bluuebunny/crossref_metadata_2025 huggingface dataset:
El Caribe que soñamos: un futuro culturalmente mestizo.
Authors: Mota Pérez Erick Jorge
Published: January 2024

El afrofutrismo surge como una tendencia dentro de la ciencia ficción norteamericana. Este movimiento está íntimamente relacionado con la lucha contra el racismo y los derechos de las minorías afrodescendientes de los Estados Unidos. Se le ha definido como un movimiento cultural de los afrodescendientes y para los afrodescendientes en Norteamérica. En la actualidad han aparecido otros movimientos centrados en la cultura africana y afroamericana fuera del contexto anglosajón americano. Estas vertientes literarias poseen grandes diferencias con el afrofuturismo clásico. En este trabajo profundizaremos en el tema para encontrar las semejanzas y diferencias entre los diferentes movimientos afrofuturistas norteamericanos, de la diáspora africana y africanos. Analizaremos la relación entre el racismo y la literatura de ciencia ficción y sus diferencias según el lugar donde se escriba.Veremos al Caribe no como un área geográfica sino como un territorio multinacional con una cultura común. Analizaremos algunas características de la ciencia ficción y la fantasía caribeñas que clasifican como afrofuturismo. Veremos que este afrofuturismo del Caribe es un movimiento propio y no una imitación al afrofuturismo norteamericano. Finalmente cuestionaremos el propio uso de la palabra afrofuturismo para el caso particular del área cultural caribeña.
Hacia un archivo de las vidas trans en la Edad de Plata española
Authors: Martínez Gil Juan , Martínez Català Laura
Published: January 2024

En el presente artículo, y en el contexto de la recuperación de la memoria trans en nuestro país en las últimas décadas, pretendemos realizar una aproximación a las vidas trans españolas de la denominada Edad de Plata (1902-1936). Este periodo, poco trabajado en la hispanística desde la óptica de los Trans Studies, brinda interesantes textualidades que son fundamentales para trazar una genealogía. Para nuestra investigación exponemos, en primer lugar, la aproximación metodológica, centrándonos en la terminología de búsqueda empleada en los repositorios bibliográficos y hemerográficos, y en los campos en los que podían hallarse las fuentes primarias. Seguidamente, clasificamos el corpus resultante en torno a tres núcleos temáticos: la medicina y la criminología, el mundo de los imitadores de estrellas y el espectáculo, y la literatura. En cada apartado analizamos los textos reunidos y problematizamos diferentes aspectos sobre la representación trans en esos años. Damos cuenta, asimismo, de las posibles interrelaciones entre ellos y de las claves que arrojan para comprender y trabajar una historia cultural trans española.
Cuerpo, enfermedad y biopolítica en la literatura española y latinoamericana contemporánea
Authors: Martínez García Miguel Ángel
Published: January 2024

En un pasaje de ‘Las partículas elementales’, de Michel Houellebecq, un personaje afirma que “los únicos acontecimientos que quedan por vivir son médicos”. Esta afirmación nos permite delimitar la circunstancia que funciona como punto de partida de este artículo: la presencia insistente de distintas formas de enfermedad en las sociedades actuales y la ocupación creciente de las formas de vida por parte de la práctica y el discurso médico. A lo largo del texto, nos aproximamos a este hecho a partir del análisis de un corpus de textos literarios recientes que tematizan el motivo de la enfermedad y su dimensión social y/o política. Creemos que la potencia de estos textos radica en haber detectado las transformaciones que estaban en curso en el mundo contemporáneo. Un mundo que ya se había convertido, antes de la irrupción de la COVID-19, en una “ilimitada patria médica”.
Effect exponentially distributed trapped charge jump transport on energy storage performance in polyetherimide nanocomposite dielectric
Authors: Song Xiao-Fan , Min Dao-Min , Gao Zi-Wei , Wang Po-Xin , Hao Yu-Tao , Gao Jing-Hui , Zhong Li-Sheng ,   State Key Laboratory of Electrical Insulation and Power Equipment, Xi’an Jiaotong University, Xi’an 710049, China
Published: January 2024

With the development of science and technology, polymer dielectric capacitors are widely used in energy, electronics, transportation, aerospace, and many other areas. For polymer dielectric energy storage capacitors to remain effective in practical applications, excellent charge and discharge performance is essential. However, the performance of the common polymer dielectric capacitors will deteriorate rapidly at high temperature, which makes them fail to work efficiently under worse working conditions. Dielectric trap energy levels and trap densities increase when nanoparticles are incorporated into the dielectric. The change in trap parameters will affect carrier transport. Therefore, the high temperature energy storage performance of polymer nanocomposite dielectric can be improved by changing the trap parameters to regulate the carrier transport process. However, the quantitative relationship between trap energy level and trap density and the energy storage properties of nanocomposite dielectric need further studying. In this paper, the energy storage and release model for exponentially distributed trapped charge jump transport in linear polymer nanocomposite dielectrics is constructed and simulated. The volume resistivity and electric displacement-electric field loops of pure polyetherimide are simulated at 150 ℃, and the simulation results match the experimental results, which demonstrates the validity of the model. Following that, under different temperatures and electric fields, the current density, electric displacement-electric field loops, discharge energy density and charge-discharge efficiency of polyetherimide nanocomposite dielectric are simulated by using different trap parameters. The results show that increasing the maximum trap energy level and the total trap density can effectively reduce the carrier mobility, current density and conductivity loss, and enhance the discharge energy density and the charge-discharge efficiency of the nanocomposite dielectric. On condition that temperature is 150 ℃ and applied electric field is 550 kV/mm, the polyetherimide nanocomposite dielectric with a maximum trap energy level of 1.0 eV and a total trap density of 1×1027 m–3, has 4.26 J·cm–3 of discharge energy density and 98.93% of energy efficiency. Compared with pure polyetherimide, the rate of improvement is 91.09% and 227.58%, respectively. The energy storage performance under high temperature and high electric field is obviously improved. It provides theoretical and model support for the research and development of capacitors with high temperature resistance and energy storage performance.
Chemo- and optogenetic activation of hypothalamic Foxb1-expressing neurons and their terminal endings in the rostral-dorsolateral PAG leads to tachypnea, bradycardia, and immobility
Authors: Cola Reto B. , Roccaro-Waldmeyer Diana M. , Naim Samara , Babalian Alexander , Seebeck Petra , Alvarez-Bolado Gonzalo , Celio Marco R.
Published: January 2024

Foxb1-expressing neurons occur in the dorsal premammillary nucleus (PMd) and further rostrally in the parvafox nucleus, a longitudinal cluster of neurons in the lateral hypothalamus of rodents. The descending projection of these Foxb1
+
neurons end in the dorsolateral part of the periaqueductal gray (dlPAG). The functional role of the Foxb1
+
neuronal subpopulation in the PMd and the parvafox nucleus remains elusive. In this study, the activity of the Foxb1
+
neurons and of their terminal endings in the dlPAG was selectively altered by employing chemo- and optogenetic tools. Our results show that in whole-body barometric plethysmography, hM3Dq-mediated, global Foxb1
+
neuron excitation activates respiration. Time-resolved optogenetic gain-of- function manipulation of the terminal endings of Foxb1
+
neurons in the rostral third of the dlPAG leads to abrupt immobility and bradycardia. Chemogenetic activation of Foxb1
+
cell bodies and ChR2-mediated excitation of their axonal endings in the dlPAG led to a phenotypical presentation congruent with a “freezing-like” situation during innate defensive behavior.
A dynamical computational model of theta generation in hippocampal circuits to study theta-gamma oscillations during neurostimulation
Authors: Vardalakis Nikolaos , Aussel Amélie , Rougier Nicolas P. , Wagner Fabien B.
Published: January 2024

Neurostimulation of the hippocampal formation has shown promising results for modulating memory but the underlying mechanisms remain unclear. In particular, the effects on hippocampal theta-nested gamma oscillations and theta phase reset, which are both crucial for memory processes, are unknown. Moreover, these effects cannot be investigated using current computational models, which consider theta oscillations with a fixed amplitude and phase velocity. Here, we developed a novel computational model that includes the medial septum, represented as a set of abstract Kuramoto oscillators producing a dynamical theta rhythm with phase reset, and the hippocampal formation, composed of biophysically-realistic neurons and able to generate theta-nested gamma oscillations under theta drive. We showed that, for theta inputs just below the threshold to induce self-sustained theta-nested gamma oscillations, a single stimulation pulse could switch the network behavior from non-oscillatory to a state producing sustained oscillations. Next, we demonstrated that, for a weaker theta input, pulse train stimulation at the theta frequency could transiently restore seemingly physiological oscillations. Importantly, the presence of phase reset influenced whether these two effects depended on the phase at which stimulation onset was delivered, which has practical implications for designing neurostimulation protocols that are triggered by the phase of ongoing theta oscillations. This novel model opens new avenues for studying the effects of neurostimulation on the hippocampal formation. Furthermore, our hybrid approach that combines different levels of abstraction could be extended in future work to other neural circuits that produce dynamical brain rhythms.
Plasma extracellular vesicle synaptic proteins as biomarkers of clinical progression in patients with Parkinson’s disease: A follow-up study
Authors: Hong Chien-Tai , Chung Chen-Chih , Yu Ruan-Ching , Chan Lung
Published: January 2024

Synaptic dysfunction plays a key role in Parkinson’s disease (PD), and plasma extracellular vesicle (EV) synaptic proteins are emerging as biomarkers for neurodegenerative diseases. This study assessed the efficacy of plasma EV synaptic proteins as biomarkers in PD and their association with disease progression. In total, 144 participants were enrolled, including 101 people with PD (PwP) and 43 healthy controls (HCs). The changes in plasma EV synaptic protein levels between baseline and 1-year follow-up did not differ significantly in both PwP and HCs. In PwP, the changes in plasma EV synaptic protein levels were significantly associated with the changes in unified PD rating scale (UPDRS) part II and III scores. Moreover, PwP with elevated levels (first quartile) of any one plasma EV synaptic proteins (synaptosome-associated protein 25, growth-associated protein 43 or synaptotagmin-1) had significantly greater disease progression in UPDRS part II score and the postural instability and gait disturbance subscore in UPDRS part III than did the other PwP after adjustment for age, sex, and disease duration. These results indicate the promising potential of plasma EV synaptic proteins as clinical biomarkers of disease progression in PD. However, a longer follow-up period is warranted to confirm their role as prognostic biomarkers.
Coupling of Slack and NaV1.6 sensitizes Slack to quinidine blockade and guides anti-seizure strategy development
Authors: Yuan Tian , Wang Yifan , Jin Yuchen , Yang Hui , Xu Shuai , Zhang Heng , Chen Qian , Li Na , Ma Xinyue , Song Huifang , Peng Chao , Geng Ze , Dong Jie , Duan Guifang , Sun Qi , Yang Yang , Yang Fan , Huang Zhuo
Published: January 2024

Quinidine has been used as an anticonvulsant to treat patients with KCNT1-related epilepsy by targeting gain-of-function KCNT1 pathogenic mutant variants. However, the detailed mechanism underlying quinidine’s blockade against KCNT1 (Slack) remains elusive. Here, we report a functional and physical coupling of the voltage-gated sodium channel Na
V
1.6 and Slack. Na
V
1.6 binds to and highly sensitizes Slack to quinidine blockade. Homozygous knockout of Na
V
1.6 reduces the sensitivity of native sodium-activated potassium currents to quinidine blockade. Na
V
1.6-mediated sensitization requires the involvement of Na
V
1.6’s N-and C-termini binding to Slack’s C-terminus, and is enhanced by transient sodium influx through Na
V
1.6. Moreover, disrupting the Slack-Na
V
1.6 interaction by viral expression of Slack’s C-terminus can protect against SlackG269S-induced seizures in mice. These insights about a Slack-Na
V
1.6 complex challenge the traditional view of “Slack as an isolated target” for anti-epileptic drug discovery efforts, and can guide the development of innovative therapeutic strategies for KCNT1-related epilepsy.
The genetic and dietary landscape of the muscle insulin signalling network
Authors: van Gerwen Julian , Masson Stewart W. C. , Cutler Harry B. , Díaz-Vegas Alexis , Potter Meg , Stöckli Jacqueline , Madsen Søren , Nelson Marin E. , Humphrey Sean J. , James David E.
Published: January 2024

Metabolic disease is caused by a combination of genetic and environmental factors, yet few studies have examined how these factors influence signal transduction, a key mediator of metabolism. Using mass spectrometry-based phosphoproteomics, we quantified 23,126 phosphosites in skeletal muscle of five genetically distinct mouse strains in two dietary environments, with and without acute
in vivo
insulin stimulation. Almost half of the insulin-regulated phosphoproteome was modified by genetic background on an ordinary diet, and high-fat high-sugar feeding affected insulin signalling in a strain-dependent manner. Our data revealed coregulated subnetworks within the insulin signalling pathway, expanding our understanding of the pathway’s organisation. Furthermore, associating diverse signalling responses with insulin-stimulated glucose uptake uncovered regulators of muscle insulin responsiveness, including the regulatory phosphosite S469 on Pfkfb2, a key activator of glycolysis. Finally, we confirmed the role of glycolysis in modulating insulin action in insulin resistance. Our results underscore the significance of genetics in shaping global signalling responses and their adaptability to environmental changes, emphasizing the utility of studying biological diversity with phosphoproteomics to discover key regulatory mechanisms of complex traits.
Explicit Ion Modeling Predicts Physicochemical Interactions for Chromatin Organization
Authors: Lin Xingcheng , Zhang Bin
Published: January 2024

Molecular mechanisms that dictate chromatin organization
in vivo
are under active investigation, and the extent to which intrinsic interactions contribute to this process remains debatable. A central quantity for evaluating their contribution is the strength of nucleosome-nucleosome binding, which previous experiments have estimated to range from 2 to 14

k
B
T

. We introduce an explicit ion model to dramatically enhance the accuracy of residue-level coarse-grained modeling approaches across a wide range of ionic concentrations. This model allows for
de novo
predictions of chromatin organization and remains computationally efficient, enabling large-scale conformational sampling for free energy calculations. It reproduces the energetics of protein-DNA binding and unwinding of single nucleosomal DNA, and resolves the differential impact of mono and divalent ions on chromatin conformations. Moreover, we showed that the model can reconcile various experiments on quantifying nucleosomal interactions, providing an explanation for the large discrepancy between existing estimations. We predict the interaction strength at physiological conditions to be 9

k
B
T

, a value that is nonetheless sensitive to DNA linker length and the presence of linker histones. Our study strongly supports the contribution of physicochemical interactions to the phase behavior of chromatin aggregates and chromatin organization inside the nucleus.
Cis-regulatory modes of Ultrabithorax inactivation in butterfly forewings
Authors: Tendolkar Amruta , Mazo-Vargas Anyi , Livraghi Luca , Hanly Joseph J. , Van Horne Kelsey C. , Gilbert Lawrence E. , Martin Arnaud
Published: January 2024

Hox gene clusters encode transcription factors that drive regional specialization during animal development: e.g. the Hox factor Ubx is expressed in the insect metathoracic (T3) wing appendages and differentiates them from T2 mesothoracic identities. Hox transcriptional regulation requires silencing activities that prevent spurious activation and regulatory crosstalks in the wrong tissues, but this has seldom been studied in insects other than Drosophila , which shows a derived Hox dislocation into two genomic clusters that disjoined Antennapedia ( Antp ) and Ultrabithorax ( Ubx ). Here we investigated how Ubx is restricted to the hindwing in butterflies, amidst a contiguous Hox cluster. By analysing Hi-C and ATAC-seq data in the butterfly Junonia coenia , we show that a Topologically Associated Domain (TAD) maintains a hindwing-enriched profile of chromatin opening around Ubx . This TAD is bordered by a Boundary Element (BE) that separates it from a region of joined wing activity around the Antp locus. CRISPR mutational perturbation of this BE releases ectopic Ubx expression in forewings, inducing homeotic clones with hindwing identities. Further mutational interrogation of two non-coding RNA encoding regions and one putative cis- regulatory module within the Ubx TAD cause rare homeotic transformations in both directions, indicating the presence of both activating and repressing chromatin features. We also describe a series of spontaneous forewing homeotic phenotypes obtained in Heliconius butterflies, and discuss their possible mutational basis. By leveraging the extensive wing specialization found in butterflies, our initial exploration of Ubx regulation demonstrates the existence of silencing and insulating sequences that prevent its spurious expression in forewings.
Stumpy forms are the predominant transmissible forms of Trypanosoma brucei
Authors: Ngoune Jean Marc Tsagmo , Sharma Parul , Crouzols Aline , Rotureau Brice
Published: January 2024

