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Abstract Repair of double-stranded breaks generated by CRISPR/Cas9 is highly dependent on the flanking DNA sequence. To learn about interactions between DNA repair and target sequence, we measure frequencies of over 236,000 distinct Cas9-generated mutational outcomes at over 2800 synthetic target sequences in 18 DNA repair deficient mouse embryonic stem cells lines. We classify the outcomes in an unbiased way, finding a specialised role for Prkdc (DNA-PKcs protein) and Polm in creating 1 bp insertions matching the nucleotide on the protospacer-adjacent motif side of the break, a variable involvement of Nbn and Polq in the creation of different deletion outcomes, and uni-directional deletions dependent on both end-protection and end-resection. Using our dataset, we build predictive models of the mutagenic outcomes of Cas9 scission that outperform the current standards. This work improves our understanding of DNA repair gene function, and provides avenues for more precise modulation of Cas9-generated mutations.

Abstract Laugh faces of humans play a key role in everyday social interactions as a pervasive tool of communication across contexts. Humans often vary the degree of mouth opening and teeth exposure when producing these facial expressions, which may depend on who their social partner is (e.g., their gender and age as well as their social relationship), serving this way different functions. Although it was found that laugh faces show evolutionary continuity across humans and non-human great apes according to the Principle of Maximum Parsimony, little is known about the function of laugh face variations from an evolutionary perspective. Hence, the present work examined the morphology of laugh faces in orangutan and chimpanzee dyadic play to test if they are modified with dependence on the playmate’s characteristics (sex, age and social relationship). In total, we analysed over 600 facial expressions of 14 orangutans and 17 chimpanzees by coding the specific muscle activations (Action Units, i.e. AUs) contributing to these expressions, using OrangFACS and ChimpFACS, respectively. Our results suggest that age difference and, to a lesser extent, playmate sex influence laugh face morphology in both taxa, but in opposite ways. While the orangutans of our study seem to expose their upper teeth (with AU10) and to pull the mouth corners (with AU12) more towards weaker partners (younger and female), possibly to communicate non-hostility, the chimpanzees showed both upper and lower teeth exposure (with AU10 and AU16) more often when interacting with the stronger partners (older individuals), possibly to communicate submissiveness. These findings suggest that the ability of humans to modify laugh faces with dependence on social partner characteristics has most likely evolved from pre-existing traits, going back at least to the last common ancestor of today’s great apes, including humans.

Luisa Bertin,1 Martina Crepaldi,1 Miriana Zanconato,1 Greta Lorenzon,1 Daria Maniero,1 Caterina De Barba,1 Erica Bonazzi,1 Sonia Facchin,1 Marco Scarpa,2 Cesare Ruffolo,2 Imerio Angriman,2 Andrea Buda,3 Fabiana Zingone,1 Edoardo Vincenzo Savarino,1 Brigida Barberio1 1Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; 2Chirurgia Generale 3 Unit, Azienda Ospedale Università di Padova, Padua, Italy; 3Gastroenterology Unit, Department of Oncological Gastrointestinal Surgery, Feltre, ItalyCorrespondence: Edoardo Vincenzo Savarino, Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy, Tel +39-049-8217749, Fax +39-049-8760820, Email edoardo.savarino@unipd.itAbstract: Crohn’s disease (CD) is a complex, chronic inflammatory bowel disease characterized by unpredictable flare-ups and periods of remission. Despite advances in treatment, CD remains a significant health burden, leading to substantial direct healthcare costs and out-of-pocket expenses for patients, especially in the first-year post-diagnosis. The impact of CD on patients’ quality of life is profound, with significant reductions in physical, emotional, and social well-being. Despite advancements in therapeutic options, including biologics, immunomodulators, and small molecules, many patients struggle to achieve or maintain remission, leading to a considerable therapeutic ceiling. This has led to an increased focus on novel and emerging treatments. This context underscores the importance of exploring advanced and innovative treatment options for managing refractory CD. By examining the latest approaches, including immunomodulators, combination therapies, stem cell therapies, and emerging treatments like fecal microbiota transplantation and dietary interventions, there is an opportunity to gain a comprehensive understanding of how best to address and manage refractory cases of CD. Keywords: refractory Crohn’s disease, mesenchymal stem cell therapy, medical therapy, combination therapy, fecal microbiota transplantation, biologic drugs, perianal Crohn’s disease, small molecules, hyperbaric oxygen therapy

Transnationals constitute one-third of the population of the economically prosperous Singapore. Applying a family language policy (FLP) framework and collaborative autoethnography from data (interviews, videos, and diaries) spanning 13 years, this study delves into the linguistic journey of an Italian-Chinese family with two children born in Singapore. The analysis demonstrates the dynamics of language ideologies, management, and practices, following changes in parental beliefs, children's linguistic proficiencies and agency, availability of resources within the family and the host country, and unexpected events like COVID-19. The article highlights how multilingual parents' ideologies shape up owning to individual experiences, beliefs, and aspirations, and how these ideologies are translated into language choices and day-to-day language maintenance, vis-à-vis Singapore's English-centric policies. This unique longitudinal case study also touches on features pertaining to transnational families in Singapore, such as the perception of the local variety 'Singlish,' caregiving, and schooling options, illustrating the intricate interplay of micro and macro factors governing family multilingualism.

This article presents the ENglish Reading Online (ENRO) project that offers data on English reading and listening comprehension from 7,338 university-level advanced learners and native speakers of English representing 19 countries. The database also includes estimates of reading rate and seven component skills of English, including vocabulary, spelling, and grammar, as well as rich demographic and language background data. We first demonstrate high reliability for ENRO tests and their convergent validity with existing meta-analyses. We then provide a bird's-eye view of first (L1) and second (L2) language comparisons and examine the relative role of various predictors of reading and listening comprehension and reading speed. Across analyses, we found substantially more overlap than differences between L1 and L2 speakers, suggesting that English reading proficiency is best considered across a continuum of skill, ability, and experiences spanning L1 and L2 speakers alike. We end by providing pointers for how researchers can mine ENRO data for future studies.

Abstract Introduction Clinical remission is the main target in the management of patients with rheumatoid arthritis (RA). However, several authors found synovitis in patients with RA in clinical remission at ultrasonography (US). Upadacitinib is a selective Janus kinase 1 inhibitor that achieved significantly higher remission rates than adalimumab and abatacept in patients with RA. Here we present the 24-week data of the UPAdacitinib Rheumatoid Arthritis REmission UltraSonography (UPARAREMUS) study. Methods This is a longitudinal multicenter observational study, enrolling bio-naïve and bio-inadequate responder patients affected by RA. The primary endpoint was the proportion of patients achieving both clinical and US remission at week 24. The proportion of patients achieving clinical remission with different composite indexes at week 12 and 24 was also evaluated. US of four target joints (wrists and second metacarpophalangeal bilaterally) was performed at baseline and weeks 12/24, and US remission was defined as the absence of power Doppler (PD) signal ≥ 2 in one target joint, or PD ≥ 1 in two target joints. Results After 12 weeks and 24 weeks, 40% and 63.6% of patients achieved US plus clinical remission. The following parameters were associated with US plus clinical remission: being bio-naïve and having a shorter disease duration, although at multivariate analysis significant odds ratio (OR) was found only for being bio-naïve. Conclusions UPARAREMUS is the first study evaluating the efficacy of upadacitinib in reaching both clinical and US remission in patients with RA. At 24 weeks, 63.6% of patients reached the primary endpoint, the only baseline associated parameter was being bio-naïve.

Abstract Background The identification and staging of Alzheimer’s Disease (AD) represent a challenge, especially in the prodromal stage of Mild Cognitive Impairment (MCI), when cognitive changes can be subtle. Worldwide efforts were dedicated to select and harmonize available neuropsychological instruments. In Italy, the Italian Network of Neuroscience and Neuro-Rehabilitation has promoted the adaptation of the Uniform Data Set Neuropsychological Test Battery (I-UDSNB), collecting normative data from 433 healthy controls (HC). Here, we aimed to explore the ability of I-UDSNB to differentiate between a) MCI and HC, b) AD and HC, c) MCI and AD. Methods One hundred thirty-seven patients (65 MCI, 72 AD) diagnosed after clinical-neuropsychological assessment, and 137 HC were included. We compared the I-UDSNB scores between a) MCI and HC, b) AD and HC, c) MCI and AD, with t-tests. To identify the test(s) most capable of differentiating between groups, significant scores were entered in binary logistic and in stepwise regressions, and then in Receiver Operating Characteristic curve analyses. Results Two episodic memory tests (Craft Story and Five Words test) differentiated MCI from HC subjects; Five Words test, Semantic Fluency (vegetables), and TMT-part B differentiated AD from, respectively, HC and MCI. Conclusions Our findings indicate that the I-UDSNB is a suitable tool for the harmonized and concise assessment of patients with cognitive decline, showing high sensitivity and specificity for the diagnosis of MCI and AD.

Este artigo objetiva compreender de que modo as ferramentas de comunicação analógicas e digitais têm sido usadas na rádio comunitária Oeste FM para proporcionar a participação da comunidade, objetivando alcançar os princípios de uma rádio comunitária. O serviço de radiodifusão comunitária foi legalizado no Brasil em 1998 por meio da lei 9.612/98, que estabelece as diretrizes do referido serviço. Esta investigação foi realizada a partir de um Estudo de Caso, com apoio da pesquisa bibliográfica, documental, entrevista semiestruturada, estudo da usabilidade e design da homepage e estudo da programação da rádio. A principal hipótese deste trabalho, é que as ferramentas analógicas e digitais aproximam a comunidade nas ações da rádio e criam novas relações, intensificando a participação na gestão. Contudo, os resultados da pesquisa mostram que, apesar da disposição de ferramentas analógicas e digitais, a participação da comunidade é extremamente limitada e se resume em boa parte ao entretenimento, com ênfase no pedido musical. Portanto, não atende completamente aos objetivos de uma rádio comunitária.

Abstract This study aimed to characterize concepts of continuities and discontinuities in the intergenerational transmission of relational models, as well as marital and parental conflict resolution tactics. This was a qualitative study, in which 12 couples attended a semi-structured interview. Through thematic content analysis, the data was divided into two main themes: Intergenerational Continuities and Intergenerational Discontinuities. The continuities indicated both the repetition of positive and constructive aspects of family models, as well as the prevalence of destructive tactics, such as avoidance between spouses and the use of corporal punishment with the child. The discontinuities revealed a break from negative or destructive patterns and the adoption of positive parenting, in contrast to that of the family of origin.

BACKGROUND AND OBJECTIVES: The locus of control (LC) of pain is the perception of the individual about pain control. The investigation of the relationship between LC, dependence and depression in elderly patients is of great importance given the high prevalence of chronic diseases among this population. The objective of this study was to analyze the association between LC of pain in elderly patients and the level of dependence and prevalence of depression. METHODS: Ninety-one elderly individuals, aged over 60 years, were selected from the Association of Retirees, Pensioners, and Elderly of Lavras and Region (AAPIL) and all participants underwent a comprehensive anamnesis to effectively describe and characterize the sample. The Health Locus of Control Multidimensional Scale was used to assess perception of pain, the Yesavage Geriatric Depression Scale was used to determine the prevalence of depression, and Katz Index to evaluate functional capacity. Chi-square test was used to analyze nominal variables with a 95% level of significance. RESULTS: The majority of the elderly participants (83.5%) reported experiencing chronic pain, while 85.7% had no suspected depression. Internal control was the most prevalent type of LC among participants, and there was no significant relationship between LC of pain and depression. CONCLUSION: Findings suggest that the type of LC of pain reported by the elderly participants in this study does not significantly interfere with the likelihood of depression. These results contribute to the understanding of the relationship between LC, dependence, and depression among senior patients and may inform interventions to improve their quality of life.

Collective modes are responsible for the emergence of novel quantum phases in topological materials. In the quasi-one dimensional (1D) Weyl semimetal (TaSe4)2I, a charge density wave (CDW) opens band gaps at the Weyl points, thus turning the system into an axionic insulator. Melting the CDW would restore the Weyl phase, but 1D fluctuations extend the gapped regime far above the 3D transition temperature (T CDW = 263 K), thus preventing the investigation of this topological phase transition with conventional spectroscopic methods. Here we use a non-equilibrium approach: we perturb the CDW phase by photoexcitation, and we monitor the dynamical evolution of the band structure by time- and angle-resolved photoelectron spectroscopy. We find that, upon optical excitation, electrons populate the linearly dispersing states at the Fermi level (E F ), and fill the CDW gap. The dynamics of both the charge carrier population and the band gap renormalization (BGR) show a fast component with a characteristic time scale of a few hundreds femtoseconds. However, the BGR also exhibits a second slow component on the μs time scale. The combination of an ultrafast response and of persistent changes in the spectral weight at E F, and the resulting sensitivity of the linearly dispersing states to optical excitations, may explain the high performances of (TaSe4)2I as a material for broadband infrared photodetectors.

Abstract Heterozygosity-rich regions (HRR) are genomic regions of high heterozygosity, which may harbor loci related to key functional traits such as immune response, survival rate, fertility, and other fitness traits. This study considered 30 Italian and 19 worldwide goat breeds genotyped with the Illumina GoatSNP50k BeadChip. The aim of the work was to study inter-breed relationships and HRR patterns using Sliding Window (SW) and Consecutive Runs (CR) detection methods. Genetic relationships highlighted a clear separation between non-European and European breeds, as well as the north–south geographic cline within the latter. The Pearson correlation coefficients between the descriptive HRR parameters obtained with the SW and CR methods were higher than 0.9. A total of 166 HRR islands were detected. CHI1, CHI11, CHI12 and CHI18 were the chromosomes harboring the highest number of HRR islands. The genes annotated in the islands were linked to various factors such as productive, reproductive, immune, and environmental adaptation mechanisms. Notably, the Montecristo feral goat showed the highest number of HRR islands despite the high level of inbreeding, underlining potential balancing selection events characterizing its evolutionary history. Identifying a species-specific HRR pattern could provide a clearer view of the mechanisms regulating the genome modelling following anthropogenic selection combined with environmental interaction.

Abstract Robertsonian translocation 1;29 (rob(1;29)), a widespread chromosomal anomaly affecting cattle fertility, appears to have originated from a common ancestor. This study utilizes routine SNP data to investigate the chromosomal region associated with rob(1;29) and confirm the presence of a shared haplotype among carriers in diverse Italian breeds. Three datasets were employed: Dataset 1 included 151 subjects from 5 beef cattle breeds genotyped with the GGP Bovine 33 k SNP chip; Dataset 2 encompassed 800 subjects from 32 Italian breeds genotyped with the Illumina 50 k SNP chip, sourced from the BOVITA dataset; Dataset 3 combined Dataset 2 with 21 karyologically tested subjects from breeds with a high carrier frequency, genotyped using the Affymetrix 65 K SNP chip. FST analysis pinpointed a distinctive genomic region on the first six Mb of BTA29, the centromeric region involved in the translocation. Haplotype comparisons within this non-recombining region revealed a common haplotype shared among all carriers, supporting the theory of a common ancestor. Principal component and haplotype analysis allowed clear differentiation of rob(1;29) homozygous and heterozygous carriers. Expanding to Dataset 2 revealed rob(1;29) carriers in unexpected breeds, all sharing the same ancestral haplotype. Notably, previously untested breeds, including Cinisara, exhibited a high carrier prevalence (nearly 50%), confirmed by karyological analysis. This study validates the presence of a shared haplotype among all identified rob(1;29) carriers, reinforcing the common ancestor theory as the origin of this translocation's spread throughout the cattle population. Furthermore, it underscores the potential of SNP data analysis as a rapid, accurate, and cost-effective tool for broad rob(1;29) screening, given the translocation's consistent nature across all analyzed breeds.

The MET receptor, commonly known as HGF (hepatocyte growth factor) receptor, is a focus of extensive scientific research. MET has been linked to embryonic development, tissue regeneration following injury, tumorigenesis, and cancer metastasis. These functions underscore its involvement in numerous cellular processes, including stemness, proliferation, motility, cell dissociation, and survival. However, the enigmatic nature of MET becomes apparent in the context of cancer. When MET remains persistently activated, since its gene undergoes genetic alterations, it initiates a complex signaling cascade setting in motion an aggressive and metastatic program that is characteristic of malignant cells and is known as “invasive growth”. The expanding knowledge of MET signaling has opened up numerous opportunities for therapeutic interventions, particularly in the realm of oncology. Targeting MET presents a promising strategy for developing novel anti-cancer treatments. In this review, we provide an updated overview of drugs designed to modulate MET signaling, highlighting MET kinase inhibitors, degraders, anti-MET/HGF monoclonal antibodies, and MET-targeted antibody–drug conjugates. Through this review, we aim to contribute to the ongoing advancement of therapeutic strategies targeting MET signaling.

Within the current scenario of cropland use and forest surface loss, there is a need for the implementation of viable urban farming systems, e.g., indoor vertical farming (VF). Light management is fundamental in VF, although responses to light spectra are often species-specific. As the interest of consumers and farmers towards baby-leaf vegetables has recently increased, this study aimed at assessing the most effective red:blue (RB) ratio for enhanced baby-leaf production of kale (Brassica oleracea). Within an ebb-and-flow system, increasing RB ratios (RB3, RB5, RB7 and RB9) were tested, sharing a photoperiod of 16 h day−1 and a light intensity of 215 μmol m−2 s−1. A larger yield was obtained for plants under RB5, featuring an intermediate B fraction compared to other treatments, with plants displaying more expanded and thinner leaves. Also, for lighting energy and cultivated surface use efficiency, RB5 was the most effective treatment, performing up to 57 g FW kWh−1 and 54 kg FW m−2 y−1, respectively. From multispectral data, a tendency of reduced Fv/Fm and Fq′/Fm′ was observed as the RB ratio increased, while the chlorophyll index was enhanced under RB ≥ 7. This study highlighted the light recipe with an RB ratio of 5 as the most effective lighting mixture for optimal baby-leaf kale production in terms of balanced growth, resource use efficiency and yield.