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Chromatin three-dimensional (3D) organization inside the cell nucleus determines the separation of euchromatin and heterochromatin domains. Their segregation results in the definition of active and inactive chromatin compartments, whereby the local concentration of associated proteins, RNA and DNA results in the formation of distinct subnuclear structures. Thus, chromatin domains spatially confined in a specific 3D nuclear compartment are expected to share similar epigenetic features and biochemical properties, in terms of accessibility and solubility. Based on this rationale, we developed the 4f-SAMMY-seq to map euchromatin and heterochromatin based on their accessibility and solubility, starting from as little as 10 000 cells. Adopting a tailored bioinformatic data analysis approach we reconstruct also their 3D segregation in active and inactive chromatin compartments and sub-compartments, thus recapitulating the characteristic properties of distinct chromatin states. A key novelty of the new method is the capability to map both the linear segmentation of open and closed chromatin domains, as well as their compartmentalization in one single experiment.

This report documents the program and the outcomes of Dagstuhl Seminar 23331 "Recent Trends in Graph Decomposition", which took place from 13. August to 18. August, 2023. The seminar brought together 33 experts from academia and industry to discuss graph decomposition, a pivotal technique for handling massive graphs in applications such as social networks and scientific simulations. The seminar addressed the challenges posed by contemporary hardware designs, the potential of deep neural networks and reinforcement learning in developing heuristics, the unique optimization requirements of large sparse data, and the need for scalable algorithms suitable for emerging architectures. Through presentations, discussions, and collaborative sessions, the event fostered an exchange of innovative ideas, leading to the creation of community notes highlighting key open problems in the field.

BACKGROUNDCOVID-19 convalescent plasma (CCP) virus-specific antibody levels that translate into recipient posttransfusion antibody levels sufficient to prevent disease progression are not defined.METHODSThis secondary analysis correlated donor and recipient antibody levels to hospitalization risk among unvaccinated, seronegative CCP recipients within the outpatient, double-blind, randomized clinical trial that compared CCP to control plasma. The majority of COVID-19 CCP arm hospitalizations (15/17, 88%) occurred in this unvaccinated, seronegative subgroup. A functional cutoff to delineate recipient high versus low posttransfusion antibody levels was established by 2 methods: (i) analyzing virus neutralization-equivalent anti-Spike receptor-binding domain immunoglobulin G (anti-S-RBD IgG) responses in donors or (ii) receiver operating characteristic (ROC) curve analysis.RESULTSSARS-CoV-2 anti-S-RBD IgG antibody was volume diluted 21.3-fold into posttransfusion seronegative recipients from matched donor units. Virus-specific antibody delivered was approximately 1.2 mg. The high-antibody recipients transfused early (symptom onset within 5 days) had no hospitalizations. A CCP-recipient analysis for antibody thresholds correlated to reduced hospitalizations found a statistical significant association between early transfusion and high antibodies versus all other CCP recipients (or control plasma), with antibody cutoffs established by both methods-donor-based virus neutralization cutoffs in posttransfusion recipients (0/85 [0%] versus 15/276 [5.6%]; P = 0.03) or ROC-based cutoff (0/94 [0%] versus 15/267 [5.4%]; P = 0.01).CONCLUSIONIn unvaccinated, seronegative CCP recipients, early transfusion of plasma units in the upper 30% of study donors antibody levels reduced outpatient hospitalizations. High antibody level plasma units, given early, should be reserved for therapeutic use.TRIAL REGISTRATIONClinicalTrials.gov NCT04373460.FUNDINGDepartment of Defense (W911QY2090012)

In this article I explain the manifold aspects of the work begun last year (2023) and still ongoing with the collection of Avvisi e Gazzette, which is being catalogued in the Public Library Planettiana di Jesi. Since this collection is without any doubts one of the most interesting among the Planettina library, it was chosen for the project of digitization of the PNRR - Mission 1 Cultural Heritage for the next generation - coordinated by the Marche Region. In this contribution I deal with the steps which led to the making of Pianetti family’s library, focusing in peculiar on the role of Bishop Giuseppe Pianetti. After a short presentation on the historical side of Avvisi e Gazzette, I aim to focus on the methodology used in setting up an experimental template to be published on MANUS platform,including in just one tab-mother all the elements in according to the rules of the two specific Italian platforms: in SBN for printed works and in MANUS for manuscripts.

The Last Glacial Maximum (LGM, from ∼26 to 20 ka BP) was the most recent period with large ice sheets in Eurasia and North America. At that time, global temperatures were 5–7 ∘C lower than today, and sea level ∼125 m lower. LGM simulations are useful to understand earth system dynamics, including climate–ice sheet interactions, and to evaluate and improve the models representing those dynamics. Here, we present two simulations of the Northern Hemisphere ice sheet climate and surface mass balance (SMB) with the Community Earth System Model v2.1 (CESM2.1) using the Community Atmosphere Model v5 (CAM5) with prescribed ice sheets for two time periods that bracket the LGM period: 26 and 21 ka BP. CESM2.1 includes an explicit simulation of snow/firn compaction, albedo, refreezing, and direct coupling of the ice sheet surface energy fluxes with the atmosphere. The simulated mean snow accumulation is lowest for the Greenland and Barents–Kara Sea ice sheets (GrIS, BKIS) and highest for British and Irish (BIIS) and Icelandic (IcIS) ice sheets. Melt rates are negligible for the dry BKIS and GrIS, and relatively large for the BIIS, North American ice sheet complex (NAISC; i.e. Laurentide, Cordilleran, and Innuitian), Scandinavian ice sheet (SIS), and IcIS, and are reduced by almost a third in the colder (lower temperature) 26 ka BP climate compared with 21 ka BP. The SMB is positive for the GrIS, BKIS, SIS, and IcIS during the LGM (26 and 21 ka BP) and negative for the NAISC and BIIS. Relatively wide ablation areas are simulated along the southern (terrestrial), Pacific and Atlantic margins of the NAISC, across the majority of the BIIS, and along the terrestrial southern margin of the SIS. The integrated SMB substantially increases for the NAISC and BIIS in the 26 ka BP climate, but it does not reverse the negative sign. Summer incoming surface solar radiation is largest over the high interior of the NAISC and GrIS, and minimum over the BIIS and southern margin of NAISC. Summer, Physical and Space Geodesy

Background: Acute hepatitis E virus (HEV) infection has recently emerged as a potential trigger for acute dysimmune neuropathies, but prospective controlled studies are lacking.AimsTo compare the frequency of concomitant acute HEV infection in patients with neuralgic amyotrophy (NA), Guillain–Barré syndrome (GBS), and Bell's palsy with a matched control population. Methods: Swiss multicenter, prospective, observational, matched case–control study over 3 years (September 2019–October 2022). Neurological cases with NA, GBS, or Bell's palsy were recruited within 1 month of disease onset. Healthy controls were matched for age, sex, geographical location, and timing of blood collection. Diagnostic criteria for acute hepatitis E were reactive serum anti‐HEV IgM and IgG assays (ELISA test) and/or HEV RNA detection in serum by real‐time polymerase chain reaction (RT‐PCR). RT‐PCR was performed on sera to confirm IgM positivity. Results: We included 180 patients (59 GBS, 51 NA, 70 Bell's palsy cases) and corresponding matched controls (blood donors) with median age 51 years for both groups and equal gender distribution. Six IgM+ cases were detected in the NA, two in the GBS, and none in the Bell's palsy group. Two controls were anti‐HEV IgM‐positive. At disease onset, most cases with acute HEV infection had increased liver enzymes. A moderate association (p = 0.027, Fisher's exact test; Cramér's V = −0.25) was observed only between acute HEV infection and NA. Conclusion: This prospective observational study suggests an association between concomitant acute HEV infection and NA, but not with GBS or Bell's palsy.

High-dimensional sparse data emerge in many critical application domains such as cybersecurity, healthcare, anomaly detection, and trend analysis. To quickly extract meaningful insights from massive volumes of these multi-dimensional data, scientists employ unsupervised analysis tools based on tensor decomposition (TD) methods. However, real-world sparse tensors exhibit highly irregular shapes, data distributions, and sparsity, which pose significant challenges for making efficient use of modern parallel architectures. This study breaks the prevailing assumption that compressing sparse tensors into coarse-grained structures (i.e., tensor slices or blocks) or along a particular dimension/mode (i.e., mode-specific) is more efficient than keeping them in a fine-grained, mode-agnostic form. Our novel sparse tensor representation, Adaptive Linearized Tensor Order (ALTO), encodes tensors in a compact format that can be easily streamed from memory and is amenable to both caching and parallel execution. To demonstrate the efficacy of ALTO, we accelerate popular TD methods that compute the Canonical Polyadic Decomposition (CPD) model across a range of real-world sparse tensors. Additionally, we characterize the major execution bottlenecks of TD methods on multiple generations of the latest Intel Xeon Scalable processors, including Sapphire Rapids CPUs, and introduce dynamic adaptation heuristics to automatically select the best algorithm based on the sparse tensor characteristics. Across a diverse set of real-world data sets, ALTO outperforms the state-of-the-art approaches, achieving more than an order-of-magnitude speedup over the best mode-agnostic formats. Compared to the best mode-specific formats, which require multiple tensor copies, ALTO achieves more than 5.1x geometric mean speedup at a fraction (25%) of their storage., Comment: We extend the results of our previous ICS paper to significantly improve the parallel performance of the Canonical Polyadic Alternating Least Squares (CP-ALS) algorithm for normally distributed data and the Canonical Polyadic Alternating Poisson Regression (CP-APR) algorithm for non-negative count data

Aim: to exploit tissue-specific interactions among thymic epithelial tumor (TETs) cells and extra-domain B fibronectin (ED-B FN). Material and methods: The stromal pattern of ED-B FN expression was investigated through tumor specimen collection and molecular profiling in 11 patients with recurrent TETs enrolled in prospective theragnostic phase I/II trials with Radretumab, an ED-B FN specific recombinant human antibody. Radretumab radioimmunotherapy (R-RIT) was offered to patients who exhibited the target expression. Experiments included immunochemical analysis (ICH), cell cultures, immunophenotypic analysis, Western blot, slot-blot assay, and quantitative RT-PCR of two primary thymoma cultures we obtained from patients’ samples and in the Ty82 cell line. Results: The in vivo scintigraphic demonstration of ED-B FN expression resulted in R-RIT eligibility in 8/11 patients, of which seven were treated. The best observed response was disease stabilization (n = 5/7) with a duration of 4.3 months (range 3–5 months). IHC data confirmed high ED-B FN expression in the peripherical microenvironment rather than in the center of the tumor, which was more abundant in B3 thymomas. Further, there was a predominant expression of ED-B FN by the stromal cells of the thymoma microenvironment rather than the epithelial cells. Conclusions: Our data support the hypothesis that thymomas induce stromal cells to shift FN production to the ED-B subtype, likely representing a favorable hallmark for tumor progression and metastasis. Collectively, results derived from clinical experience and molecular insights of the in vitro experiments suggested that R-RIT inefficacy is unlikely related to low target expression in TET, being the mechanism of R-RIT resistance eventually related to patients’ susceptibility (i.e., inherent characteristics), the pattern expression of the target (i.e., at periphery), the biological characteristics of the tumor (i.e., aggressive and resistant phenotypes), and/or t

The debate on the opportunity to use organs from donors testing positive for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in recipients with naïve resolved or active COVID-19 is ongoing. We aim to present the ethical analyses underlying the decision to perform liver transplantation (LT) in selected patients with resolved or active COVID-19 in Italy. We used Jonsen, Siegler, and Winslade's Four-Boxes casuistic method, addressing the four topics considered as constitutive of the essential structure of single clinical cases for their ethical analysis (medical indications, patient preferences, quality of life, and contextual features) to enable decision-making on a case-by-case basis. Based on these topics, we elucidate the meaning and balance among the principles of biomedical ethics. Clinical ethics judgment based on the relation between the risk of acquiring SARS-CoV-2 along with its potentially negative effects and the expected benefits of transplant lead to consider LT as clinically appropriate. Shared decision-making allows the integration of clinical options with the patient's subjective preferences and considerations, enabling a valid informed consent specifically tailored to the patients’ individual circumstances. The inclusion of carefully selected SARS-CoV-2 positive donors represents an opportunity to offer lifesaving LT to patients who might otherwise have limited opportunities to receive one. COVID-19 positive donor livers are fairly allocated among equals, and respect for fundamental rights of the individual and the broader community in a context of healthcare rationing is guaranteed.The ethical analysis of the decision to perform LT in selected patients shows that the decision is ethically justifiable.

Syftet med den här studien är att undersöka speciallärares uppfattningar om samt hur hunden kan användas som specialpedagogisk resurs i den svenska skolan som tar sitt avstamp i en skola för alla. Vi har genomfört en kvalitativ semistrukturerad internetbaserad intervjustudie med nio speciallärare från olika delar av Sverige. Fem speciallärare arbetar med hund och fyra speciallärare har ingen erfarenhet av att arbeta med hund i skolan. Vårt teoretiska perspektiv är anknytningsteori (Bowlby, 1988) samt känslan av sammanhang (KASAM) (Vinje et al., 2022). Vårt resultat visar att samtliga speciallärare är positiva till hunden som specialpedagogisk resurs vid bland annat läs- och skrivsvårigheter. Speciallärare beskriver hur hunden kan vara en nyckel till eleverna och vara en hjälp för både välmående och lärande. Hundens förmåga att stödja elever för att genomföra och få en god utbildning kom fram som den främsta orsaken till att hunden har en roll i en skola för alla. Trots speciallärarnas positiva inställning finns det utmaningar med att ta in hunden i skolan. Viss tveksamhet finns från Skolverket (Bilaga 1) och kritik från astma och allergiförbundet (Cederlöf, 2019) dock behöver det inte vara ett hinder vilket flera av speciallärarna berättar eftersom hundarna inte befinner sig i hela skolan. Dessutom följs noggranna hygienrutiner enligt Jordbruksverket (SJVFS 2021:5) för de elever som är i kontakt med hunden. Speciallärare i vår studie lyfter att hunden är en del av samhället där den gör stor nytta inom många områden och därför kan hunden även ha en plats i skolan.

In order for businesses to increase their chances of survival in the global market, adaptable organizations and competent change leaders are required. Leadership and change management are becoming increasingly important, with a particular emphasis on engaged and transformative leadership. Despite the proven ability of female leadership to facilitate transformative change, it is often overlooked. This qualitative study examines the knowledge gap regarding key factors for successful change leadership, characteristics of successful change leaders, and the significance of gender. Semi-structured interviews were conducted with participants who have held or currently hold leadership positions and have implemented change processes. The study explores the importance of gender in successful change leadership, differences among successful leaders, and the role of gender. Participants included both men and women in leadership positions with experience in driving change. The results showed that clear, direct, and honest communication tailored to the recipient is crucial for managing change. The study emphasizes the need for change leaders to possess communication and social skills in order to thrive in a dynamic global market. Employee involvement and heterogeneous groups were also identified as important factors that increase the likelihood of success. A good leader is outward-facing and engages with individuals who have diverse and stimulating tasks. The findings of the study revealed that female leaders are often not recognized as a success factor, despite their ability to implement transformative changes. Gender itself does not differentiate successful change leaders from others; rather, individual characteristics play a significant role., För att verksamheter ska öka sina överlevnadschanser i den globala marknaden krävs det att organisationen är förändringsbenägen och innehar kompetenta förändringsledare. Ledarskap och förändringsarbete blir allt viktigare, med särskild vikt för engagerat och transformativt ledarskap. Denna kvalitativa studie undersöker det forskningsgap som identifierats kring viktiga faktorer för framgångsrik förändringsledning och egenskaper hos framgångsrika förändringsledare. Vidare undersöker studien könets betydelse hos framgångsrika förändringsarbeten. Studiens frågeställningar har besvarats genom semistrukturerade intervjuer av deltagare som varit i ledarskapspositioner och genomfört förändringsprocesser. Studien undersöker könets betydelse för framgångsrik förändringsledning och skillnader mellan framgångsrika ledare samt könets roll varför studiens deltagare bestått av både män och kvinnor i ledarskapspositioner med förändringserfarenhet. Resultaten visade att tydlig, direkt och ärlig kommunikation anpassad till mottagaren är avgörande för att hanteringen kring förändringar. Förändringsledare behöver enligt studiens resultat sådana typer av egenskaper som främjar kommunikations- och sociala färdigheter för att verksamheten ska överleva på en föränderlig global marknad. Studiens resultat påvisar att en bra ledare är utåtriktad och socialiserar med människor med varierande och stimulerande uppgifter. Medarbetarinvolvering och heterogena grupper är ytterligare faktorer som ökar också chanserna till framgång. Könet hos en ledare i sig skiljer inte framgångsrika förändringsledare från andra, utan det är de individuella egenskaper hos ledaren som spelar en betydande roll.

Bakgrund: Vården före, under och efter graviditet skiljer sig mellan de olika regionerna i Sverige. Kontinuitet spelar en stor roll både för kvinnans och familjens upplevelse men även för det medicinska utfallet. Vårdkedjan brister ofta i den postnatala vården och därmed brister även kontinuiteten, detta trots att de första två postnatala veckorna anses som de mest kritiska.Rekommendationer angående den postnatala perioden har lyfts fram att målet är att alla kvinnor ska erhålla en säker vård och känna trygghet. Syfte: Syftet var att beskriva känsla av trygghet bland kvinnor som gått på tidig hemgång från förlossning/BB där BB-vård i hemmet inte erbjuds. Metod: Webbaserad tvärsnittsstudie med kvantitativ ansats. Deskriptiv och analytisk statistik har tagits fram genom SPSS. Resultat: I studiens resultat (N=31) framkom det att majoriteten av kvinnorna kände trygghet i samband med tidig hemgång från förlossning/BB. Känslan av trygghet ökade om kvinnan själv valt att gå på tidig hemgång (p=0.002). Kvinnor vars partner var delaktiga genererade även en känsla av trygghet i hemmet (p=0.016). Slutsats: Studien visade att om kvinnorna skulle känna trygghet vid tillfället för tidig hemgång behövde beslutet vara kvinnans egna. Partnern hade en stor betydelse för att kvinnorna skulle ha en känsla av trygghet i hemmet efter tidig hemgång.

IntroductionSweden has been a pioneer in the prophylactic treatment of haemophilia. Magnetic resonance imaging (MRI) can detect small changes in joints and can therefore give an indication of a risk of developing arthropathy. AimTo use MRI to evaluate the outcome of the Swedish high-dose regimen and correlate the findings to age, bleeds, joint score and physical activity. MethodsThe study group comprised 48 Swedish male patients, mean age 25 years (range 12-33 years), with severe or moderate haemophilia A or B. Data on the Haemophilia Joint Health Score (HJHS) were available and physical activity was evaluated by a self-reported questionnaire. ResultsMRI score was recorded in 188 joints. Twenty out of 48 patients had a score of >= 1 (range 1-13) in 31 joints of which 3/31 scores were in the knees and 28/31 in the ankles. No correlation was found between the number of recorded bleeds and the MRI score or between HJHS and MRI score. There was no correlation between the physical activity and the number of joint bleeds per se, but a trend (OR 3.0) that those most physically active (19/48; 39.6%), more frequently had an MRI score of >= 1 with an overweight for the right ankle. ConclusionThe Swedish prophylactic model offers protection against haemophilia joint arthropathy but will still not prevent osteochondral changes in some patients at young age. MRI of the ankles can signal risk of future arthropathy and indicate need to modify the prophylactic regimen., Funding Agencies|Baxter Sweden AB (now part of Takeda)

BackgroundThe efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent plasma (CCP) for preventing infection in exposed, uninfected individuals is unknown. CCP might prevent infection when administered before symptoms or laboratory evidence of infection.MethodsThis double-blinded, phase 2 randomized, controlled trial (RCT) compared the efficacy and safety of prophylactic high titer (≥1:320 by Euroimmun ELISA) CCP with standard plasma. Asymptomatic participants aged ≥18 years with close contact exposure to a person with confirmed coronavirus disease 2019 (COVID-19) in the previous 120 hours and negative SARS-CoV-2 test within 24 hours before transfusion were eligible. The primary outcome was new SARS-CoV-2 infection.ResultsIn total, 180 participants were enrolled; 87 were assigned to CCP and 93 to control plasma, and 170 transfused at 19 sites across the United States from June 2020 to March 2021. Two were excluded for screening SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) positivity. Of the remaining 168 participants, 12/81 (14.8%) CCP and 13/87 (14.9%) control recipients developed SARS-CoV-2 infection; 6 (7.4%) CCP and 7 (8%) control recipients developed COVID-19 (infection with symptoms). There were no COVID-19-related hospitalizations in CCP and 2 in control recipients. Efficacy by restricted mean infection free time (RMIFT) by 28 days for all SARS-CoV-2 infections (25.3 vs 25.2 days; P = .49) and COVID-19 (26.3 vs 25.9 days; P = .35) was similar for both groups.ConclusionsAdministration of high-titer CCP as post-exposure prophylaxis, although appearing safe, did not prevent SARS-CoV-2 infection.Clinical trials registrationNCT04323800.

Ogni ordinamento giuridico, se vuole essere davvero a misura d’uomo, deve comprendere la natura intrinsecamente narrativa dell’umano, del nostro essere per vocazione narratori e ascoltatori di storie: solo attraverso questa riconciliazione con la mutevolezza dell’esistenza è possibile mantenere la stabilità e coerenza delle regole ma al contempo venire incontro pienamente alla richiesta di giustizia della società umana. È qui che nasce il bisogno di un dialogo sempre aperto tra diritto e letteratura, essenziale per tutti coloro che concorrono a vario titolo all’amministrazione della giustizia: magistrati, avvocati, ma anche semplici cittadini. Questo volume sintetizza la grande avventura scaturita da una tale consapevolezza e attraversata nell’arco di quasi quindici anni dall’Alta Scuola “Federico Stella” sulla Giustizia Penale con il progetto ‘Giustizia e letteratura’. Gli agili saggi di taglio divulgativo che lo compongono illustrano alcune delle opere e degli ambiti letterari esplorati nel corso di questo lungo cammino, da Manzoni a Sciascia, da Shakespeare a Steinbeck, dal grande canone letterario a qualificate opere di genere, con incursioni nel giallo e nella fantascienza. [Seconda di copertina]

Zipf’s law of abbreviation, the tendency of more frequent words to be shorter, is one of the most solid candidates for a linguistic universal, in the sense that it has the potential for being exceptionless or with a number of exceptions that is vanishingly small compared to the number of languages on Earth. Since Zipf’s pioneering research, this law has been viewed as a manifestation of a universal principle of communication, i.e. the minimization of word lengths, to reduce the effort of communication. Here we revisit the concordance of written language with the law of abbreviation. Crucially, we provide wider evidence that the law holds also in speech (when word length is measured in time), in particular in 46 languages from 14 linguistic families. Agreement with the law of abbreviation provides indirect evidence of compression of languages via the theoretical argument that the law of abbreviation is a prediction of optimal coding. Motivated by the need of direct evidence of compression, we derive a simple formula for a random baseline indicating that word lengths are systematically below chance, across linguistic families and writing systems, and independently of the unit of measurement (length in characters or duration in time). Our work paves the way to measure and compare the degree of optimality of word lengths in languages., SP is funded by the grant ’Thesis abroad 2021/2022’ from the University of Milan. CB was partly funded by the Deutsche Forschungsgemeinschaft (FOR 2237: Words, Bones, Genes, Tools - Tracking Linguistic, Cultural and Biological Trajectories of the Human Past), and the Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Non-randomness in Morphological Diversity: A Computational Approach Based on Multilingual Corpora, 176305). RFC is supported by a recognition 2021SGR-Cat (01266 LQMC) from AGAUR (Generalitat de Catalunya)., Peer Reviewed, Postprint (published version)

The objectives of this study were twofold: (1) to identify potential differences in the ruminal and fecal metabolite profiles of Nelore bulls under different nutritional interventions; and (2) to identify metabolites associated with cattle sustainability related-traits. We used different nutritional interventions in the feedlot: conventional (Conv; n = 26), and by-product (ByPr, n = 26). Thirty-eight ruminal fluid and 27 fecal metabolites were significantly different (P < 0.05) between the ByPr and Conv groups. Individual dry matter intake (DMI), residual feed intake (RFI), observed water intake (OWI), predicted water intake (WI), and residual water intake (RWI) phenotypes were lower (P < 0.05) in the Conv group, while the ByPr group exhibited lower methane emission (ME) (P < 0.05). Ruminal fluid dimethylamine was significantly associated (P < 0.05) with DMI, RFI, FE (feed efficiency), OWI and WI. Aspartate was associated (P < 0.05) with DMI, RFI, FE and WI. Fecal C22:1n9 was significantly associated with OWI and RWI (P < 0.05). Fatty acid C14:0 and hypoxanthine were significantly associated with DMI and RFI (P < 0.05). The results demonstrated that different nutritional interventions alter ruminal and fecal metabolites and provided new insights into the relationship of these metabolites with feed efficiency and water intake traits in Nelore bulls.

African swine fever virus (ASFV) is the etiological agent of a haemorrhagic disease that threatens the global pig industry. There is an urgency to develop a safe and efficient vaccine, but the knowledge of the immune–pathogenetic mechanisms behind ASFV infection is still very limited. In this paper, we evaluated the haematological and immunological parameters of domestic pigs vaccinated with the ASFV Lv17/WB/Rie1 strain or its derived mutant Lv17/WB/Rie1/d110-11L and then challenged with virulent Armenia/07 ASFV. Circulating levels of C-reactive protein (CRP), 13 key cytokines and 11 haematological parameters were evaluated throughout the study. Lv17/WB/Rie1 triggered an inflammatory response, with increased levels of CRP and pro-inflammatory cytokines, and induced lymphopenia, thrombocytopenia and a decline in red blood cell (RBC) parameters, although this was transitory. Lv17/WB/Rie1/d110-11L triggered only transitory thrombocytopenia and a mild inflammatory reaction, with no increase in serum levels of pro-inflammatory cytokines, but it raised IL-1Ra levels. Both strains counteracted several adverse reactions elicited by virulent challenge, like thrombocytopenia, a decline in RBC parameters, and inflammation. Within this paper, we provided a deep portrayal of the impact of diverse ASFV strains on the domestic pig’s immune system. A better understanding of these immune–pathological mechanisms would help to design suitable vaccines against this disease.

Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m(2) of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m(2) with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to < 10 ml per minute per 1.73 m(2), a sustained decrease in eGFR of & GE;40% from baseline, or death from renal causes) or death from cardiovascular causes. Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P < 0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P=0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.

BACKGROUND: Chronic constipation represents a widespread medical condition, mainly in elderly people. The management is compelling as these patients frequently have comorbidity and polypharmacy. Polyethylene glycol (PEG) is commonly used but does not resolve some complaints, mainly concerning pain and bloating. Therefore, a new medical device containing PEG plus simethicone, an antifoaming agent, has been developed. The present survey explored its use in clinical practice. METHODS: A group of 64 Italian gastroenterologists visited 2426 patients with chronic primary constipation. In about two/third, gastroenterologists freely prescribed the new medical device, and in the remaining patients, other treatments were freely chosen by doctors. Patients were followed up for three months. The number of evacuations, stool characteristics, patients’ perception of illness assessed by VAS, frequency of patients with pain and intestinal symptoms, and discontinuing patients was observed during the experience. RESULTS: The new medical device was significantly better than other therapies in improving all parameters (P<0.05 for all parameters). CONCLUSIONS: The present survey demonstrated that a new medical device containing PEG plus simethicone represents a favorable option in managing patients with chronic primary constipation as significantly and safely improves intestinal transit, reduces stool consistency, reduces symptom severity, and is highly satisfactory.

NO ABSTRACT

In this paper, we present PolarStar, a novel family of diameter-3 network topologies derived from the star product of two low-diameter factor graphs. The proposed PolarStar construction gives the largest known diameter-3 network topologies for almost all radixes. When compared to state-of-the-art diameter-3 networks, PolarStar achieves 31% geometric mean increase in scale over Bundlefly, 91% over Dragonfly, and 690% over 3-D HyperX. PolarStar has many other desirable properties including a modular layout, large bisection, high resilience to link failures and a large number of feasible sizes for every radix. Our evaluation shows that it exhibits comparable or better performance than other diameter-3 networks under various traffic patterns., Comment: 13 pages, 13 figures, 4 tables

Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10−8) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10−7). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus.

Zipf's law of abbreviation, the tendency of more frequent words to be shorter, is one of the most solid candidates for a linguistic universal, in the sense that it has the potential for being exceptionless or with a number of exceptions that is vanishingly small compared to the number of languages on Earth. Since Zipf's pioneering research, this law has been viewed as a manifestation of a universal principle of communication, i.e. the minimization of word lengths, to reduce the effort of communication. Here we revisit the concordance of written language with the law of abbreviation. Crucially, we provide wider evidence that the law holds also in speech (when word length is measured in time), in particular in 46 languages from 14 linguistic families. Agreement with the law of abbreviation provides indirect evidence of compression of languages via the theoretical argument that the law of abbreviation is a prediction of optimal coding. Motivated by the need of direct evidence of compression, we derive a simple formula for a random baseline indicating that word lengths are systematically below chance, across linguistic families and writing systems, and independently of the unit of measurement (length in characters or duration in time). Our work paves the way to measure and compare the degree of optimality of word lengths in languages., Comment: In press in Glottometrics. arXiv admin note: substantial text overlap with arXiv:2208.10384

Drawing on the literature of social movements and emotions, this article analyses a case of the union-led movement against outsourcing in the UK. Our focus is on the emotional processes of collective identity formation and the movement culture of new grassroot unions, addressing the themes of movement culture, collective identity and political solidarity. Data consists of participant observations, interviews, and additional website and media material. The results show that the movement culture of the new grassroot unions is characterised by direct action and a collective identity based on a proud re-centring of BAME workers as subjects of labour struggles. Key emotional processes consist of sharing emotions of humiliation, anger, and exclusion, but also joy and feelings of solidarity. A crucial part of the movement’s expansion is due to the construction of political solidarity and coalition-building. The results demonstrate the importance of heeding the crucial mobilising power of shared emotions in the analysis of new labour unions. The article contributes to labour movement research with an enhanced understanding of immaterial claims on dignity, respect and care, alongside the cognitivist focus on material work conditions and labour rights.

Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10−8) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10−7). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus.

Lv17/WB/Rie1-Δ24 was produced via illegitimate recombination mediated by low-dilution serial passage in the Cos7 cell line and isolated on PAM cell culture. The virus contains a huge ~26.4 Kb deletion in the left end of its genome. Lv17/WB/Rie1-ΔCD-ΔGL was generated via homologous recombination, crossing two ASFV strains (Lv17/WB/Rie1-ΔCD and Lv17/WB/Rie1-ΔGL containing eGFP and mCherry markers) during PAM co-infection. The presence of unique parental markers in the Lv17/WB/Rie1-ΔCD-ΔGL genome indicates at least two recombination events during the crossing, suggesting that homologous recombination is a relatively frequent event in the ASFV genome during replication in PAM. Pigs infected with Lv17/WB/Rie1-Δ24 and Lv17/WB/Rie1/ΔCD-ΔGL strains have shown mild clinical signs despite that ASFV could not be detected in their sera until a challenge infection with the Armenia/07 ASFV strain. The two viruses were not able to induce protective immunity in pigs against a virulent Armenia/07 challenge.

(1) Background: dental pathologies are the most frequent reason for requesting a CT scan of the head in rabbits and guinea pigs. The study aimed to review head CT exams of both species to identify and characterize lesions secondary to dental disease. (2) Methods: head CT studies of 48 rabbits and 52 guinea pigs with dental pathologies were reviewed. (3) Results: dental abnormalities of mandibular teeth were the most represented, both in rabbits (81.2%) and guinea pigs (98%). The aggressive bone lesion associated with teeth was the more frequently observed bone lesion in rabbits’ mandible and maxilla; in guinea pigs, the more frequent bone lesions were bulging around the roots of the teeth with focal lysis in the maxilla, and without focal lysis in the mandible. In the maxilla, the increased attenuation of nasal cavities (rhinitis) was the most frequently observed abnormality both in rabbits (60%) and guinea pigs (83.3%); the exophthalmos was more represented in rabbits (53.3%). In the mandible, the cavernous space-occupying lesion was more represented both in rabbits (92.3%) and guinea pigs (73.3%). (4) Conclusions: lesions secondary to dental pathologies were often observed both in rabbits and guinea pigs; CT examination has proven to be valuable in detecting secondary alterations in both species.

(1) Background: Rabbits and guinea pigs are popular pet animals and often undergo computed tomography (CT) examination for assessment of pathologies of the head. The goal of the study was to review CT examinations of the heads of rabbits and guinea pigs to identify and classify incidental findings. (2) Methods: 60 CT studies of the heads of rabbits and 65 of guinea pigs presented at 2 Institutions were reviewed and the indications for the study recorded. (3) Results: The presence of CT findings not directly related to the reason for the CT examination was present in 40/60 (66.7%) studies of rabbits and in 42/65 (64.4%) studies of guinea pigs. Most commonly, the incidental findings involved the ears, in 24/60 studies in rabbits and in 29/65 studies in guinea pigs. Incidental findings involved the nasal cavities, respectively, in 9 and 7 rabbits and guinea pigs. Soft tissue mineralization was present in 11 rabbits and 17 guinea pigs. (4) Conclusions: Based on the present study, incidental findings detected on CT studies are often present in rabbits and guinea pigs. Veterinarians should be aware of the possible clinical impact of these findings.

Artificial intelligence, particularly the subfield of machine learning, has seen a paradigm shift towards data-driven models that learn from and adapt to data. This has resulted in unprecedented advancements in various domains such as natural language processing and computer vision, largely attributed to deep learning, a special class of machine learning models. Deep learning arguably surpasses traditional approaches by learning the relevant features from raw data through a series of computational layers. This thesis explores the theoretical foundations of deep learning by studying the relationship between the architecture of these models and the inherent structures found within the data they process. In particular, we ask What drives the efficacy of deep learning algorithms and allows them to beat the so-called curse of dimensionality-i.e. the difficulty of generally learning functions in high dimensions due to the exponentially increasing need for data points with increased dimensionality? Is it their ability to learn relevant representations of the data by exploiting their structure? How do different architectures exploit different data structures? In order to address these questions, we push forward the idea that the structure of the data can be effectively characterized by its invariances-i.e. aspects that are irrelevant for the task at hand. Our methodology takes an empirical approach to deep learning, combining experimental studies with physics-inspired toy models. These simplified models allow us to investigate and interpret the complex behaviors we observe in deep learning systems, offering insights into their inner workings, with the far-reaching goal of bridging the gap between theory and practice., Comment: PhD Thesis @ EPFL

Large networks are useful in a wide range of applications. Sometimes problem instances are composed of billions of entities. Decomposing and analyzing these structures helps us gain new insights about our surroundings. Even if the final application concerns a different problem (such as traversal, finding paths, trees, and flows), decomposing large graphs is often an important subproblem for complexity reduction or parallelization. This report is a summary of discussions that happened at Dagstuhl seminar 23331 on "Recent Trends in Graph Decomposition" and presents currently open problems and future directions in the area of (hyper)graph decomposition.

Novel low-diameter network topologies such as Slim Fly (SF) offer significant cost and power advantages over the established Fat Tree, Clos, or Dragonfly. To spearhead the adoption of low-diameter networks, we design, implement, deploy, and evaluate the first real-world SF installation. We focus on deployment, management, and operational aspects of our test cluster with 200 servers and carefully analyze performance. We demonstrate techniques for simple cabling and cabling validation as well as a novel high-performance routing architecture for InfiniBand-based low-diameter topologies. Our real-world benchmarks show SF's strong performance for many modern workloads such as deep neural network training, graph analytics, or linear algebra kernels. SF outperforms non-blocking Fat Trees in scalability while offering comparable or better performance and lower cost for large network sizes. Our work can facilitate deploying SF while the associated (open-source) routing architecture is fully portable and applicable to accelerate any low-diameter interconnect.

Deep learning algorithms demonstrate a surprising ability to learn high-dimensional tasks from limited examples. This is commonly attributed to the depth of neural networks, enabling them to build a hierarchy of abstract, low-dimensional data representations. However, how many training examples are required to learn such representations remains unknown. To quantitatively study this question, we introduce the Random Hierarchy Model: a family of synthetic tasks inspired by the hierarchical structure of language and images. The model is a classification task where each class corresponds to a group of high-level features, chosen among several equivalent groups associated with the same class. In turn, each feature corresponds to a group of sub-features chosen among several equivalent ones and so on, following a hierarchy of composition rules. We find that deep networks learn the task by developing internal representations invariant to exchanging equivalent groups. Moreover, the number of data required corresponds to the point where correlations between low-level features and classes become detectable. Overall, our results indicate how deep networks overcome the curse of dimensionality by building invariant representations, and provide an estimate of the number of data required to learn a hierarchical task., Comment: 9 pages, 8 figures

Lamin A is a component of the inner nuclear membrane that, together with epigenetic factors, organizes the genome in higher order structures required for transcriptional control. Mutations in the lamin A/C gene cause several diseases belonging to the class of laminopathies, including muscular dystrophies. Nevertheless, molecular mechanisms involved in the pathogenesis of lamin A-dependent dystrophies are still largely unknown. The polycomb group (PcG) of proteins are epigenetic repressors and lamin A interactors, primarily involved in the maintenance of cell identity. Using a murine model of Emery-Dreifuss muscular dystrophy (EDMD), we show here that lamin A loss deregulated PcG positioning in muscle satellite stem cells, leading to derepression of non-muscle-specific genes and p16INK4a, a senescence driver encoded in the Cdkn2a locus. This aberrant transcriptional program caused impairment in self-renewal, loss of cell identity, and premature exhaustion of the quiescent satellite cell pool. Genetic ablation of the Cdkn2a locus restored muscle stem cell properties in lamin A/C-null dystrophic mice. Our findings establish a direct link between lamin A and PcG epigenetic silencing and indicate that lamin A-dependent muscular dystrophy can be ascribed to intrinsic epigenetic dysfunctions of muscle stem cells.

Tuft cells are chemosensory epithelial cells in the respiratory tract and several other organs. Recent studies revealed tuft cell-like gene expression signatures in some pulmonary adenocarcinomas, squamous cell carcinomas (SQCC), small cell carcinomas (SCLC), and large cell neuroendocrine carcinomas (LCNEC). Identification of their similarities could inform shared druggable vulnerabilities. Clinicopathological features of tuft cell-like (tcl) subsets in various lung cancer histotypes were studied in two independent tumor cohorts using immunohistochemistry (n = 674 and 70). Findings were confirmed, and additional characteristics were explored using public datasets (RNA seq and immunohistochemical data) (n = 555). Drug susceptibilities of tuft cell-like SCLC cell lines were also investigated. By immunohistochemistry, 10–20% of SCLC and LCNEC, and approximately 2% of SQCC expressed POU2F3, the master regulator of tuft cells. These tuft cell-like tumors exhibited “lineage ambiguity” as they co-expressed NCAM1, a marker for neuroendocrine differentiation, and KRT5, a marker for squamous differentiation. In addition, tuft cell-like tumors co-expressed BCL2 and KIT, and tuft cell-like SCLC and LCNEC, but not SQCC, also highly expressed MYC. Data from public datasets confirmed these features and revealed that tuft cell-like SCLC and LCNEC co-clustered on hierarchical clustering. Furthermore, only tuft cell-like subsets among pulmonary cancers significantly expressed FOXI1, the master regulator of ionocytes, suggesting their bidirectional but immature differentiation status. Clinically, tuft cell-like SCLC and LCNEC had a similar prognosis. Experimentally, tuft cell-like SCLC cell lines were susceptible to PARP and BCL2 co-inhibition, indicating synergistic effects. Taken together, pulmonary tuft cell-like cancers maintain histotype-related clinicopathologic characteristics despite overlapping unique molecular features. From a therapeutic perspective, identification of tuft

BackgroundPolyclonal convalescent plasma may be obtained from donors who have recovered from coronavirus disease 2019 (Covid-19). The efficacy of this plasma in preventing serious complications in outpatients with recent-onset Covid-19 is uncertain.MethodsIn this multicenter, double-blind, randomized, controlled trial, we evaluated the efficacy and safety of Covid-19 convalescent plasma, as compared with control plasma, in symptomatic adults (≥18 years of age) who had tested positive for severe acute respiratory syndrome coronavirus 2, regardless of their risk factors for disease progression or vaccination status. Participants were enrolled within 8 days after symptom onset and received a transfusion within 1 day after randomization. The primary outcome was Covid-19-related hospitalization within 28 days after transfusion.ResultsParticipants were enrolled from June 3, 2020, through October 1, 2021. A total of 1225 participants underwent randomization, and 1181 received a transfusion. In the prespecified modified intention-to-treat analysis that included only participants who received a transfusion, the primary outcome occurred in 17 of 592 participants (2.9%) who received convalescent plasma and 37 of 589 participants (6.3%) who received control plasma (absolute risk reduction, 3.4 percentage points; 95% confidence interval, 1.0 to 5.8; P = 0.005), which corresponded to a relative risk reduction of 54%. Evidence of efficacy in vaccinated participants cannot be inferred from these data because 53 of the 54 participants with Covid-19 who were hospitalized were unvaccinated and 1 participant was partially vaccinated. A total of 16 grade 3 or 4 adverse events (7 in the convalescent-plasma group and 9 in the control-plasma group) occurred in participants who were not hospitalized.ConclusionsIn participants with Covid-19, most of whom were unvaccinated, the administration of convalescent plasma within 9 days after the onset of symptoms reduced the risk of disease progress

(1) Background: carbonic anhydrases (CAs) are attractive targets for the development of new anticancer therapies; in particular, CAs IX and XII isoforms are overexpressed in numerous tumors. (2) Methods: following the tail approach, we have appended a hydrophobic aromatic tail to a pharmacophore responsible for the CA inhibition (aryl sulfonamide, coumarin). As a linker, we have used squaramides, featured with strong hydrogen bond acceptor and donor capacities. (3) Results: Starting from easily accessible dimethyl squarate, the title compounds were successfully obtained as crystalline solids, avoiding the use of chromatographic purifications. Interesting and valuable SARs could be obtained upon modification of the length of the hydrocarbon chain, position of the sulfonamido moiety, distance of the aryl sulfonamide scaffold to the squaramide, stereoelectronic effects on the aromatic ring, as well as the number and type of substituents on C-3 and C-4 positions of the coumarin. (4) Conclusions: For sulfonamides, the best profile was achieved for the m-substituted derivative 11 (Ki = 29.4, 9.15 nM, CA IX and XII, respectively), with improved selectivity compared to acetazolamide, a standard drug. Coumarin derivatives afforded an outstanding selectivity (Ki > 10,000 nM for CA I, II); the lead compound (16c) was a strong CA IX and XII inhibitor (Ki = 19.2, 7.23 nM, respectively). Docking simulations revealed the key ligand-enzyme interactions.

Tuft cells are chemosensory epithelial cells in the respiratory tract and several other organs. Recent studies revealed tuft cell-like gene expression signatures in some pulmonary adenocarcinomas, squamous cell carcinomas (SQCC), small cell carcinomas (SCLC), and large cell neuroendocrine carcinomas (LCNEC). Identification of their similarities could inform shared druggable vulnerabilities. Clinicopathological features of tuft cell-like (tcl) subsets in various lung cancer histotypes were studied in two independent tumor cohorts using immunohistochemistry (n = 674 and 70). Findings were confirmed, and additional characteristics were explored using public datasets (RNA seq and immunohistochemical data) (n = 555). Drug susceptibilities of tuft cell-like SCLC cell lines were also investigated. By immunohistochemistry, 10-20% of SCLC and LCNEC, and approximately 2% of SQCC expressed POU2F3, the master regulator of tuft cells. These tuft cell-like tumors exhibited lineage ambiguity as they co-expressed NCAM1, a marker for neuroendocrine differentiation, and KRT5, a marker for squamous differentiation. In addition, tuft cell-like tumors co-expressed BCL2 and KIT, and tuft cell-like SCLC and LCNEC, but not SQCC, also highly expressed MYC. Data from public datasets confirmed these features and revealed that tuft cell-like SCLC and LCNEC co-clustered on hierarchical clustering. Furthermore, only tuft cell-like subsets among pulmonary cancers significantly expressed FOXI1, the master regulator of ionocytes, suggesting their bidirectional but immature differentiation status. Clinically, tuft cell-like SCLC and LCNEC had a similar prognosis. Experimentally, tuft cell-like SCLC cell lines were susceptible to PARP and BCL2 co-inhibition, indicating synergistic effects. Taken together, pulmonary tuft cell-like cancers maintain histotype-related clinicopathologic characteristics despite overlapping unique molecular features. From a therapeutic perspective, identification of tuft ce

The cells possess several mechanisms to counteract the over-production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), including enzymes such as superoxide dismutase, catalase and glutathione peroxidase. Moreover, an important sensor involved in the anti-oxidant response is KEAP1-NRF2-ARE signaling complex. Under oxidative stress (OS), the transcription factor NRF2 can dissociate from the KEAP1-complex in the cytosol and translocate into the nucleus to promote the transcriptional activation of anti-oxidant genes, such as heme oxygenase 1 and NADPH quinone oxidoreductase. Within this context, the activation of NRF2 response is further regulated by BACH1, a transcription repressor, that compete with the KEAP1-NRF2-ARE complex. In this work, we focused on the role of BACH1/NRF2 ratio in the regulation of the anti-oxidant response, proposing their antithetical relation as a valuable target for a therapeutic strategy to test drugs able to exert neuroprotective effects, notably in aging and neurodegenerative diseases. Among these, Down syndrome (DS) is a complex genetic disorder characterized by BACH1 gene triplication that likely results in the impairment of NRF2 causing increased OS. Our results revealed that BACH1 overexpression alters the BACH1/NRF2 ratio in the nucleus and disturbs the induction of antioxidant response genes ultimately resulting in the accumulation of oxidative damage both in Ts2Cje mice (a mouse model of DS) and human DS lymphoblastoid cell lines (LCLs). Based on this evidence, we tested Caffeic Acid Phenethyl Ester (CAPE) and the synthetic analogue VP961, which have been proven to modulate NRF2 activity. We showed that CAPE and VP961 administration to DS LCLs was able to promote NRF2 nuclear translocation, which resulted in the amelioration of antioxidant response. Overall, our study supports the hypothesis that BACH1 triplication in DS subjects is implicated in the alteration of redox homeostasis and therapeutic strategies to

The syntactic structure of a sentence can be represented as a graph where vertices are words and edges indicate syntactic dependencies between them. In this setting, the distance between two syntactically linked words can be defined as the difference between their positions. Here we want to contribute to the characterization of the actual distribution of syntactic dependency distances, and unveil its relationship with short-term memory limitations. We propose a new double-exponential model in which decay in probability is allowed to change after a break-point. This transition could mirror the transition from the processing of words chunks to higher-level structures. We find that a two-regime model -- where the first regime follows either an exponential or a power-law decay -- is the most likely one in all 20 languages we considered, independently of sentence length and annotation style. Moreover, the break-point is fairly stable across languages and averages values of 4-5 words, suggesting that the amount of words that can be simultaneously processed abstracts from the specific language to a high degree. Finally, we give an account of the relation between the best estimated model and the closeness of syntactic dependencies, as measured by a recently introduced optimality score.

A central question of machine learning is how deep nets manage to learn tasks in high dimensions. An appealing hypothesis is that they achieve this feat by building a representation of the data where information irrelevant to the task is lost. For image datasets, this view is supported by the observation that after (and not before) training, the neural representation becomes less and less sensitive to diffeomorphisms acting on images as the signal propagates through the net. This loss of sensitivity correlates with performance, and surprisingly correlates with a gain of sensitivity to white noise acquired during training. These facts are unexplained, and as we demonstrate still hold when white noise is added to the images of the training set. Here, we (i) show empirically for various architectures that stability to image diffeomorphisms is achieved by both spatial and channel pooling, (ii) introduce a model scale-detection task which reproduces our empirical observations on spatial pooling and (iii) compute analitically how the sensitivity to diffeomorphisms and noise scales with depth due to spatial pooling. The scalings are found to depend on the presence of strides in the net architecture. We find that the increased sensitivity to noise is due to the perturbing noise piling up during pooling, after being rectified by ReLU units.

In this short paper, we introduce the Ridgeline model, an extension of the Roofline model [4] for distributed systems. The Roofline model targets shared memory systems, bounding the performance of a kernel based on its operational intensity, and the peak compute throughput and memory bandwidth of the execution system. In a distributed setting, with multiple communicating compute entities, the network must be taken into account to model the system behavior accurately. The Ridgeline aggregates information on compute, memory, and network limits in one 2D plot to show, in an intuitive way, which of the resources is the expected bottleneck. We show the applicability of the Ridgeline in a case study based on a data-parallel Multi-Layer Perceptron (MLP) instance., Comment: 5 pages

Zipf's law of abbreviation, namely the tendency of more frequent words to be shorter, has been viewed as a manifestation of compression, i.e. the minimization of the length of forms -- a universal principle of natural communication. Although the claim that languages are optimized has become trendy, attempts to measure the degree of optimization of languages have been rather scarce. Here we present two optimality scores that are dualy normalized, namely, they are normalized with respect to both the minimum and the random baseline. We analyze the theoretical and statistical pros and cons of these and other scores. Harnessing the best score, we quantify for the first time the degree of optimality of word lengths in languages. This indicates that languages are optimized to 62 or 67 percent on average (depending on the source) when word lengths are measured in characters, and to 65 percent on average when word lengths are measured in time. In general, spoken word durations are more optimized than written word lengths in characters. Our work paves the way to measure the degree of optimality of the vocalizations or gestures of other species, and to compare them against written, spoken, or signed human languages., Comment: On the one hand, the article has been reduced: analyses of the law of abbreviation and some of the methods have been moved to another article; appendix B has been reduced. On the other hand, various parts have been rewritten for clarity; new figures have been added to ease the understanding of the scores; new citations added. Many typos have been corrected

In this paper we present PolarFly, a diameter-2 network topology based on the Erdos-Renyi family of polarity graphs from finite geometry. This is a highly scalable low-diameter topology that asymptotically reaches the Moore bound on the number of nodes for a given network degree and diameter PolarFly achieves high Moore bound efficiency even for the moderate radixes commonly seen in current and near-future routers, reaching more than 96% of the theoretical peak. It also offers more feasible router degrees than the state-of-the-art solutions, greatly adding to the selection of scalable diameter-2 networks. PolarFly enjoys many other topological properties highly relevant in practice, such as a modular design and expandability that allow incremental growth in network size without rewiring the whole network. Our evaluation shows that PolarFly outperforms competitive networks in terms of scalability, cost and performance for various traffic patterns., Comment: In Proceedings of International Conference for High Performance Computing, Networking, Storage, and Analysis (SC) 2022