Recently, Schuster
et al
. demonstrated that bloodstream slender forms of African trypanosomes are readily transmissible to young tsetse flies where they can complete their complex life cycle (1). In their experimental conditions, a single slender parasite was sufficient for productive infection. Here, we compared the infectivity of slender and stumpy bloodstream forms in adult flies with a mature immune system, and without using any chemical compounds that would alter the insect immune response and/or promote the infection. After ingestion of slender forms, infected flies were observed only in one out of 24 batches of non-immunocompetent teneral flies and with a high number of parasites. In contrast, infected flies were detected in 75% (18/24) of the batches infected with stumpy parasites, and as few as 10 stumpy parasites produced mature infections in immune adult flies. We discuss that, although Schuster
et al
. have demonstrated the intrinsic capacity of slender form trypanosomes to infect young and naive tsetse flies, highlighting the remarkable plasticity and adaptability of these protists, this phenomenon is unlikely to significantly contribute to the epidemiology of African trypanosomiases. According to both experimental and field observations, stumpy forms appear to be the most adapted forms for African trypanosome transmission from the mammalian host to the tsetse fly vector in natural conditions.
Gcn5 – mTORC1 – TFEB signalling axis mediated control of autophagy regulates Drosophila blood cell homeostasis
Authors: Arjun AR , Math Suraj , Kata Laxmi , Khadilkar Rohan Jayant
Published: January 2024

Blood progenitors are regulated by a variety of signals from their environment. In the Drosophila lymph gland (LG), the Posterior Signalling Center (PSC) acts as a stem cell niche striking a balance between progenitors and differentiated blood cells. While the response of blood progenitors to extrinsic signals is well characterized, their ability to respond to cell intrinsic cues is unexplored. Autophagy is one such intrinsic cellular process that maintains cellular homeostasis by removing unnecessary or dysfunctional cell components through autophagic degradation and recycling. Here, we show that autophagy plays a critical role in regulating blood cell homeostasis in the lymph gland. General control non-derepressible 5 (Gcn5), a histone acetyltransferase is expressed in all the cellular subsets of the LG and modulation of Gcn5 levels in various cellular subsets of the LG perturbs LG homeostasis. Gcn5 through its known non-histone acetylation target, TFEB controls autophagic flux thereby regulating hematopoiesis. Additionally, we demonstrate that modulation of mTORC1 activity can perturb hematopoiesis. We show that Gcn5 acts as a nutrient sensor and mTORC1 activity regulates Gcn5. mTORC1 over-rides the effect exerted by Gcn5 in regulating LG hematopoiesis. Together, our findings indicate that Gcn5 – mTORC1 – TFEB signaling axis mediated control of autophagy is required for maintaining blood cell homeostasis in Drosophila .
PKCδ is an activator of neuronal mitochondrial metabolism that mediates the spacing effect on memory consolidation
Authors: Comyn Typhaine , Preat Thomas , Pavlowsky Alice , Plaçais Pierre-Yves
Published: January 2024

Relevance-based selectivity and high energy cost are two distinct features of long-term memory (LTM) formation that warrant its default inhibition. Spaced repetition of learning is a highly conserved cognitive mechanism that can lift this inhibition. Here, we questioned how the spacing effect integrates experience selection and energy efficiency at the cellular and molecular levels. We showed in Drosophila that spaced training triggers LTM formation by extending over several hours an increased mitochondrial metabolic activity in neurons of the associative memory center, the mushroom bodies (MBs). We found that this effect is mediated by PKCδ, a member of the so-called ‘novel PKC’ family of enzymes, which uncovers the critical function of PKCδ in neurons as a regulator of mitochondrial metabolism for LTM. Additionally, PKCδ activation and translocation to mitochondria result from LTM-specific dopamine signaling on MB neurons. By bridging experience-dependent neuronal circuit activity with metabolic modulation of memory-encoding neurons, PKCδ signaling binds the cognitive and metabolic constraints underlying LTM formation into a unified gating mechanism.
Conformational dynamics of a nicotinic receptor neurotransmitter binding site
Authors: Singh Mrityunjay , Indurthi Dinesh C. , Mittal Lovika , Auerbach Anthony , Asthana Shailendra
Published: January 2024

Agonists activate receptors by interacting more strongly with active versus resting conformations of their target sites. For each ligand, the strong-weak binding free energy difference sets efficacy and the weak/strong ratio sets efficiency. We performed molecular dynamics simulations to explore the conformational dynamics of a nicotinic receptor neurotransmitter binding site in the weak→strong structural transition. The alternative conformations were identified by comparing calculated and experimental binding free energies for 4 agonists. In weak→strong, the agonist rotates about its cationic center (a ‘flip’), loop C moves in (a ‘flop’) to reposition αY190 to form a water-mediated cross-subunit hydrogen bond with the ligand. The flop restructures the aromatic core, and the flip increases van der Waals interactions to generate a more compact, hydrophobic and stable pocket. The simulations reveal a transient intermediate state as well as changes in a salt bridge that may distinguish agonists.
Single-cell RNA sequencing unveils the hidden powers of zebrafish kidney for generating both hematopoiesis and adaptive antiviral immunity
Authors: Hu Chongbin , Zhang Nan , Hong Yun , Tie Ruxiu , Fan Dongdong , Lin Aifu , Chen Ye , Xiang Lixin , Shao Jianzhong
Published: January 2024

The vertebrate kidneys play two evolutionary conserved roles in waste excretion and osmoregulation. Besides, the kidney of fish is considered as a functional ortholog of mammalian bone marrow that serves as a hematopoietic hub for generating blood cell lineages and immunological responses. However, knowledge about the properties of kidney hematopoietic cells, and the functionality of kidney in fish immune systems remain to be elucidated. To this end, our present study generated a comprehensive atlas with 59 hematopoietic stem/progenitor cell (HSPC) and immune-cell types from zebrafish kidney via single-cell transcriptome profiling analysis. These populations included almost all known cells associated with innate and adaptive immunity, and displayed differential responses to viral infection, indicating their diverse functional roles in antiviral immunity. Remarkably, HSPCs were found to have extensive reactivities to viral infection, and the trained immunity can be effectively induced in certain HSPCs. In addition, the antigen-stimulated adaptive immunity can be fully generated in kidney, suggesting kidney acting as a secondary lymphoid organ. These results indicated that fish kidney is a dual-functional entity with functionalities of both primary and secondary lymphoid organs. Our findings illustrated the unique features of fish immune system, and highlighted the multifaced biology of kidney in ancient vertebrates.
Mutant mice lacking alternatively spliced p53 isoforms unveil Ackr4 as a male-specific prognostic factor in Myc-driven B-cell lymphomas
Authors: Fajac Anne , Simeonova Iva , Leemput Julia , Gabriel Marc , Morin Aurélie , Lejour Vincent , Hamon Annaïg , Vaysse-Zinkhöfer Wilhelm , Eldawra Eliana , Rakotopare Jeanne , Pinskaya Marina , Morillon Antonin , Bourdon Jean-Christophe , Bardot Boris , Toledo Franck
Published: January 2024

The gene encoding p53, a major tumor suppressor protein, encodes several alternative isoforms of elusive biological significance. Here we show that mice lacking the
Trp53
Alternatively Spliced (AS) exon, thereby expressing the canonical p53 protein but not isoforms with the AS C-terminus, have unexpectedly lost a male-specific protection against Myc-induced B-cell lymphomas. Lymphomagenesis was delayed in p53
+/+
Eμ-Myc males compared to p53
ΔAS/ΔAS
Eμ-Myc males, but also compared to p53
+/+
Eμ-Myc and p53
ΔAS/ΔAS
Eμ-Myc females. Pre-tumoral splenocytes from p53
+/+
Eμ-Myc males exhibited a higher expression of
Ackr4,
encoding an atypical chemokine receptor with tumor suppressive effects. We show that
Ackr4
is a p53 target gene, but that its p53-mediated transactivation is inhibited by estrogens. We identify
Ackr4
as a male-specific factor of good prognosis, relevant for murine Eμ-Myc-induced and human Burkitt lymphomas. These data demonstrate the functional relevance of alternatively spliced p53 isoforms and reveal sex disparities in Myc-driven B-cell lymphomagenesis.
Heterozygous expression of a Kcnt1 gain-of-function variant has differential effects on SST- and PV-expressing cortical GABAergic neurons
Authors: Shore Amy N. , Qunies Alshaima’a M. , Spitznagel Brittany D. , Weaver C. David , Emmitte Kyle A. , Frankel Wayne N. , Weston Matthew C.
Published: January 2024

More than twenty recurrent missense gain-of-function (GOF) mutations have been identified in the sodium-activated potassium (K
Na
) channel gene
KCNT1
in patients with severe developmental and epileptic encephalopathies (DEEs), most of which are resistant to current therapies. Defining the neuron types most vulnerable to KCNT1 GOF will advance our understanding of disease mechanisms and provide refined targets for precision therapy efforts. Here, we assessed the effects of heterozygous expression of a
Kcnt1
GOF variant (Y777H) on K
Na
currents and neuronal physiology among cortical glutamatergic and GABAergic neurons in mice, including those expressing vasoactive intestinal polypeptide (VIP), somatostatin (SST), and parvalbumin (PV), to identify and model the pathogenic mechanisms of autosomal dominant
KCNT1
GOF variants in DEEs. Although the
Kcnt1
-Y777H variant had no effects on glutamatergic or VIP neuron function, it increased subthreshold K
Na
currents in both SST and PV neurons but with opposite effects on neuronal output; SST neurons became hypoexcitable with a higher rheobase current and lower action potential (AP) firing frequency, whereas PV neurons became hyperexcitable with a lower rheobase current and higher AP firing frequency. Further neurophysiological and computational modeling experiments showed that the differential effects of the Y777H variant on SST and PV neurons are not likely due to inherent differences in these neuron types, but to an increased persistent sodium current in PV, but not SST, neurons. The Y777H variant also increased excitatory input onto, and chemical and electrical synaptic connectivity between, SST neurons. Together, these data suggest differential pathogenic mechanisms, both direct and compensatory, contribute to disease phenotypes, and provide a salient example of how a pathogenic ion channel variant can cause opposite functional effects in closely related neuron subtypes due to interactions with other ionic conductances.
Visual experience shapes functional connectivity between occipital and non-visual networks
Authors: Tian Mengyu , Xiao Xiang , Hu Huiqing , Cusack Rhodri , Bedny Marina
Published: January 2024

