in the Single-cell Resolution
Authors: Wang Ziguang , Li Shuai , Zhang Sheng , Zhang Tianyu , Wu Yujie , Liu Anqi , Wang Kui , Ji Xiaowen , Cao Haiqun , Zhang Yinglao , Tan Eng-King , Wang Yongcheng , Wang Yirong , Liu Wei
Published: August 2024

Host-microbe interactions are virtually bidirectional, but how the host affects their microbiome is poorly understood. Here, we report that the host is a critical modulator to regulate the lifestyle switch and pathogenicity heterogeneity of the opportunistic pathogens
Serratia marcescens
utilizing the
Drosophila
and bacterium model system. First, we find that
Drosophila
larvae efficiently outcompete
S. marcescens
and typically drive a bacterial switch from pathogenicity to commensalism toward the fly. Furthermore,
Drosophila
larvae reshape the transcriptomic and metabolic profiles of
S. marcescens
characterized by a lifestyle switch. More important, the host alters pathogenicity and heterogeneity of
S. marcescens
in the single-cell resolution. Finally, we find that larvae-derived AMPs are required to recapitulate the response of
S. marcescens
to larvae. Altogether, our findings provide an insight into the pivotal roles of the host in harnessing the life history and heterogeneity of symbiotic bacterial cells, advancing knowledge of the reciprocal relationships between the host and pathogen.
Astrogliosis And Neuroinflammation Underlie Scoliosis Upon Cilia Dysfunction
Authors: Djebar Morgane , Anselme Isabelle , Pezeron Guillaume , Bardet Pierre-Luc , Cantaut-Belarif Yasmine , Eschstruth Alexis , Santos Diego López , Ribeuz Hélène Le , Jenett Arnim , Khoury Hanane , Véziers Joelle , Parmentier Caroline , Hirschler Aurélie , Carapito Christine , Bachmann-Gagescu Ruxandra , Schneider-Maunoury Sylvie , Vesque Christine
Published: August 2024

Cilia defects lead to scoliosis in zebrafish, but the underlying pathogenic mechanisms are poorly understood and may diverge depending on the mutated gene. Here, we dissected the mechanisms of scoliosis onset in a zebrafish mutant for the
rpgrip1l
gene encoding a ciliary transition zone protein.
rpgrip1l
mutant fish developed scoliosis with near-total penetrance but asynchronous onset in juveniles. Taking advantage of this asynchrony, we found that curvature onset was preceded by ventricle dilations and was concomitant to the perturbation of Reissner fiber polymerization and to the loss of multiciliated tufts around the subcommissural organ. Rescue experiments showed that Rpgrip1l was exclusively required in
foxj1a
-expressing cells to prevent axis curvature. Genetic interactions investigations ruled out Urp1/2 levels as a main driver of scoliosis in
rpgrip1
mutants. Transcriptomic and proteomic studies identified neuroinflammation associated with increased Annexin levels as a potential mechanism of scoliosis development in
rpgrip1l
juveniles. Investigating the cell types associated with
annexin2
over-expression, we uncovered astrogliosis, arising in glial cells surrounding the diencephalic and rhombencephalic ventricles just before scoliosis onset and increasing with time in severity. Anti-inflammatory drug treatment reduced scoliosis penetrance and severity and this correlated with reduced astrogliosis and macrophage/microglia enrichment around the diencephalic ventricle. Mutation of the
cep290
gene encoding another transition zone protein also associated astrogliosis with scoliosis. Thus, we propose astrogliosis induced by perturbed ventricular homeostasis and associated with immune cell activation as a novel pathogenic mechanism of zebrafish scoliosis caused by cilia dysfunction.
Task dependent coarticulation of movement sequences
Authors: Kalidindi Hari Teja , Crevecoeur Frederic
Published: August 2024

Combining individual actions into sequences is a hallmark of everyday activities. Classical theories propose that the motor system forms a single specification of the sequence as a whole, leading to coarticulation of the different elements. In contrast, recent neural recordings challenge this idea and suggest independent execution of each element specified separately. Here we show that separate or coarticulated sequences can result from the same task-dependent controller, without implying different representations in the brain. Simulations show that planning for multiple reaches simultaneously allows separate or coarticulated sequences depending on instructions about intermediate goals. Human experiments in a two-reach sequence task validated this model. Furthermore, in co-articulated sequences, the second goal influenced long-latency stretch responses to external loads applied during the first reach, demonstrating the involvement of the sensorimotor network supporting fast feedback control. Overall, our study establishes a computational framework for sequence production that highlights the importance of feedback control in this essential motor skill.
A molecular proximity sensor based on an engineered, dual-component guide RNA
Authors: Choi Junhong , Chen Wei , Liao Hanna , Li Xiaoyi , Shendure Jay
Published: August 2024

