Searching for Neural Mechanisms of Social Cognition

Social cognition involves the integration and pruning of perceptual information which leads to the formation of an abstract representation, which is also known as the perceptual gist. This study examined 87 differences in visual perception of Mooney face stimuli of differing sizes and the relationship to gist formation in ten individuals with autism compared to neurotypical controls. Parents of both groups completed the Social Responsiveness Scale (SRS-2) to assess social functioning in real-world scenarios

Modern foraminifera from coastal settings in northern Argentina: implications for the paleoenvironmental interpretation of Mid Holocene littoral deposits

En las costas de la provincia de Buenos Aires, los procesos sedimentarios fueron especialmente activos durante el Cuaternario, debido a las fluctuaciones eustáticas en el nivel del mar. Como resultado, durante las transgresiones del Cuaternario tardío se depositaron  en la planicie costera  sedimentos marinos y marino-marginales. Con el objetivo de interpretar estas secuencias litorales holocenas, se analizó la distribución, diversidad, composición específi ca  y características tafonómicas de las asociaciones totales de foraminíferos bentónicos en ambientes litorales actuales, desde el tope de la duna hasta la anteplaya, en dos transectas cercanas pero geomorfológicamente diferentes, ubicadas en las costas atlánticas del norte de la Provincia de Buenos Aires (Argentina, Sudamérica). Las asociaciones totales de ambientes submareales y supramareales son diferenciables en términos de composición específi ca, diversidad y características tafonómicas. En los ambientes de anteplaya superior, cara de playa, playa distal y duna, las asociaciones están dominadas por tres especies: Buccella peruviana, Ammonia beccarii y Elphidium discoidale (grupo BAE). Esta dominancia es el resultado de procesos tafonómicos que favorecen la preservación selectiva de dichas especies. Las características tafonómicas de las asociaciones modernas permiten una mejor discriminación de los subambientes que la composición taxonómica. Si bien las asociaciones holocenas no poseen homólogos estrictos entre las asociaciones totales de ambientes actuales, la composición taxonómica y los rasgos tafonómicos de las asociaciones permiten inferir que la sucesión holocena se depositó entre la parte superior de la anteplaya y la playa distal.In Buenos Aires coasts, sedimentary processes were particularly active during the Quaternary owing to eustatic fluctuations in sea level. As a result, during the late Quaternary transgressions, marine and marginal marine sediments were deposited in the coastal plain. In order to interpret these Holocene littoral sequences, we analyzed the distribution, diversity, species composition and taphonomic features of total benthic foraminifera assemblages from modern littoral settings, from the top of the dune to the lower shoreface, in two close but geomorphologically different transects located in the Atlantic coast of Northern Buenos Aires Province (Argentina, South America). Total benthic foraminiferal assemblages from subtidal and supratidal environments are distinguishable in terms of composition, diversity and taphonomic features. In upper shoreface, foreshore, backshore and foredune environments, assemblages are clearly dominated by three species: Buccella peruviana, Ammonia beccarii and Elphidium discoidale (the BAE group). This feature is the result of taphonomic processes that favor the selective preservation of such species. The study of taphonomic modifications of shells in modern assemblages allows a better discrimination between subenvironments than the analysis of taxonomic composition. Although Holocene assemblages have no strict counterparts between total modern assemblages, taxonomic composition and taphonomic modification of shells allow us to infer that the Holocene sequence was deposited between the upper shoreface and the backshore.Fil: Laprida, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Estudios Andinos "Don Pablo Groeber". Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Estudios Andinos "Don Pablo Groeber"; ArgentinaFil: Chandler, Damián Diego Enrique. Universidad de Buenos Aires; ArgentinaFil: Ramón Mercau, María Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Estudios Andinos "Don Pablo Groeber". Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Estudios Andinos "Don Pablo Groeber"; ArgentinaFil: López, Rubén Álvaro. Universidad de Buenos Aires; ArgentinaFil: Marcomini, Silvia Cristina. Universidad de Buenos Aires; Argentin

The potential and challenges of targeting MTAP-negative cancers beyond synthetic lethality

Approximately 15% of cancers exhibit loss of the chromosomal locus 9p21.3 – the genomic location of the tumour suppressor gene CDKN2A and the methionine salvage gene methylthioadenosine phosphorylase (MTAP). A loss of MTAP increases the pool of its substrate methylthioadenosine (MTA), which binds to and inhibits activity of protein arginine methyltransferase 5 (PRMT5). PRMT5 utilises the universal methyl donor S-adenosylmethionine (SAM) to methylate arginine residues of protein substrates and regulate their activity, notably histones to regulate transcription. Recently, targeting PRMT5, or MAT2A that impacts PRMT5 activity by producing SAM, has shown promise as a therapeutic strategy in oncology, generating synthetic lethality in MTAP-negative cancers. However, clinical development of PRMT5 and MAT2A inhibitors has been challenging and highlights the need for further understanding of the downstream mediators of drug effects. Here, we discuss the rationale and methods for targeting the MAT2A/PRMT5 axis for cancer therapy. We evaluate the current limitations in our understanding of the mechanism of MAT2A/PRMT5 inhibitors and identify the challenges that must be addressed to maximise the potential of these drugs. In addition, we review the current literature defining downstream effectors of PRMT5 activity that could determine sensitivity to MAT2A/PRMT5 inhibition and therefore present a rationale for novel combination therapies that may not rely on synthetic lethality with MTAP loss

Enhancement of Adeno-Associated Virus-Mediated Gene Therapy Using Hydroxychloroquine in Murine and Human Tissues.

The therapeutic effects of gene therapy using adeno-associated virus (AAV) vectors are dependent on the efficacy of viral transduction. Currently, we have reached the safe limits of AAV vector dose, beyond which damaging inflammatory responses are seen. To improve the efficacy of AAV transduction, we treated mouse embryonic fibroblasts, primate retinal pigment epithelial cells, and human retinal explants with hydroxychloroquine (HCQ) 1 h prior to transduction with an AAV2 vector encoding GFP driven by a ubiquitous CAG promoter. This led to a consistent increase in GFP expression, up to 3-fold, compared with vector alone. Comparing subretinal injections of AAV2.CAG.GFP vector alone versus co-injection with 18.75 μM HCQ in paired eyes in mice, mean GFP expression was 4.6-fold higher in retinae co-treated with HCQ without retinal toxicity. A comparative 5.9-fold effect was seen with an AAV8(Y733F).GRK1.GFP vector containing the photoreceptor-specific rhodopsin kinase promoter. While the mechanism of action remains to be fully elucidated, our data suggest that a single pulse of adjunctive HCQ could safely improve AAV transduction in vivo, thus providing a novel strategy for enhancing the clinical effects of gene therapy

Development of a new CEDAR for kaon identification at the NA62 experiment at CERN

The NA62 experiment at CERN utilises a differential Cherenkov counter with achromatic ring focus (CEDAR) for tagging kaons within an unseparated monochromatic beam of charged hadrons. The CEDAR-H detector was developed to minimise the amount of material in the path of the beam by using hydrogen gas as the radiator medium. The detector was shown to satisfy the kaon tagging requirements in a test-beam before installation and commissioning at the experiment. The CEDAR-H performance was measured using NA62 data collected in 2023