Comparisons across adults with different sensory histories (blind vs. sighted) have uncovered effects of experience on human brain function. In people born blind visual cortices are responsive to non-visual tasks and show altered functional connectivity at rest. Since almost all research has been done with adults, little is known about the developmental origins of this plasticity. Are infant visual cortices initially functionally like those of sighted adults and blindness causes reorganization? Alternatively, do infants start like blind adults, with vision required to set up the sighted pattern? To distinguish between these possibilities, we compare resting state functional connectivity across blind (
n
= 30) and blindfolded sighted (
n
= 50) adults to a large cohort of sighted infants (Developing Human Connectome Project,
n
= 475). Remarkably, we find that infant secondary visual cortices functionally resemble those of blind more than sighted adults, consistent with the idea that visual experience is required to set up long-range functional connectivity. Primary visual cortices show a mixture of instructive effects of vision and reorganizing effects of blindness. Specifically, in sighted adults, visual cortices show stronger functional coupling with nonvisual sensory-motor networks (i.e., auditory, somatosensory/motor) than with higher-cognitive prefrontal cortices (PFC). In blind adults, visual cortices show stronger coupling with PFC. In infants, connectivity of secondary visual cortices is stronger with PFC, while V1 shows equal sensory-motor/PFC connectivity. In contrast, lateralization of occipital-to-frontal connectivity resembles the sighted adults at birth and is reorganized by blindness, possibly due to recruitment of occipital networks for lateralized cognitive functions, such as language.
The Genomic Legacy of Human Management and sex-biased Aurochs hybridization in Iberian Cattle
Authors: Günther Torsten , Chisausky Jacob , Galindo-Pellicena M. Ángeles , Iriarte Eneko , Gardyn Oscar Cortes , Eusebi Paulina G. , García-González Rebeca , Urena Irene , Moreno Marta , Alday Alfonso , Rojo Manuel , Pérez Amalia , Rodríguez Cristina Tejedor , de Lagrán Iñigo García Martínez , Arsuaga Juan Luis , Carretero José-Miguel , Götherström Anders , Smith Colin , Valdiosera Cristina
Published: January 2024

Cattle have been a valuable economic resource and cultural icon since prehistory. From the initial expansion of domestic cattle into Europe during the Neolithic period, taurine cattle (
Bos taurus
) and their wild ancestor, the aurochs (
B. primigenius
), had overlapping ranges leading to ample opportunities for intentional and unintentional hybridization. We performed a bioarchaeological analysis of 24
Bos
remains from Iberia dating from the Mesolithic to the Roman period. The archaeogenomic dataset allows us to investigate the extent of domestic-wild hybridization over time, providing insight into the species’ behavior and human management by aligning changes with cultural and genomic transitions in the archaeological record. Our results show frequent hybridization during the Neolithic and Chalcolithic, likely reflecting a mix of hunting and herding or relatively unmanaged herds, with mostly male aurochs and female domestic cattle involved in hybridization. This is supported by isotopic evidence of ecological niche sharing, with only a few domestic cattle possibly being managed. The proportion of aurochs ancestry in domestic cattle remains relatively constant from about 4000 years ago, probably due to herd management and selection against hybrids, coinciding with other cultural transitions. The constant level of wild ancestry (~20%) continues into modern western European breeds including the Spanish Lidia breed which is bred for its aggressiveness and fighting ability, but does not display elevated levels of aurochs ancestry. This study takes a genomic glance at the impact of human actions and wild introgression in the establishment of cattle as one of the most important domestic species today.
Infection pressure in apes has driven selection for CD4 alleles that resist lentivirus (HIV/SIV) infection
Authors: Warren Cody J. , Barbachano-Guerrero Arturo , Bauer Vanessa L. , Stabell Alex C. , Dirasantha Obaiah , Yang Qing , Sawyer Sara L.
Published: January 2024

Simian immunodeficiency viruses (SIVs) comprise a large group of primate lentiviruses that endemically infect African monkeys. HIV-1 spilled over to humans from this viral reservoir, but the spillover did not occur directly from monkeys to humans. Instead, a key event was the introduction of SIVs into great apes, which then set the stage for infection of humans. Here, we investigate the role of the lentiviral entry receptor, CD4, in this key and fateful event in the history of SIV/HIV emergence. First, we reconstructed and tested ancient forms of CD4 at two important nodes in ape speciation, prior to the infection of chimpanzees and gorillas with these viruses. These ancestral CD4s fully supported entry of diverse SIV isolates related to the virus(es) that made this initial jump to apes. In stark contrast, modern chimpanzee and gorilla CD4s are more resistant to these viruses. To investigate how this resistance in CD4 was gained, we acquired CD4 sequences from 32 gorilla individuals of 2 species, and identified alleles that encode 8 unique CD4 proteins. Function testing of these identified allele-specific CD4 differences in susceptibility to virus entry. By engineering single point mutations from gorilla CD4 alleles into a permissive human CD4 receptor, we demonstrate that acquired SNPs in gorilla CD4 did convey resistance to virus entry. We provide a population genetic analysis to support the theory that selection is acting in favor of more and more resistant CD4 alleles in apes with endemic SIV infection (gorillas and chimpanzees), but not in other ape species (bonobo and orangutan) that lack SIV infections. Taken together, our results show that SIV has placed intense selective pressure on ape CD4, acting to drive the generation of SIV-resistant CD4 alleles in chimpanzees and gorillas.
Structure of the human heparan-α-glucosaminide N-acetyltransferase (HGSNAT)
Authors: Navratna Vikas , Kumar Arvind , Mosalaganti Shyamal
Published: January 2024

Degradation of heparan sulfate (HS), a glycosaminoglycan (GAG) comprised of repeating units of
N
-acetylglucosamine and glucuronic acid, begins in the cytosol and is completed in the lysosomes. Acetylation of the terminal non-reducing amino group of α-D-glucosamine of HS is essential for its complete breakdown into monosaccharides and free sulfate. Heparan-α-glucosaminide
N
-acetyltransferase (HGSNAT), a resident of the lysosomal membrane, catalyzes this essential acetylation reaction by accepting and transferring the acetyl group from cytosolic acetyl-CoA to terminal α-D-glucosamine of HS in the lysosomal lumen. Mutation-induced dysfunction in HGSNAT causes abnormal accumulation of HS within the lysosomes and leads to an autosomal recessive neurodegenerative lysosomal storage disorder called mucopolysaccharidosis IIIC (MPS IIIC). There are no approved drugs or treatment strategies to cure or manage the symptoms of, MPS IIIC. Here, we use cryo-electron microscopy (cryo-EM) to determine a high-resolution structure of the HGSNAT-acetyl-CoA complex in an open-to-lumen conformation, the first step in HGSNAT catalyzed acetyltransferase reaction. In addition, we map the known MPS IIIC mutations onto the structure and elucidate the molecular basis for mutation-induced HGSNAT dysfunction.
Sub-surface deformation of individual fingerprint ridges during tactile interactions
Authors: Corniani Giulia , Lee Zing S , Carré Matt J , Lewis Roger , Delhaye Benoit P , Saal Hannes P
Published: January 2024

The human fingertip can detect small tactile features with a spatial acuity roughly the width of a fingerprint ridge. However, how individual ridges deform under contact to support accurate and high-precision tactile feedback is currently unknown. The complex mechanical structure of the glabrous skin, composed of multiple layers and intricate morphology within which mechanoreceptors are embedded, makes this question challenging. Here, we used optical coherence tomography to image and track sub-surface deformations of hundreds of individual fingerprint ridges during contact events at high spatial resolution in vivo. We calculated strain patterns in both the stratum corneum and viable epidermis in response to a variety of tactile stimuli, including static indentation, stick-to-slip events, sliding of a flat surface in different directions, and interaction with small tactile features, such as edges and grooves. We found that ridges could stretch, compress, and undergo considerable shearing orthogonal to the skin surface, but there was limited horizontal shear. Therefore, it appears that the primary components of ridge deformation and, potentially, neural responses are deformations of the ridge flanks and their relative movement, rather than overall bending of the ridges themselves. We conclude that the local distribution of mechanoreceptors across the ridges might be ideally suited to extract the resulting strain gradients and that the fingertip skin may possess a higher mechanical spatial resolution than that of a single ridge.
pluralismo educativo: desafíos y discusiones internacionales. Las nuevas tendencias de soft-law
Authors: Grau Callizo Ignasi , San Andrés Mayca
Published: January 2024

El artículo presenta la naturaleza de las discusiones relativas al pluralismo educativo en organismos internacionales. Tras una amplia exposición referente a la protección de los derechos de los padres en materia de educación en tratados jurídicamente vinculantes, se enuncian las nuevas iniciativas susceptibles de crear soft-law susceptible de redefinir el contenido de los derechos humanos –no solo del derecho a la educación, en pos de nuevos intereses o de lo que se suele denominar “nuevos derechos”. El artículo aporta un enfoque internacional a lo que hoy en día es ya un fenómeno global.
Verdadera elección: La elusiva calidad y equidad educativa en El Salvador
Authors: Martin Pauline
Published: January 2024

En El Salvador, el marco jurídico y político educativos respalda una educación inclusiva y de calidad como derecho humano, gratuita, y participativa, con proveedores públicos y privados y el derecho de los padres a elegir el tipo de educación que desean. Aun así, el derecho a la educación no se cumple, manifestado en la baja matrícula y condiciones de calidad desiguales en poblaciones en desventaja económica y social. Dos estudios de caso recientes – uno sobre educación basada en la fe y el otro sobre educación inclusiva en El Salvador– señalan que, aun con proveedores públicos y privados, subsidios a algunos centros educativos católicos, y suministros de recursos y alimentación, existen resultados deficientes de aprendizaje y ciertas poblaciones que no asisten regularmente a la escuela. Los estudios señalan que las realidades económicas y sociales limitan la posibilidad que las familias salvadoreñas decidan sobre el tipo de educación que desean y poco visualizan el valor de la educación para sus hijos. La educación basada en la fe está sujeta a las dinámicas de oferta y demanda y el modelo privado de financiamiento, aunque ofrece algunas ventajas que puedan enriquecer a todas las escuelas. Para una verdadera elección educativa basada en el derecho a la educación y conducente a la igualdad, es necesario unir todos los sectores de la sociedad, tanto instituciones privadas como públicas, con aprendizaje mutuo entre sectores, y fomentar un protagonismo y compromiso de las familias para disminuir aspectos que van en detrimento de la calidad y la inclusión educativas.
Об одном способе исследования литосферных плит неклассической формы и сложной реологии, "Наука юга России"
Authors: Лозовой В.В. , Горшкова Е.М. , Плужник А.В. , Уафа С.Б.
Published: January 2024

Изучена возможность оценки поведения литосферных плит неклассической формы, находящихся на многослойном основании. Исследование диктуется необходимостью исследования динамических свойств таких литосферных плит в связи с обнаружением возможности возникновения у них резонансов. Резонансы могут влиять на сейсмическое состояние территории литосферной плиты и провоцировать землетрясения. В качестве литосферной плиты изучается клиновидная плита в форме четверти плоскости. Решение рассматриваемой задачи опирается на возможность решения контактной задачи в клиновидной области, в которой действует деформируемый штамп. Решения граничных задач для штампов сложной реологии после этого представляются комбинацией решений граничных задач для штампов простой реологии. В настоящей статье ранее разработанный новый математический аппарат, основанный на фрактальных свойствах блочных элементов, применяется для анализа рассматриваемой задачи. С учетом практики применения этого подхода удается достигнуть определенных результатов. В более ранних работах для получения всех параметров, описывающих поведение литосферных плит в квадранте, требовалось изучение трех уравнений. В настоящей работе построено одно уравнение второго рода с вполне непрерывным оператором, позволяющее охватить все необходимые параметры. Это дает возможность аппроксимировать его конечной системой алгебраических уравнений и достаточно просто получать дисперсионное уравнение. Обсуждаются вопросы рассмотрения литосферных плит сложных реологий.
Assessment of Food Safety Knowledge, Hygienic Practices and Microbiological Quality of Halwa Produced in Urban West Region, Zanzibar
Authors: Ali Ali Hamad , Kilima Beatrice M. , Wenaty Alex
Published: January 2024

Contamination of food by microorganisms poses both economic and health threats. Knowledge of food safety and hygienic practices is a crucial in the prevention of microbial contamination of food. This study aimed to determine the microbiological quality of halwa and assess the level of food safety knowledge and hygienic practices of halwa processors. For microbiological quality, 13 samples were used to analyse the total bacteria count, Staphylococcus aureus, yeasts and moulds. Total bacteria counts were analysed using ISO 4833-1:2013, Staphylococcus aureus were analysed using ISO 6888-1:2003, and yeasts and moulds were analysed using ISO 21527-2:2017. Semi-structured questionnaires were administered to 13 halwa processors to assess their level of food safety knowledge and hygienic practices. The total bacteria count in halwa, detected in 11 samples, ranged from 2.0x102 CFU/g to 4.9x102 CFU/g, while the moulds were detected in 11 samples in a range from 1.4x102 CFU/g to 5.5x102 CFU/g; the yeasts were detected in three samples in a range from 1.4x102 CFU/g to 2.6x102 CFU/g; and Staphylococcus aureus were detected in 8 samples in a range from 1.4x102 CFU/g to 2.1x102 CFU/g. Twelve out of 13 analysed samples were in accordance with Zanzibar standards for halwa (ZNS 574:2023) for yeasts, while only seven samples were found to comply with ZNS 574:2023 for moulds requirements. Five samples were in accordance with ZNS 574:2023 for S. aureus. All samples were in accordance with ZNS 574:2023 for total bacteria count. The halwa processors had poor food safety knowledge and lacked formal training in food safety management aspects. Poor personal hygiene and hygienic practices, such as wearing protective gear, covering hair, and hand washing after toilet and nose blowing, were observed.
The Dysregulation of Cyclin Dependent Kinase Regulators Role in SV40 Related Renal Cell Carcinoma
Authors: Kadhim Dhuha Abdullah
Published: January 2024

The purpose of this study was to explore the possible involvement of SV40 polyomavirus in the development of renal cell carcinoma (RCC) in patients from the province of Al-Najaf. The study analyzed 75 paraffin-embedded block tissues of RCC, collected from archives of AL-Sader Medical City, and some private histopathology laboratories in Najaf governorate. The patients included 45 males and 30 females, aged between 22 and 70 years. The study used advanced scientific techniques, including Polymerase Chain Reaction (PCR) and immunohistochemistry (IHC), to detect the presence of SV40 and evaluate the expression state of Cyclin-Dependent Kinase Regulators (KAP or cyclin-dependent kinase inhibitor 3 (CDKN3) & Cyclin E1 markers). Hematoxylin and Eosin staining was used for diagnosing RCC. The study found that RCC is associated with the dysregulation of Cyclin-Dependent Kinase regulators (CDK), caused by the SV40 polyomavirus. The results of the IHC analysis showed an increased positive percentage for KAP or CDKN3 marker and a decreased positive percentage of Cyclin E1 marker. Additionally, the clear cell type was found to be the most common, accounting for 56% of the cases, while grade I was the most prevalent, representing 41.3% of the cases. Tumor stage type I was found to be higher, with 25 cases. PCR detected the presence of SV40 in 20 cases, accounting for 26.7% of the total cases studied. The study concluded that the Simian Virus 40 (SV40), particularly its Large T Antigen (Tag), affects CDK regulators and disrupts the delicate equilibrium of cell cycle regulation systems. Therefore, the study suggests a possible link between the development of renal cell carcinoma and the SV40 polyomavirus. The study recommends routine testing for the detection of RCC using PCR and IHC methods.