One of the goals of synthetic biology is to enable the design of arbitrary molecular circuits with programmable inputs and outputs. Such circuits bridge the properties of electronic and natural circuits, processing information in a predictable manner within living cells. Genome editing is a potentially powerful component of synthetic molecular circuits, whether for modulating the expression of a target gene or for stably recording information to genomic DNA. However, programming molecular events such as protein-protein interactions or induced proximity as triggers for genome editing remains challenging. Here, we demonstrate a strategy termed ‘P3 editing’, which links protein-protein proximity to the formation of a functional CRISPR-Cas9 dual-component guide RNA. By engineering the crRNA:tracrRNA interaction, we demonstrate that various known protein-protein interactions, as well as the chemically induced dimerization of protein domains, can be used to activate prime editing or base editing in human cells. Additionally, we explore how P3 editing can incorporate outputs from ADAR-based RNA sensors, potentially allowing specific RNAs to induce specific genome edits within a larger circuit. Our strategy enhances the controllability of CRISPR-based genome editing, facilitating its use in synthetic molecular circuits deployed in living cells.
Empowering AlphaFold2 for protein conformation selective drug discovery with AlphaFold2-RAVE
Authors: Gu Xinyu , Aranganathan Akashnathan , Tiwary Pratyush
Published: August 2024

Small molecule drug design hinges on obtaining co-crystallized ligand-protein structures. Despite AlphaFold2’s strides in protein native structure prediction, its focus on apo structures overlooks ligands and associated holo structures. Moreover, designing selective drugs often benefits from the targeting of diverse metastable conformations. Therefore, direct application of AlphaFold2 models in virtual screening and drug dis-covery remains tentative. Here, we demonstrate an AlphaFold2 based framework combined with all-atom enhanced sampling molecular dynamics and induced fit docking, named AF2RAVE-Glide, to conduct computational model based small molecule binding of metastable protein kinase conformations, initiated from protein sequences. We demonstrate the AF2RAVE-Glide workflow on three different protein kinases and their type I and II inhibitors, with special emphasis on binding of known type II kinase inhibitors which target the metastable classical DFG-out state. These states are not easy to sample from AlphaFold2. Here we demonstrate how with AF2RAVE these metastable conformations can be sampled for different kinases with high enough ac- curacy to enable subsequent docking of known type II kinase inhibitors with more than 50% success rates across docking calculations. We believe the protocol should be deployable for other kinases and more proteins generally.
Differences in size and number of embryonic type-II neuroblast lineages are associated with divergent timing of central complex development between beetle and fly
Authors: Rethemeier Simon , Fritzsche Sonja , Mühlen Dominik , Bucher Gregor , Hunnekuhl Vera S
Published: August 2024

Despite its conserved basic structure, the morphology of the insect brain and the timing of its development underwent evolutionary adaptions. However, little is known on the developmental processes that create this diversity. The central complex is a brain centre required for multimodal information processing and an excellent model to understand neural development and divergence. It is produced in large parts by type-II neuroblasts, which produce intermediate progenitors, another type of cycling precursor, to increase their neural progeny. These neural stem cells are believed to be conserved among insects, but their molecular characteristics and their role in brain development in other insect neurogenetics models, such as the beetle
Tribolium castaneum
have so far not been studied.Using CRISPR-Cas9 we created a fluorescent enhancer trap marking expression of
Tribolium fez/earmuff
, a key marker for type-II neuroblast derived intermediate progenitors. Using combinatorial labelling of further markers including
Tc-pointed
,
Tc-deadpan
,
Tc-asense
and
Tc-prospero
we characterized the type-II neuroblast lineages present in the
Tribolium
embryo and their sub-cell-types. Intriguingly, we found 9 type-II neuroblast lineages in the
Tribolium
embryo while
Drosophila
produces only 8 per brain hemisphere. In addition, these lineages are significantly larger at the embryonic stage than they are in
Drosophila
and contain more intermediate progenitors, enabling the relative earlier development of the central complex. Finally, we mapped these lineages to the domains of early expressed head pattering genes. Notably,
Tc-otd
is absent from all type-II neuroblasts and intermediate progenitors, whereas
Tc-six3
marks an anterior subset of the type-II-lineages. The placodal marker
Tc-six4
specifically marks the territory where anterior medial type-II neuroblasts differentiate.Homologous type-II neuroblasts show a conserved molecular signature between fly and beetle. Enhanced activity of the embryonic beetle neuroblasts-type-II and intermediate progenitors is associated with an earlier central complex development when compared to the fly. Our findings on the differentiation of beetle type-II neuroblasts and on specific marker genes open the possibility to decipher the cellular and molecular mechanisms acting at the stem cell level that contribute to evolutionary divergence in developmental timing and neural morphology.
Offset-fed Slotted Antenna Practically Loaded with Split Ring as Water Quality Sensor for X-Band Industrial Applications
Authors: Varshney A. , Gençoğlan D.  N.
Published: August 2024

This article communicates an offset-fed split ring loaded slotted-antenna design, testing, and analysis for different water quality sensor. The antenna was designed to resonate at 10GHz on a low-cost FR-4 substrate of dimensions 0.621λo×0.467λo×.053λo, where λo is the free space wavelength. The measured antenna parameters are found in excellent agreements. The antenna achieves a gain of 7.61dBi with nearly unidirectional radiation pattern and a radiation efficiency of 76% at 10GHz. Further, the research is explored to use the antenna as a water sample sensor. Different water samples are tested with the antenna by dipping the antenna into the water samples and in the second case contactless measurements at 10mm apart from the upper water level in the container. The quality of water is examined by observing the shift in the resonant frequency (fr), antenna quality factor with different total dissolved solvents (TDS) water samples, and changes in the reflection coefficient (S11) values in the water samples. It is observed that the antenna shows less than 1.5% numerical sensitivity (NS) with fr and high NS with the S11. The S11 and bandwidth of the antenna vary with different water samples. This antenna is suitable for X-band industrial and microwave laboratory applications.
El cuerpo propio entre la naturaleza y el espíritu
Authors: Rabanaque Luis Román
Published: August 2024

Edith Stein escribió su tesis doctoral sobre la empatía bajo la dirección de Edmund Husserl. La empatía es el tipo de vivencia intencional por la cual nos relacionamos con los otros en el mundo. Siguiendo los análisis de Husserl, Stein investiga el yo, el alma y el cuerpo viviente como los elementos para la comprensión del fenómeno de la empatía, que no es una mera conexión formal entre polos yo vacíos sino una relación plena entre personas. En esta exposición procuramos mostrar la manera como Stein, siguiendo a Husserl, aborda la cuestión de la corporalidad en vistas a la pregunta por las maneras de darse de la naturaleza y el espíritu.
Edith Stein sobre la motivación
Authors: Viaña Rubio Carlos Guillermo
Published: August 2024

El artículo analiza la fenomenología de la motivación de Stein, explorando la intencionalidad de la conciencia y los sentidos a través de los cuales se manifiestan los diversos seres del mundo circundante. Stein demuestra cómo cualquier psicología que prescinda de estos aspectos es insuficiente para comprender la complejidad humana. En este sentido, explora la relación entre la psique y el espíritu, y distingue entre causalidad y motivación. También se centra en la relación entre el individuo, la comunidad y el mundo espiritual. Stein asocia la causalidad con el estrato psíquico y la motivación con el espiritual, y demuestra las diversas conexiones entre estos estratos mediante detallados análisis fenomenológicos. Además, discute la validez de las críticas al concepto de causalidad, argumentando que solo la fenomenología puede abordar estas objeciones. En síntesis, el texto ofrece un profundo examen de la motivación humana y su relación con la conciencia y el mundo circundante desde una perspectiva fenomenológica.
Edith Stein, Descartes y nuestras filosofías
Authors: Moreno Romo Juan Carlos
Published: August 2024

Si bien es cierto que la filosofía —la original, la de quien pregunta por todo o todo lo examina, como Sócrates, o la de quien como Descartes duda de todas las cosas (o las pone en suspenso, como Husserl) al menos una vez en la vida— es un ejercicio eminentemente personal, también es cierto que no puede darse sino en el seno de una cultura, y de una comunidad. Tan importante es entonces, para comprender una determinada filosofía, la consideración de la persona concreta —de carne y hueso que diría Unamuno— que la ha realizado, como la de su “sujeto colectivo”: qué comunidad, qué instituciones, y hasta qué poderes sostienen o suscitan tal o cual filosofía, y por qué. Tras ocupar un lugar bastante promisorio en una de las escuelas filosóficas más importantes del siglo XX europeo, Edith Stein quiso ser parte de la Iglesia católica y, en ésta, de la estricta orden del Carmelo. Nos interesa destacar, en lo que sigue, algo de lo que un paso como ese le hizo ver a ella, y nos ayuda a ver a nosotros sobre nuestra propia relación con la filosofía y con la comunidad (Iglesia y/o nación) de la que formamos parte.
Un acercamiento a las bases de la experiencia mística en Edith Stein y Gerda Walther
Authors: Santasilia Stefano
Published: August 2024

Las reflexiones elaboradas por Edith Stein y Gerda Walter alrededor de la experiencia religiosa, y más precisamente de la experiencia mística, revelan ahondar sus raíces en una precisa concepción antropológica de corte relacional. De hecho, las dos filósofas presentan la idea de un ser humano caracterizado por un fondo (alma o yo) cuyo punto más hondo corresponde al lugar de presencia de una alteridad fundamental. El análisis de las condiciones de la experiencia mística, en estas dos autoras, podrá mostrar como esta misma presencia se manifiesta bajo la forma de la relación.
Analogia Entis. Stein - Dionisio - Tomás
Authors: Redmond Walter
Published: August 2024

La analogía del ser es un tema clave en la filosofía y espiritualidad de Edith Stein, Santa Teresa Benedicta de la Cruz.  El mismo título de su obra principal, Ser finito, ser eterno/ Ensayo de un ascenso al sentido del ser, revela cómo comprende la analogía.  Refiere “finito” a un algo limitado en su ser y en su tiempo y “eterno” a un todo, repleto de ser y sentido atemporal.  La analogia entis es el “golfo infinito” entre los dos: una “subida” al sentido de este todo desde el algo, la cual evoca La subida del Monte Carmelo de su compañero Carmelita san Juan de la Cruz. Quiero sugerir cómo Stein interpretó la analogía del ser desde la fenomenología en el marco de una “teología pre” de san Dionisio el Areopagita y santo Tomás de Aquino.  Me referiré a esta obra principal de Stein así como a su monografía “Caminos al conocimiento de Dios/ La ‘teología simbólica’ de Dionisio el Areopagita y sus presuposiciones objetivas”
The unfinished existence of man
Authors: Szalay Matyas
Published: August 2024

This article focuses on the term unfinished existence, accepted by both Christian and secular anthropology; however, both perspectives differ in their understanding of how to reach existential fulfillment. Acquiring such fullness implies a liberation, both external and internal, but the attainment of personal autonomy depends on which path of liberation is given priority. According to the contemporary philosopher, Byung-Chul Han, in the new postmodern paradigm, the oppression of the person intensifies when the fruits of technical-computer progress are internalized (self-optimization). When this praxis is established as a proposal for liberation and as a way of acquiring autonomy, the contradictory and devastating nature of self-aggrandizement becomes evident. The traditional path of theosis, especially if one considers the Steinian interpretation, not only seems reasonable but acquires a particular appeal, since for it, conversion is a complete reintegration of the individual person and is the path to the reconstruction of human community, i.e. social and political life including resilience, which is opposed to the destructive economic power of the liberal market.
Podcast STEM: Fortalecer el Uso de Lenguaje Especializado en Estudiantes de Segundo Medio como Primera Acción para su Realización
Authors:   , Lizana Chaparro Lorena Paz
Published: August 2024

El siguiente trabajo tiene como objetivo configurar bases para desarrollar un guion de podcast de divulgación científica a partir del análisis del discurso de programas creados por actuales estudiantes de segundo medio de un liceo técnico, ubicado en la comuna de San Joaquín, durante el año 2023. El método utilizado para lograr este objetivo es el cualitativo, pues la propuesta didáctica que se expone se desarrolló a partir de la crítica que desarrollaron los estudiantes respecto a los programas de su autoría. Para lograr este propósito, las profesoras de las asignaturas involucradas identificaron las problemáticas que se desarrollaron durante la feria científica del año 2023, focalizada en la transmisión de conocimientos adquiridos mediante una investigación relacionada a métodos anticonceptivos e infecciones de transmisión sexual. La articulación disciplinar se concentra en la creación de un podcast de divulgación científica que permitirá escuchar los discursos de los estudiantes libremente, pues su capacidad de difusión es más amplia que una presentación oral en vivo.A través de la escucha activa y colaborativa, los estudiantes lograron identificar que las mejoras respecto al guion de los podcasts se deben enfocar en la configuración del lenguaje especializado para lograr la posterior difusión de resultados de manera precisa, en virtud de informar a la comunidad escolar con tecnicismos propios del área de Ciencias.
Construyendo currículum consciente. Una propuesta desde el Mindfulness para integrar curricularmente el Aprendizaje Socio Emocional en la asignatura de Química.
Authors:   , Osses Santelices Ernesto
Published: August 2024

El trabajo indaga sobre la experiencia de integración curricular del aprendizaje socioemocional (ASE), desde la perspectiva del Mindfulness, en la asignatura de Química de Enseñanza Media (EM) en Chile. Se plantea desde la necesidad de equilibrar la dimensión académica con la dimensión socioemocional en la escuela, considerando las implicancias que esta tiene sobre el desempeño, salud mental e incluso la felicidad de los estudiantes, especialmente adolescentes. Así, se pretende proponer orientaciones integrar curricularmente el ASE en Química.Para esto, se utiliza una metodología cualitativa y descriptiva con un diseño del tipo fenomenológico hermenéutico, realizando entrevistas semiestructuras en profundidad a 4 docentes de Química en ejercicio en EM. Los principales hallazgos relevan 3 categorías asociadas a las percepciones del profesorado: conceptualización del ASE, ASE en química y ASE en el rol docente. Para la conceptualización se destaca que se realiza desde la experiencia vivida, emociones vividas y relaciones vividas en el contexto de la práctica en el aula. Además, se identifica la necesidad de la construcción de una relación con la química, considerando aspectos curriculares y metodológicos que influyen en la integración efectiva del ASE en la asignatura. Finalmente, el rol docente emerge como crucial en la práctica adecuada de la integración del ASE en el aula.De estos hallazgos, se obtiene una base sólida y robusta que permite diseñar orientaciones para integrar curricularmente el ASE, basado en Mindfulness, en la asignatura de Química en EM, promoviendo así una educación más integral.
Impact of Black Soldier Fly Larval Frass on Growth and Yield of Cluster Bean (Cyamopsis tetragonoloba L.)
Authors: Vasavi G. , Arunakumari J. , Reddy G. Kiran , Nirmala A. , Anitha V.
Published: August 2024

Hermetia illucens L., commonly known as the Black Soldier Fly (BSF), has garnered global attention for its role in insect farming due to its efficient conversion of organic waste into nutrient-rich larval biomass, with frass as a primary byproduct. This study aimed to explore the potential of BSF larval frass (BSFF) as an organic fertilizer for agricultural production, especially evaluating its performance compared to vermicompost on cluster bean growth and yield under field conditions during rabi season at Rajendranagar, Hyderabad. Using a completely randomized block design with eight treatments, various growth parameters such as plant height, number of branches plant-1 and dry matter production, along with yield attributes including number of clusters plant-1, number of pods cluster-1, number of pods plant-1, pod weight (g), pod yield plant-1 and yield (t ha-1) were assessed. Significant differences were observed among treatments, the highest growth and yield parameters were recorded in application of 25 % N through BSF frass + 75 % RDN (T5) and it was on par with 25 % N through vermicompost + 75 % RDN (T6), 50 % N through BSF frass + 50 % RDN (T7), 50 % N through vermicompost + 50 % RDN (T8) and RDF (T2) compared to 100 % N through BSF frass (T3), 100 % N through vermicompost (T4) and control (T1).These treatments resulted in yield increase of 35.7 % (T5), 24.7 % (T6), 23.4 % (T7), 22 %(T8) and 24.36 % (T2) respectively, compared to the control. These findings indicated that BSF larval frass holds promise as a sustainable alternative to vermicompost for enhancing cluster bean production, offering potential benefits for agricultural sustainability and organic waste management.
The Annals of Covent Garden Theatre from 1732 to 1897
Authors: Wyndham Henry Saxe
Published: December 2014

Commissioned by the enterprising actor-manager John Rich, Covent Garden's Theatre Royal first opened its doors in December 1732. Principally a playhouse during its first century, the venue has had an eventful history involving two disastrous fires and riots over ticket prices. Most notably, it hosted Handel's incomparable operas and oratorios, and was where he presented regular seasons from 1735 until his death in 1759. Not until 1847, under Michael Costa, did the theatre dedicate itself to opera, and in 1892 it received the name by which it is known today: the Royal Opera House. Secretary of the Guildhall School of Music from 1901 to 1935, Henry Saxe Wyndham (1867–1940) published this richly illustrated two-volume account in 1906, celebrating the venue's legendary personalities and productions. Volume 1 covers the period 1732 to 1819 and includes discussion of John Rich, John Philip Kemble, Sarah Siddons, and Handel's operas.