CONSTRUÇÃO E VALIDAÇÃO DE BIODIGESTOR DE BANCADA, TIPO BATELADA, PARA QUANTIFICAR BIOGÁS A BAIXO CUSTO

The objective of this work was to build and validate 24 batch-type biodigestors to quantify biogas produced from the anaerobic fermentation of agro-industrial residues. The effluents and effluents of the biodigesters were characterized in terms of physical parameters (Total Solids, Fixed Solids and Volatile Solids) and physical chemical parameters: (pH and Electrical Conductivity). The yield (L biogás.kg-1SV.ad), the productivity (Lbiogás.L-1reactor.d-1) of biogas and the Volumetric Organic Load added COVad (kgSV.L-1reactor.d-1) were calculated. . The experiment was carried out at the Campus of Agricultural Sciences of the Federal University of Vale do São Francisco with a hydraulic retention time of 30 days, using a randomized block design (DBC). The production of biogas from the anaerobic fermentation of the analyzed treatments did not have a significant difference at 5% probability. The physical parameters of the effluents and affluents of the biodigesters showed values similar to those found in the literature for both treatments. The physical chemical parameters of the effluents and effluents of the biodigesters did not remain within the ranges, called ideal described in the literature for biogas production, except for the treatments bovine manure (T2) and sorghum 25% + bovine manure 75% (T4). Cattle manure (T2) showed the highest yield (240.04 Lbiogás.kg-1SVad) and a higher mean COVad of 8.00 kgSV.L-1reactor.d-1.El objetivo de este trabajo fue construir y validar 24 biodigestores de sobremesa, tipo lote, para cuantificar el biogás producido a partir de la fermentación anaeróbica de residuos agroindustriales. Los efluentes y afluentes de los biodigestores se caracterizaron en términos de parámetros físicos (Sólidos Totales, Sólidos Fijos y Sólidos Volátiles) y parámetros físico-químicos (pH y Conductividad Eléctrica). Se calculó el rendimiento (Lbiogás.kg-1SVad), la productividad (Lbiogas.L-1reator.d-1) del biogás y la Carga Orgánica Volumétrica añadida COVad (kgSV.L-1reator.d-1). El experimento fue realizado en el Campus de Ciencias Agrícolas de la Universidad Federal de Vale do São Francisco con un tiempo de retención hidráulica de 30 días, utilizando un diseño de bloque aleatorio (DBC). La producción de biogás a partir de la fermentación anaeróbica de los tratamientos analizados no tuvo diferencia significativa con una probabilidad del 5%. Los parámetros físicos de los efluentes y afluentes de los biodigestores presentaron valores similares a los encontrados en la literatura para ambos tratamientos. Los parámetros fisicoquímicos de los efluentes y afluentes de los biodigestores no se mantuvieron dentro de los rangos, llamados ideales descritos en la literatura para la producción de biogás, a excepción de los tratamientos de residuos bovinos (T2) y sorgo 25% + estiércol bovino 75% (T4). El estiércol bovino (T2) mostró mayor rendimiento (240,04 Lbiogás.kg-1SVad) y un COVad promedio mayor de 8,00 kgSV.L-1reator.d-1.Objetivou-se com este trabalho construir e validar 24 biodigestores de bancada, tipo batelada, para quantificar biogás produzido a partir da fermentação anaeróbia de resíduos agroindustriais. Caracterizou-se os efluentes e afluentes dos biodigestores quanto aos parâmetros físicos (Sólidos Totais, Sólidos Fixos e Sólidos Voláteis) e físico químicos: (pH e Condutividade Elétrica). Calculou-se o rendimento (Lbiogás.kg-1SVad), a produtividade (Lbiogás.L-1reator.d-1) de biogás e a Carga Orgânica Volumétrica adicionada COVad (kgSV.L-1reator.d-1). O experimento foi conduzido no Campus de Ciências Agrárias da Universidade Federal do Vale do São Francisco com tempo de retenção hidráulica de 30 dias, utilizando o delineamento em blocos casualizados (DBC). A produção de biogás a partir da fermentação anaeróbia dos tratamentos analisados não teve diferença significativa a 5% de probabilidade. Os parâmetros físicos dos efluentes e afluentes dos biodigestores apresentaram valores similares aos encontrados na literatura para ambos os tratamentos. Os parâmetros físico químicos dos efluentes e afluentes dos biodigestores não permaneceram dentro das faixas, denominadas ideais descritas na literatura para produção de biogás, exceto os tratamentos dejetos bovino (T2) e sorgo 25% + dejeto bovino 75% (T4). O dejeto bovino (T2) apresentou maior rendimento (240,04 Lbiogás.kg-1SVad) e uma maior COVad média de 8,00 kgSV.L-1reator.d-1.Objetivou-se com este trabalho construir e validar 24 biodigestores de bancada, tipo batelada, para quantificar biogás produzido a partir da fermentação anaeróbia de resíduos agroindustriais. Caracterizou-se os efluentes e afluentes dos biodigestores quanto aos parâmetros físicos (Sólidos Totais, Sólidos Fixos e Sólidos Voláteis) e físico químicos: (pH e Condutividade Elétrica). Calculou-se o rendimento (Lbiogás.kg-1SVad), a produtividade (Lbiogás.L-1reator.d-1) de biogás e a Carga Orgânica Volumétrica adicionada COVad (kgSV.L-1reator.d-1). O experimento foi conduzido no Campus de Ciências Agrárias da Universidade Federal do Vale do São Francisco com tempo de retenção hidráulica de 30 dias, utilizando o delineamento em blocos casualizados (DBC). A produção de biogás a partir da fermentação anaeróbia dos tratamentos analisados não teve diferença significativa a 5% de probabilidade. Os parâmetros físicos dos efluentes e afluentes dos biodigestores apresentaram valores similares aos encontrados na literatura para ambos os tratamentos. Os parâmetros físico químicos dos efluentes e afluentes dos biodigestores não permaneceram dentro das faixas, denominadas ideais descritas na literatura para produção de biogás, exceto os tratamentos dejetos bovino (T2) e sorgo 25% dejeto bovino 75% (T4). O dejeto bovino (T2) apresentou maior rendimento (240,04 Lbiogás.kg-1SVad) e uma maior COVad média de 8,00 kgSV.L-1reator.d-1

The first 142 amino acids of glutamate decarboxylase do not contribute to epitopes recognized by autoantibodies associated with Type 1 diabetes

Human adenovirus (HAdV) E1B-55K is a multifunctional regulator of productive viral replication and oncogenic transformation in nonpermissive mammalian cells. These functions depend on E1B-55K's posttranslational modification with the SUMO protein and its binding to HAdV E4orf6. Both early viral proteins recruit specific host factors to form an E3 ubiquitin ligase complex that targets antiviral host substrates for proteasomal degradation. Recently, we reported that the PML-NB associated factor Daxx represses efficient HAdV productive infection and is proteasomally degraded via a SUMO-E1B-55K-dependent, E4orf6-independent pathway, the details of which remained to be established. RNF4, a cellular SUMO-targeted ubiquitin ligase (STUbL), induces ubiquitinylation of specific SUMOy lated proteins and plays an essential role during DNA repair. Here, we show that E1B-55K recruits RNF4 to the insoluble nuclear matrix fraction of the infected cell to support RNF4/Daxx association, promoting Daxx PTM and thus inhibiting this antiviral factor. Removing RNF4 from infected cells using RNA interference resulted in blocking the proper establishment of viral replication centers and significantly diminished viral gene expression. These results provide a model for how HAdV antagonize the antiviral host responses by exploiting the functional capacity of cellular STUbLs. Thus, RNF4 and its STUbL function represent a positive factor during lytic infection and a novel candidate for future therapeutic antiviral intervention strategies.IMPORTANCE Daxx is a PML-NB-associated transcription factor that was recently shown to repress efficient HAdV productive infection. To counteract this antiviral measurement during infection, Daxx is degraded via a novel pathway including viral E1B-55K and host proteasomes. This virus-mediated degradation is independent of the classical HAdV E3 ubiquitin ligase complex, which is essential during viral infection to target other host antiviral substrates. To maintain a productive viral life cycle, HAdV E1B-55K early viral protein inhibits the chromatin-remodeling factor Daxx in a SUMO-dependent manner. In addition, viral E1B-55K protein recruits the STUbL RNF4 and sequesters it into the insoluble fraction of the infected cell. E1B-55K promotes complex formation between RNF4-and E1B-55K-targeted Daxx protein, supporting Daxx posttranslational modification prior to functional inhibition. Hence, RNF4 represents a novel host factor that is beneficial for HAdV gene expression by supporting Daxx counteraction. In this regard, RNF4 and other STUbL proteins might represent novel targets for therapeutic intervention

Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness

cAMP mediates autonomic regulation of heart rate by means of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which underlie the pacemaker current If. cAMP binding to the C-terminal cyclic nucleotide binding domain enhances HCN open probability through a conformational change that reaches the pore via the C-linker. Using structural and functional analysis, we identified a binding pocket in the C-linker of HCN4. Cyclic dinucleotides, an emerging class of second messengers in mammals, bind the C-linker pocket (CLP) and antagonize cAMP regulation of the channel. Accordingly, cyclic dinucleotides prevent cAMP regulation of If in sinoatrial node myocytes, reducing heart rate by 30%. Occupancy of the CLP hence constitutes an efficient mechanism to hinder β-adrenergic stimulation on If. Our results highlight the regulative role of the C-linker and identify a potential drug target in HCN4. Furthermore, these data extend the signaling scope of cyclic dinucleotides in mammals beyond their first reported role in innate immune system

Ribosome-Inactivating Proteins: From Plant Defense to Tumor Attack

Ribosome-inactivating proteins (RIPs) are EC3.2.32.22 N-glycosidases that recognize a universally conserved stem-loop structure in 23S/25S/28S rRNA, depurinating a single adenine (A4324 in rat) and irreversibly blocking protein translation, leading finally to cell death of intoxicated mammalian cells. Ricin, the plant RIP prototype that comprises a catalytic A subunit linked to a galactose-binding lectin B subunit to allow cell surface binding and toxin entry in most mammalian cells, shows a potency in the picomolar range. The most promising way to exploit plant RIPs as weapons against cancer cells is either by designing molecules in which the toxic domains are linked to selective tumor targeting domains or directly delivered as suicide genes for cancer gene therapy. Here, we will provide a comprehensive picture of plant RIPs and discuss successful designs and features of chimeric molecules having therapeutic potential

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely