Gated recurrent neural networks discover attention

Recent architectural developments have enabled recurrent neural networks (RNNs) to reach and even surpass the performance of Transformers on certain sequence modeling tasks. These modern RNNs feature a prominent design pattern: linear recurrent layers interconnected by feedforward paths with multiplicative gating. Here, we show how RNNs equipped with these two design elements can exactly implement (linear) self-attention, the main building block of Transformers. By reverse-engineering a set of trained RNNs, we find that gradient descent in practice discovers our construction. In particular, we examine RNNs trained to solve simple in-context learning tasks on which Transformers are known to excel and find that gradient descent instills in our RNNs the same attention-based in-context learning algorithm used by Transformers. Our findings highlight the importance of multiplicative interactions in neural networks and suggest that certain RNNs might be unexpectedly implementing attention under the hood

Gene expression profiling in equine polysaccharide storage myopathy revealed inflammation, glycogenesis inhibition, hypoxia and mitochondrial dysfunctions

<p>Abstract</p> <p>Background</p> <p>Several cases of myopathies have been observed in the horse Norman Cob breed. Muscle histology examinations revealed that some families suffer from a polysaccharide storage myopathy (PSSM). It is assumed that a gene expression signature related to PSSM should be observed at the transcriptional level because the glycogen storage disease could also be linked to other dysfunctions in gene regulation. Thus, the functional genomic approach could be conducted in order to provide new knowledge about the metabolic disorders related to PSSM. We propose exploring the PSSM muscle fiber metabolic disorders by measuring gene expression in relationship with the histological phenotype.</p> <p>Results</p> <p>Genotypying analysis of GYS1 mutation revealed 2 homozygous (AA) and 5 heterozygous (GA) PSSM horses. In the PSSM muscles, histological data revealed PAS positive amylase resistant abnormal polysaccharides, inflammation, necrosis, and lipomatosis and active regeneration of fibers. Ultrastructural evaluation revealed a decrease of mitochondrial number and structural disorders. Extensive accumulation of an abnormal polysaccharide displaced and partially replaced mitochondria and myofibrils. The severity of the disease was higher in the two homozygous PSSM horses.</p> <p>Gene expression analysis revealed 129 genes significantly modulated (p < 0.05). The following genes were up-regulated over 2 fold: IL18, CTSS, LUM, CD44, FN1, GST01. The most down-regulated genes were the following: mitochondrial tRNA, SLC2A2, PRKCα, VEGFα. Data mining analysis showed that protein synthesis, apoptosis, cellular movement, growth and proliferation were the main cellular functions significantly associated with the modulated genes (p < 0.05). Several up-regulated genes, especially IL18, revealed a severe muscular inflammation in PSSM muscles. The up-regulation of glycogen synthase kinase-3 (GSK3β) under its active form could be responsible for glycogen synthase (GYS1) inhibition and hypoxia-inducible factor (HIF1α) destabilization.</p> <p>Conclusion</p> <p>The main disorders observed in PSSM muscles could be related to mitochondrial dysfunctions, glycogenesis inhibition and the chronic hypoxia of the PSSM muscles.</p

Adult Low-Hypodiploid Acute Lymphoblastic Leukemia Emerges from Preleukemic TP53-Mutant Clonal Hematopoiesis

UNLABELLED Low hypodiploidy defines a rare subtype of B-cell acute lymphoblastic leukemia (B-ALL) with a dismal outcome. To investigate the genomic basis of low-hypodiploid ALL (LH-ALL) in adults, we analyzed copy-number aberrations, loss of heterozygosity, mutations, and cytogenetics data in a prospective cohort of Philadelphia (Ph)-negative B-ALL patients (n = 591, ages 18-84 years), allowing us to identify 80 LH-ALL cases (14%). Genomic analysis was critical for evidencing low hypodiploidy in many cases missed by cytogenetics. The proportion of LH-ALL within Ph-negative B-ALL dramatically increased with age, from 3% in the youngest patients (under 40 years old) to 32% in the oldest (over 55 years old). Somatic TP53 biallelic inactivation was the hallmark of adult LH-ALL, present in virtually all cases (98%). Strikingly, we detected TP53 mutations in posttreatment remission samples in 34% of patients. Single-cell proteogenomics of diagnosis and remission bone marrow samples evidenced a preleukemic, multilineage, TP53-mutant clone, reminiscent of age-related clonal hematopoiesis. SIGNIFICANCE We show that low-hypodiploid ALL is a frequent entity within B-ALL in older adults, relying on somatic TP53 biallelic alteration. Our study unveils a link between aging and low-hypodiploid ALL, with TP53-mutant clonal hematopoiesis representing a preleukemic reservoir that can give rise to aneuploidy and B-ALL. See related commentary by Saiki and Ogawa, p. 102. This article is highlighted in the In This Issue feature, p. 101

Macrophage-B Cell Interactions in the Inverted Porcine Lymph Node and Their Response to Porcine Reproductive and Respiratory Syndrome Virus

Swine lymph nodes (LN) present an inverted structure compared to mouse and human, with the afferent lymph diffusing from the center to the periphery. This structure, also observed in close and distant species such as dolphins, hippopotamus, rhinoceros, and elephants, is poorly described, nor are the LN macrophage populations and their relationship with B cell follicles. B cell maturation occurs mainly in LN B cell follicles with the help of LN macrophage populations endowed with different antigen delivery capacities. We identified three macrophage populations that we localized in the inverted LN spatial organization. This allowed us to ascribe porcine LN MΦ to their murine counterparts: subcapsular sinus MΦ, medullary cord MΦ and medullary sinus MΦ. We identified the different intra and extrafollicular stages of LN B cells maturation and explored the interaction of MΦ, drained antigen and follicular B cells. The porcine reproductive and respiratory syndrome virus (PRRSV) is a major porcine pathogen that infects tissue macrophages (MΦ). PRRSV is persistent in the secondary lymphoid tissues and induces a delay in neutralizing antibodies appearance. We observed PRRSV interaction with two LN MΦ populations, of which one interacts closely with centroblasts. We observed BCL6 up-regulation in centroblast upon PRRSV infection, leading to new hypothesis on PRRSV inhibition of B cell maturation. This seminal study of porcine LN will permit fruitful comparison with murine and human LN for a better understanding of normal and inverted LN development and functioning

Discrimination, Reliability, Sensitivity, and Specificity of Robotic Surgical Proficiency Assessment With Global Evaluative Assessment of Robotic Skills and Binary Scoring Metrics: Results From a Randomized Controlled Trial

Objective: To compare binary metrics and Global Evaluative Assessment of Robotic Skills (GEARS) evaluations of training outcome assessments for reliability, sensitivity, and specificity. Background: GEARS–Likert-scale skills assessment are a widely accepted tool for robotic surgical training outcome evaluations. Proficiency-based progression (PBP) training is another methodology but uses binary performance metrics for evaluations. Methods: In a prospective, randomized, and blinded study, we compared conventional with PBP training for a robotic suturing, knot-tying anastomosis task. Thirty-six surgical residents from 16 Belgium residency programs were randomized. In the skills laboratory, the PBP group trained until they demonstrated a quantitatively defined proficiency benchmark. The conventional group were yoked to the same training time but without the proficiency requirement. The final trial was video recorded and assessed with binary metrics and GEARS by robotic surgeons blinded to individual, group, and residency program. Sensitivity and specificity of the two assessment methods were evaluated with area under the curve (AUC) and receiver operating characteristics (ROC) curves. Results: The PBP group made 42% fewer objectively assessed performance errors than the conventional group (P &lt; 0.001) and scored 15% better on the GEARS assessment (P = 0.033). The mean interrater reliability for binary metrics and GEARS was 0.87 and 0.38, respectively. Binary total error metrics AUC was 97% and for GEARS 85%. With a sensitivity threshold of 0.8, false positives rates were 3% and 25% for, respectively, the binary and GEARS assessments. Conclusions: Binary metrics for scoring a robotic VUA task demonstrated better psychometric properties than the GEARS assessment. </jats:sec

Margarita de Sossa, Sixteenth-Century Puebla de los Ángeles, New Spain (Mexico)

Margarita de Sossa’s freedom journey was defiant and entrepreneurial. In her early twenties, still enslaved in Portugal, she took possession of her body; after refusing to endure her owner’s sexual demands, he sold her, and she was transported to Mexico. There, she purchased her freedom with money earned as a healer and then conducted an enviable business as an innkeeper. Sossa’s biography provides striking insights into how she conceptualized freedom in terms that included – but was not limited to – legal manumission. Her transatlantic biography offers a rare insight into the life of a free black woman (and former slave) in late sixteenth-century Puebla, who sought to establish various degrees of freedom for herself. Whether she was refusing to acquiesce to an abusive owner, embracing entrepreneurship, marrying, purchasing her own slave property, or later using the courts to petition for divorce. Sossa continued to advocate on her own behalf. Her biography shows that obtaining legal manumission was not always equivalent to independence and autonomy, particularly if married to an abusive husband, or if financial successes inspired the envy of neighbors

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Research for specific methods of functionalization of L-lysine dendrigraft (DGL)

Les dendrimères greffés de L-lysine (DGL) sont des matériaux aux applications potentielles variées (agents antibactériens, antifongiques, ?). Ces dendrimères greffés sont obtenus selon un procédé original mis au point au laboratoire, basé sur la polymérisation des N-carboxyanhydrides (NCA) de Llysine. Le travail effectué au cours de cette thèse a pour objectif d'explorer les différents modes de modification des DGL et d'en évaluer la faisabilité. Pour ce faire, dans une première partie, nous avons détaillé le processus de synthèse et de polymérisation en milieu hétérogène des NCA. Cela nous a permis, ensuite, en modulant la nature de l'agent d'amorçage de la polymérisation des NCA, d'examiner la possibilité d'introduire de nouvelles fonctionnalités (fluorophore, bras de liaison adapté à la ligation) sur la première génération de DGL. Cela a nécessité, en amont, la synthèse d'un bras espaceur hétérobifonctionnel de type polyéthylène glycol. Par la suite, une ligation de type oxime entre les nouveaux DGL de 1ère et de 2e génération et une molécule modèle a été réalisée afin de valider cette approche. Enfin, nous avons pu démontrer que ces dendrimères greffés pouvaient être fonctionnalisés en surface par divers substrats (sucre, guanidine, acide aspartique, acide succinique) leur conférant de nouvelles propriétés et ouvrant ainsi un vaste champ d'application pour ces macromolécules.L-lysine Dendrigraft (DGL) are materials with various potential applications (antibacterial, antifungal, ...). These dendrigrafts are obtained by an original process, developed in our laboratory, based on the polymerization of N-carboxyanhydrides (NCA) of L-lysine. The work carried out during this thesis was aimed at exploring different methods of modification of DGL and assessing their feasibility. In the first part, we detailed the process of synthesis and polymerization of NCAs in a heterogeneous medium. This allowed us then by modulating the initiator of NCA polymerization to introduce new features (fluorophore, spacer adapted to the ligation) on the first generation of DGL. This required, upstream, the synthesis of a heterobifunctional polyethylene glycol type spacer. Subsequently, an oxime ligation between the new 1st and 2nd generation of DGL and an aldehyde model has been conducted to validate this approach. Finally, we demonstrated that these dendrigrafts could be functionalized on the surface by various substrates (sugar, guanidine, aspartic acid, succinic acid) giving them new properties and opening up a wide scope of applications for these macromolecules

Recherche de voies spécifiques de fonctionnalisation des dendrimères greffés de L-lysine (DGL)

Les dendrimères greffés de L-lysine (DGL) sont des matériaux aux applications potentielles variées (agents antibactériens, antifongiques, ?). Ces dendrimères greffés sont obtenus selon un procédé original mis au point au laboratoire, basé sur la polymérisation des N-carboxyanhydrides (NCA) de Llysine. Le travail effectué au cours de cette thèse a pour objectif d'explorer les différents modes de modification des DGL et d'en évaluer la faisabilité. Pour ce faire, dans une première partie, nous avons détaillé le processus de synthèse et de polymérisation en milieu hétérogène des NCA. Cela nous a permis, ensuite, en modulant la nature de l'agent d'amorçage de la polymérisation des NCA, d'examiner la possibilité d'introduire de nouvelles fonctionnalités (fluorophore, bras de liaison adapté à la ligation) sur la première génération de DGL. Cela a nécessité, en amont, la synthèse d'un bras espaceur hétérobifonctionnel de type polyéthylène glycol. Par la suite, une ligation de type oxime entre les nouveaux DGL de 1ère et de 2e génération et une molécule modèle a été réalisée afin de valider cette approche. Enfin, nous avons pu démontrer que ces dendrimères greffés pouvaient être fonctionnalisés en surface par divers substrats (sucre, guanidine, acide aspartique, acide succinique) leur conférant de nouvelles propriétés et ouvrant ainsi un vaste champ d'application pour ces macromolécules.L-lysine Dendrigraft (DGL) are materials with various potential applications (antibacterial, antifungal, ...). These dendrigrafts are obtained by an original process, developed in our laboratory, based on the polymerization of N-carboxyanhydrides (NCA) of L-lysine. The work carried out during this thesis was aimed at exploring different methods of modification of DGL and assessing their feasibility. In the first part, we detailed the process of synthesis and polymerization of NCAs in a heterogeneous medium. This allowed us then by modulating the initiator of NCA polymerization to introduce new features (fluorophore, spacer adapted to the ligation) on the first generation of DGL. This required, upstream, the synthesis of a heterobifunctional polyethylene glycol type spacer. Subsequently, an oxime ligation between the new 1st and 2nd generation of DGL and an aldehyde model has been conducted to validate this approach. Finally, we demonstrated that these dendrigrafts could be functionalized on the surface by various substrates (sugar, guanidine, aspartic acid, succinic acid) giving them new properties and opening up a wide scope of applications for these macromolecules.MONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF