Neighbor-specific gene expression revealed from physically interacting cells during mouse embryonic development.

Development of multicellular organisms is orchestrated by persistent cell-cell communication between neighboring partners. Direct interaction between different cell types can induce molecular signals that dictate lineage specification and cell fate decisions. Current single-cell RNA-seq technology cannot adequately analyze cell-cell contact-dependent gene expression, mainly due to the loss of spatial information. To overcome this obstacle and resolve cell-cell contact-specific gene expression during embryogenesis, we performed RNA sequencing of physically interacting cells (PIC-seq) and assessed them alongside similar single-cell transcriptomes derived from developing mouse embryos between embryonic day (E) 7.5 and E9.5. Analysis of the PIC-seq data identified gene expression signatures that were dependent on the presence of specific neighboring cell types. Our computational predictions, validated experimentally, demonstrated that neural progenitor (NP) cells upregulate Lhx5 and Nkx2-1 genes, when exclusively interacting with definitive endoderm (DE) cells. Moreover, there was a reciprocal impact on the transcriptome of DE cells, as they tend to upregulate Rax and Gsc when in contact with NP cells. Using individual cell transcriptome data, we formulated a means of computationally predicting the impact of one cell type on the transcriptome of its neighboring cell types. We have further developed a distinctive spatial-t-distributed stochastic neighboring embedding to display the pseudospatial distribution of cells in a 2-dimensional space. In summary, we describe an innovative approach to study contact-specific gene regulation during embryogenesis.

Cell competition in intratumoral and tumor microenvironment interactions.

Tumors are complex cellular and acellular environments within which cancer clones are under continuous selection pressures. Cancer cells are in a permanent mode of interaction and competition with each other as well as with the immediate microenvironment. In the course of these competitive interactions, cells share information regarding their general state of fitness, with less-fit cells being typically eliminated via apoptosis at the hands of those cells with greater cellular fitness. Competitive interactions involving exchange of cell fitness information have implications for tumor growth, metastasis, and therapy outcomes. Recent research has highlighted sophisticated pathways such as Flower, Hippo, Myc, and p53 signaling, which are employed by cancer cells and the surrounding microenvironment cells to achieve their evolutionary goals by means of cell competition mechanisms. In this review, we discuss these recent findings and explain their importance and role in evolution, growth, and treatment of cancer. We further consider potential physiological conditions, such as hypoxia and chemotherapy, that can function as selective pressures under which cell competition mechanisms may evolve differently or synergistically to confer oncogenic advantages to cancer.

Flower isoforms promote competitive growth in cancer.

In humans, the adaptive immune system uses the exchange of information between cells to detect and eliminate foreign or damaged cells; however, the removal of unwanted cells does not always require an adaptive immune system1,2. For example, cell selection in Drosophila uses a cell selection mechanism based on 'fitness fingerprints', which allow it to delay ageing3, prevent developmental malformations3,4 and replace old tissues during regeneration5. At the molecular level, these fitness fingerprints consist of combinations of Flower membrane proteins3,4,6. Proteins that indicate reduced fitness are called Flower-Lose, because they are expressed in cells marked to be eliminated6. However, the presence of Flower-Lose isoforms at a cell's membrane does not always lead to elimination, because if neighbouring cells have similar levels of Lose proteins, the cell will not be killed4,6,7. Humans could benefit from the capability to recognize unfit cells, because accumulation of damaged but viable cells during development and ageing causes organ dysfunction and disease8-17. However, in Drosophila this mechanism is hijacked by premalignant cells to gain a competitive growth advantage18. This would be undesirable for humans because it might make tumours more aggressive19-21. It is unknown whether a similar mechanism of cell-fitness comparison is present in humans. Here we show that two human Flower isoforms (hFWE1 and hFWE3) behave as Flower-Lose proteins, whereas the other two isoforms (hFWE2 and hFWE4) behave as Flower-Win proteins. The latter give cells a competitive advantage over cells expressing Lose isoforms, but Lose-expressing cells are not eliminated if their neighbours express similar levels of Lose isoforms; these proteins therefore act as fitness fingerprints. Moreover, human cancer cells show increased Win isoform expression and proliferate in the presence of Lose-expressing stroma, which confers a competitive growth advantage on the cancer cells. Inhibition of the expression of Flower proteins reduces tumour growth and metastasis, and induces sensitivity to chemotherapy. Our results show that ancient mechanisms of cell recognition and selection are active in humans and affect oncogenic growth.

CellNeighborEX: deciphering neighbor-dependent gene expression from spatial transcriptomics data.

Cells have evolved their communication methods to sense their microenvironments and send biological signals. In addition to communication using ligands and receptors, cells use diverse channels including gap junctions to communicate with their immediate neighbors. Current approaches, however, cannot effectively capture the influence of various microenvironments. Here, we propose a novel approach to investigate cell neighbor-dependent gene expression (CellNeighborEX) in spatial transcriptomics (ST) data. To categorize cells based on their microenvironment, CellNeighborEX uses direct cell location or the mixture of transcriptome from multiple cells depending on ST technologies. For each cell type, CellNeighborEX identifies diverse gene sets associated with partnering cell types, providing further insight. We found that cells express different genes depending on their neighboring cell types in various tissues including mouse embryos, brain, and liver cancer. Those genes are associated with critical biological processes such as development or metastases. We further validated that gene expression is induced by neighboring partners via spatial visualization. The neighbor-dependent gene expression suggests new potential genes involved in cell-cell interactions beyond what ligand-receptor co-expression can discover.

Telecoaching as a new training method for elderly people: a systematic review.

BACKGROUND: The numerous restrictive measures implemented during the recent COVID-19 pandemic have reduced the levels of physical activity (PA) carried out by elderly people and telecoaching (TC) could be a training method to maintain the recommended levels of PA. In fact, TC uses information and digital communications technologies, such as computers and mobile devices, to access training services remotely. Thus, this study aimed to systematically review the scientific literature to verify the application, efficacy, and safety of TC training programs. METHODS: PubMed, Scopus, and Web of Sciences databases were used for this review, and randomized controlled trials analyzing TC training programs for elderly people were included. Only articles written in English and published in the last decade were considered. RESULTS: 3 articles were included in the qualitative synthesis including 194 elderly people. The sample size ranged from 12 to 117 and the TC training program from 8 to 12 weeks. The TC training programs were applied to elderly people with metabolic diseases and respiratory diseases. TC training program was effective in elderly people with metabolic diseases while the benefits for respiratory diseases have yet to be clarified. CONCLUSION: TC seems to be a safe, effective, and injury-free training method, despite its limited application in elderly population. Future studies should better investigate this training method in elderly people in order to evaluate the effectiveness in a wider range of diseases.

Pathophysiology and Main Molecular Mechanisms of Urinary Stone Formation and Recurrence.

Kidney stone disease (KSD) is one of the most common urological diseases. The incidence of kidney stones has increased dramatically in the last few decades. Kidney stones are mineral deposits in the calyces or the pelvis, free or attached to the renal papillae. They contain crystals and organic components, and they are made when urine is supersaturated with minerals. Calcium-containing stones are the most common, with calcium oxalate as the main component of most stones. However, many of these form on a calcium phosphate matrix called Randall's plaque, which is found on the surface of the kidney papilla. The etiology is multifactorial, and the recurrence rate is as high as 50% within 5 years after the first stone onset. There is a great need for recurrence prevention that requires a better understanding of the mechanisms involved in stone formation to facilitate the development of more effective drugs. This review aims to understand the pathophysiology and the main molecular mechanisms known to date to prevent recurrences, which requires behavioral and nutritional interventions, as well as pharmacological treatments that are specific to the type of stone.

Acute effects of static stretching and proprioceptive neuromuscular facilitation on non-local range of movement.

Acute effects of static stretching (SS) and proprioceptive neuromuscular facilitation (PNF) on local and non-local range of motion (ROM) were assessed in 29 participants. Three evaluations were performed one week apart: week-1 Control session (CS); weeks 2-3 either SS or PNF interventions (randomized). Dominant and non-dominant limbs, local (hamstring extensibility) and non-local ROMs (Shoulder extension-ShE) were collected at baseline (T0), immediately after (T1), and fifteen minutes post-intervention (T2). No differences were found between time-points during the CS. Local-ROM significantly increased (p=0.0002, ES=0.74 and 0.0079, 0.56, for dominant and non-dominant lower limbs, respectively) after both SS and PNF. No interaction between time and treatment was detected for ShE in both limbs. However, post-hoc analysis revealed a significant increase in dominant upper limb ShE between T0 and T1 only after SS (p=0.002; +6.5%). Acute bouts of SS and PNF can increase local-ROM, however, no clear effects were observed for non-local ROM.

Does Stretching Training Influence Muscular Strength? A Systematic Review With Meta-Analysis and Meta-Regression.

ABSTRACT: Thomas, E, Ficarra, S, Nunes, JP, Paoli, A, Bellafiore, M, Palma, A, and Bianco, A. Does stretching training influence muscular strength? A systematic review with meta-analysis and meta-regression. J Strength Cond Res 37(5): 1145-1156, 2023-The aim of this study was to review articles that performed stretching training and evaluated the effects on muscular strength. Literature search was performed using 3 databases. Studies were included if they compared the effects on strength following stretching training vs. a nontraining control group or stretching training combined with resistance training (RT) vs. an RT-only group, after at least 4 weeks of intervention. The meta-analyses were performed using a random-effect model with Hedges' g effect size (ES). A total of 35 studies ( n = 1,179 subjects) were included in this review. The interventions lasted for a mean period of 8 weeks (range, 4-24 weeks), 3-4 days per week, applying approximately 4 sets of stretching of approximately 1-minute duration. The meta-analysis for the stretching vs. nontraining control group showed a significant small effect on improving dynamic (k = 14; ES = 0.33; p = 0.007) but not isometric strength (k = 8; ES = 0.10; p = 0.377), following static stretching programs (k = 17; ES = 0.28; p = 0.006). When stretching was added to RT interventions, the main analysis indicated no significant effect (k = 17; ES = -0.15; p = 0.136); however, moderator analysis indicated that performing stretching before RT sessions has a small but negative effect (k = 7; ES = -0.43; p = 0.014); the meta-regression revealed a significant negative association with study length (ß = -0.100; p = 0.004). Chronic static stretching programs increase dynamic muscular strength to a small magnitude. Performing stretching before RT and for a prolonged time (>8 weeks) can blunt the strength gains to a small-to-moderate magnitude. Performing stretching in sessions distant from RT sessions might be a strategy to not hinder strength development.

Toward a New Conceptual Approach to "Intensity" in Soccer Player's Monitoring: A Narrative Review.

ABSTRACT: Pillitteri, G, Clemente, FM, Petrucci, M, Rossi, A, Bellafiore, M, Bianco, A, Palma, A, and Battaglia, G. Toward a new conceptual approach to "intensity" in soccer player's monitoring: A narrative review. J Strength Cond Res 37(9): 1896-1911, 2023-In the last decade, monitoring physiological and match-related demands in soccer has become an increasingly common practice in sports sciences. One of the great challenges during monitoring process is the identification of key indicators that permit to generalize evidence and sustain decision-making process during training prescription. Actually, one of the major debates in the scientific community and among practitioners is the identification of the "intensity" concept. Defining a given training session or exercise based on "intensity" is difficult due to the fact that a huge amount of indicators are available (related both to the performed activities and to the athletes' psychophysiological responses). These indicators can lead to specific outcomes with different interpretations. The current narrative review aims to discuss the different measures approaches used in soccer to describe the intensity for both internal and external demands. In addition, a second purpose of this review is to propose general recommendations for combining intensity indicators with the aim of defining an overall intensity score of a training session or drill.

Relationship between external and internal load indicators and injury using machine learning in professional soccer: a systematic review and meta-analysis.

This study verified the relationship between internal load (IL) and external load (EL) and their association on injury risk (IR) prediction considering machine learning (ML) approaches. Studies were included if: (1) participants were male professional soccer players; (2) carried out for at least 2 sessions, exercises, or competitions; (3) correlated training load (TL) with non-contact injuries; (4) applied ML approaches to predict TL and non-contact injuries. TL included: IL indicators (Rating of Perceived Exertion, RPE; Session-RPE, Heart Rate, HR) and EL indicators (Global Positioning System, GPS variables); the relationship between EL and IL through index, ratio, formula; ML indicators included performance measures, predictive performance of ML methods, measure of feature importance, relevant predictors, outcome variable, predictor variable, data pre-processing, features selection, ML methods. Twenty-five studies were included. Eleven addressed the relationship between EL and IL. Five used EL/IL indexes. Five studies predicted IL indicators. Three studies investigated the association between EL and IL with IR. One study predicted IR using ML. Significant positive correlations were found between S-RPE and total distance (TD) (r = 0.73; 95% CI (0.64 to 0.82)) as well as between S-RPE and player load (PL) (r = 0.76; 95% CI (0.68 to 0.84)). Association between IL and EL and their relationship with injuries were found. RPE, S-RPE, and HR were associated with different EL indicators. A positive relationship between EL and IL indicators and IR was also observed. Moreover, new indexes or ratios (integrating EL and IL) to improve knowledge regarding TL and fitness status were also applied. ML can predict IL indicators (HR and RPE), and IR. The present systematic review was registered in PROSPERO (CRD42021245312).

Time spent on the smartphone does not relate to manual dexterity in young adults.

BACKGROUND: The Grooved Pegboard Test (GPT) is widely adopted to evaluate manual dexterity, it presents normative data but the test is influenced by different factors. The influence of time spent on smartphones has not been considered before, for this reason, the objective of this study was to evaluate if smartphone use influences the time to complete the GPT. A total of 38 (21 women; 17 men) young adults 20.7 (1.5) years participated in the study. The time spent on the smartphones during the last seven days was recorded through the device itself and the GPT performance was measured. A correlation analysis between the time spent on the smartphone and GPT was performed while the t-test was adopted to evaluate gender differences. RESULTS: No statistically significant differences were detected between men and women in the time to complete the GPT (p = 0.20) and in the time spent on the smartphone (p = 0.87). The GPT and the time spent using the smartphone were not correlated (r = 0.044, p = 0.78). CONCLUSION: The time spent on the smartphone by young adults does not influence the time to complete the GPT, indicating that smartphone use does not influence measures of manual dexterity.

HIF-transcribed p53 chaperones HIF-1α.

Chronic hypoxia is associated with a variety of physiological conditions such as rheumatoid arthritis, ischemia/reperfusion injury, stroke, diabetic vasculopathy, epilepsy and cancer. At the molecular level, hypoxia manifests its effects via activation of HIF-dependent transcription. On the other hand, an important transcription factor p53, which controls a myriad of biological functions, is rendered transcriptionally inactive under hypoxic conditions. p53 and HIF-1α are known to share a mysterious relationship and play an ambiguous role in the regulation of hypoxia-induced cellular changes. Here we demonstrate a novel pathway where HIF-1α transcriptionally upregulates both WT and MT p53 by binding to five response elements in p53 promoter. In hypoxic cells, this HIF-1α-induced p53 is transcriptionally inefficient but is abundantly available for protein-protein interactions. Further, both WT and MT p53 proteins bind and chaperone HIF-1α to stabilize its binding at its downstream DNA response elements. This p53-induced chaperoning of HIF-1α increases synthesis of HIF-regulated genes and thus the efficiency of hypoxia-induced molecular changes. This basic biology finding has important implications not only in the design of anti-cancer strategies but also for other physiological conditions where hypoxia results in disease manifestation.

The effect of resistance training programs on lean body mass in postmenopausal and elderly women: a meta-analysis of observational studies.

Aging and menopause are associated with morphological and functional changes which may lead to loss of muscle mass and therefore quality of life. Resistance training (RT) is an effective training mode to increase muscle mass. We reviewed the existing literature to identify studies implementing RT protocols and evaluating muscle hypertrophy exclusively in healthy, postmenopausal and elderly women. Participants' age range was comprised between 50 and 80 years. The primary outcome observed was muscle hypertrophy. Fat mass was also evaluated, if available. PubMed and Web of Science were the screened database, and original articles written in English and published from 2000 up to 2020 were included. 26 articles were considered eligible and included. Quality assessment revealed a "moderate quality" of the included studies, however the majority of studies was able to reach level 4 of evidence and on overall grade of recommendation C. In total, data from 745 female participants subjected to different forms of resistance training were considered. Heterogeneity across studies was present regarding study design, intervention length (mean 16 weeks), training frequency (3 d/w), no. of exercises (n = 7.4) and participants' age (65.8 ± 4.9 years). Small-to-moderate significant increases (k = 43; SMD = 0.44; 95% CI 0.28; 0.60; p < 0.0001) of lean body mass were observed in post-menopausal and elderly women, regardless of age, intervention period, weekly training frequency and no. of exercises. No effects were noted for fat mass (k = 17; SMD = 0.27; 95% CI - 0.02; 0.55; p = 0.07). Studies need to concentrate on providing information regarding training parameters to more effectively counteract the effects of aging and menopause on skeletal muscle mass.

Cardiovascular Responses to Muscle Stretching: A Systematic Review and Meta-analysis.

The aim of this study will be to review the current body of literature to understand the effects of stretching on the responses of the cardiovascular system. A literature search was performed using the following databases: Scopus, NLM Pubmed and ScienceDirect. Studies regarding the effects of stretching on responses of the cardiovascular system were investigated. Outcomes regarded heart rate(HR), blood pressure, pulse wave velocity (PWV of which baPWV for brachial-ankle and cfPWV for carotid-femoral waveforms), heart rate variability and endothelial vascular function. Subsequently, the effects of each outcome were quantitatively synthetized using meta-analytic synthesis with random-effect models. A total of 16 studies were considered eligible and included in the quantitative synthesis. Groups were also stratified according to cross-sectional or longitudinal stretching interventions. Quality assessment through the NHLBI tools observed a "fair-to-good" quality of the studies. The meta-analytic synthesis showed a significant effect of d=0.38 concerning HR, d=2.04 regarding baPWV and d=0.46 for cfPWV. Stretching significantly reduces arterial stiffness and HR. The qualitative description of the studies was also supported by the meta-analytic synthesis. No adverse effects were reported, after stretching, in patients affected by cardiovascular disease on blood pressure. There is a lack of studies regarding vascular adaptations to stretching.

Dual-Task Conditions on Static Postural Control in Older Adults: A Systematic Review and Meta-Analysis.

Dual-task (DT) consists of the performance of two tasks simultaneously. An index of DT difficulty has been linked to decreased postural control. Because a wide range of DT is employed, this study aimed to evaluate its effects in static balance in older adults. PubMed, Web of Science, and Scopus were screened, and the secondary tasks were grouped as manual, reaction time, discrimination and decision making, mental tracking, verbal fluency, working memory, or "other" tasks. A total of 66 studies have been included. The meta-analysis was conducted on 28 effects and showed a significant mean effect size of d = 0.24 (p = .02, SE = 0.10; confidence interval [0.04, 0.44]), indicating a worsening in stability during DT. In conclusion, postural control was worsened by the Stroop test and the arithmetic tasks improved it. The results do not underpin any conclusive statement on the impact of DT, and a standard operating procedure was created.

Peripheral Nerve Responses to Muscle Stretching: A Systematic Review.

Stretching is commonly used to increase range of motion and flexibility. Therefore, investigations are usually oriented towards the muscle-tendon unit. Limited evidence exists regarding potential effects of stretching on peripheral nerves which lie within muscles. The objective of this investigation will be to elucidate the responses of peripheral nerves to stretching. A literature search was performed using the following databases: Scopus, NLM Pubmed and ScienceDirect. Studies regarding the effects of stretching protocols on responses of peripheral nerves were retrieved for investigation. The NHLBI tool was used for quality assessment. Outcomes included nerve stiffness, nerve displacement, pain pressure thresholds and resistive torque. A total of 10 studies were considered eligible and were included in this investigation. The quality assessment of the studies revealed an overall "fair to good" methodological quality across the included studies. All studies except for one involved healthy participants. High heterogeneity of stretching protocols was retrieved. As a consequence of stretching, nerve stiffness (-15.6%) and pain pressure thresholds (-1.9kg) increased. Nerve displacements on each movement plane for all the considered nerves and nerve deformation were also frequently observed. Peripheral nerve responses to muscle stretching include decreased nerve stiffness and increased pain pressure thresholds. Nerve displacement also frequently occurs. It is still unclear if reduced nerve displacement may lead to clinical outcomes. There is a lack of longitudinal studies regarding peripheral nerve adaptations to stretching.

Adherence to prophylaxis in adult patients with severe haemophilia A.

INTRODUCTION: Adherence is a cornerstone of factor VIII prophylactic treatment. Information regarding the factors with potential influence on adherence is limited, particularly in adult patients. AIM: To assess adherence in adult patients with severe haemophilia A receiving prophylactic treatment in a real-life setting, and investigate the factors influencing adherence. METHODS: Observational, prospective study including adult patients receiving factor VIII therapy in 15 Spanish centres. Patients recorded infusion doses on a logbook and answered various questionnaires to assess their health beliefs. Adherence rate was the percentage of infused doses over the prescribed ones. Self-perceived adherence was assessed using the VERITAS-Pro questionnaire, the psychometric properties of which were validated in the Spanish population. The relationship between adherence rate and treatment, clinical and demographic characteristics, health beliefs and perceived self-efficacy was investigated. RESULTS: A total of 66 patients were followed up for 12 months. Mean adherence rate at the end of follow-up was 82.5%. Most of the study patients (n = 53, 80.3%) showed a moderate-to-high adherence rate (>70%). The VERITAS-Pro revealed a high perception of adherence. Multivariate analyses to predict treatment adherence identified the knee as a target joint and longer treatment duration as variables with significant (negative) influence on adherence. Adherence rate was not influenced by the patient's health beliefs or perceived self-efficacy. CONCLUSION: Most adult patients receiving factor VIII prophylactic treatment in Spain have moderate-to-high treatment adherence. Treatment duration and the knee as a target joint are factors with a moderate negative influence on treatment adherence.

Food literacy predictors and associations with physical and emergent literacy in pre-schoolers: results from the Training-to-Health Project.

OBJECTIVE: Food literacy (FL) is a crucial need encompassing basic literacy and fundamental movement skills. The present study aimed to investigate the FL level in pre-schoolers and to evaluate the effect of potential predictors and the associations with gross motor and emergent literacy skills. DESIGN: Cross-sectional study conducted within the Training-to-Health Project. SETTING: Kindergartens (n 21) in the Palermo City Council, Italy. PARTICIPANTS: Pre-school children aged 3-6 years (n 921) followed education sessions on nutritional topics, practical activities and compiled prearranged sheets. FL was assessed by the five-domain toolkit 'preschool-FLAT'; gross motor and emergent literacy skills were assessed by the Italian version of the gross motor development test and the PRCR-2/2009, respectively. Correlation and regression analyses were performed to assess relationships between FL scores and gender, age, weight, height, BMI, gross motor and emergent literacy skills. RESULTS: Independent predictors (ß, se) of higher FL were female gender (1·06, 0·315, P < 0·01), older age (0·08, 0·019, P < 0·001) and greater height (0·13, 0·03, P < 0·001). The adjusted coefficients were significant for quotient of gross motor development and in particular for the locomotor component (0·03, 0·01, P < 0·01 and 0·16, 0·046, P < 0·001, respectively). Almost all associations with the emergent literacy skills were significant (ß = -0·02 to 0·47). CONCLUSIONS: The study suggests that children raised in an environment where both cognitive and motor skills are enhanced can have better chances of increasing FL and success at school. Thus, the need for monitoring FL and its predictors since early age is highlighted.

The posterior talocalcaneal ligament: an MRI evaluation.

PURPOSE: A wide inter-individual variability in terms of size, orientation and insertion is observed regarding ankle ligaments. The aim of this study is to identify and describe the anatomical features of the posterior talocalcaneal ligament (PTCL) observed through the use of magnetic resonance imaging (MRI) of the ankle. METHODS: The study was retrospectively carried out on 893 ankle MRI's exams. The exams have all been performed using a 1.5-T (T) MRI. The same scanning protocols and scan planes were carried out in all the exams. The first evaluated parameter was the recognition of the PTCL. Subsequently, in all those cases where the ligament was present, its features such as insertion sites, length, and thickness were evaluated. RESULTS: The PTCL identification was possible in 77 exams (8.6% of the total number). Among these, we were able to identify some variants regarding insertion sites, length, and thickness. The PTCL could be further classified into four categories based on the most common characteristics observed. CONCLUSIONS: Our study has identified different characteristics of the PTCL that allow us to further understand the characteristics of the ligament itself. In conclusion, the need for further studies focused on the biomechanical role of the PTCL in the ankle joint appears mandatory.