Chimeric contribution of human extended pluripotent stem cells to monkey embryos ex vivo.

Interspecies chimera formation with human pluripotent stem cells (hPSCs) represents a necessary alternative to evaluate hPSC pluripotency in vivo and might constitute a promising strategy for various regenerative medicine applications, including the generation of organs and tissues for transplantation. Studies using mouse and pig embryos suggest that hPSCs do not robustly contribute to chimera formation in species evolutionarily distant to humans. We studied the chimeric competency of human extended pluripotent stem cells (hEPSCs) in cynomolgus monkey (Macaca fascicularis) embryos cultured ex vivo. We demonstrate that hEPSCs survived, proliferated, and generated several peri- and early post-implantation cell lineages inside monkey embryos. We also uncovered signaling events underlying interspecific crosstalk that may help shape the unique developmental trajectories of human and monkey cells within chimeric embryos. These results may help to better understand early human development and primate evolution and develop strategies to improve human chimerism in evolutionarily distant species.

Generation of Blastocyst-like Structures from Mouse Embryonic and Adult Cell Cultures.

A single mouse blastomere from an embryo until the 8-cell stage can generate an entire blastocyst. Whether laboratory-cultured cells retain a similar generative capacity remains unknown. Starting from a single stem cell type, extended pluripotent stem (EPS) cells, we established a 3D differentiation system that enabled the generation of blastocyst-like structures (EPS-blastoids) through lineage segregation and self-organization. EPS-blastoids resembled blastocysts in morphology and cell-lineage allocation and recapitulated key morphogenetic events during preimplantation and early postimplantation development in vitro. Upon transfer, some EPS-blastoids underwent implantation, induced decidualization, and generated live, albeit disorganized, tissues in utero. Single-cell and bulk RNA-sequencing analysis revealed that EPS-blastoids contained all three blastocyst cell lineages and shared transcriptional similarity with natural blastocysts. We also provide proof of concept that EPS-blastoids can be generated from adult cells via cellular reprogramming. EPS-blastoids provide a unique platform for studying early embryogenesis and pave the way to creating viable synthetic embryos by using cultured cells.

In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming.

Aging is the major risk factor for many human diseases. In vitro studies have demonstrated that cellular reprogramming to pluripotency reverses cellular age, but alteration of the aging process through reprogramming has not been directly demonstrated in vivo. Here, we report that partial reprogramming by short-term cyclic expression of Oct4, Sox2, Klf4, and c-Myc (OSKM) ameliorates cellular and physiological hallmarks of aging and prolongs lifespan in a mouse model of premature aging. Similarly, expression of OSKM in vivo improves recovery from metabolic disease and muscle injury in older wild-type mice. The amelioration of age-associated phenotypes by epigenetic remodeling during cellular reprogramming highlights the role of epigenetic dysregulation as a driver of mammalian aging. Establishing in vivo platforms to modulate age-associated epigenetic marks may provide further insights into the biology of aging.

Cutibacterium species valvular and cardiac device-related infective endocarditis: contemporary data from the GAMES prospective cohort (2008-2023).

BACKGROUND: Information on infective endocarditis (IE) caused by Cutibacterium spp. is limited and new Duke-ISCVID criteria have not yet been properly assessed. We examined clinical characteristics, outcomes and performance of diagnostic tests for Cutibacterium valvular and cardiac implantable electronic device-related IE (CIED-IE). METHODS: Data corresponding to all episodes of Cutibacterium IE recorded from 2008 to 2023 in a prospective national cohort including 46 Spanish hospitals were examined. Possible IE cases were reassessed using the new criteria. The sensitivity of blood cultures, valvular and CIED cultures, and PCR of the 16SrRNA gene and sequencing (16SPCR) was evaluated. RESULTS: There were 67/6,692 (1%) episodes of IE caused by Cutibacterium spp., 85% affecting men. Of these, 50 were valve-related (45 prosthetic, 5 native) and 17 CIED-related. The new criteria identified 8 additional cases and reclassified 15 as definite IE. Intracardiac complications (abscess, pseudoaneurysm, perforation or intracardiac fistula) occurred in 23/50 (46%) valvular IE episodes, leading to 18% mortality, and up to 40% mortality if surgery was indicated but could not be performed. All CIED-IE cases underwent device removal and no deaths were recorded. Positive diagnosis rates for blood cultures, valve/device cultures and 16SPCR were 52%, 70% and 82%, respectively. CONCLUSION: Cutibacterium IE is a rare yet potentially life-threatening condition that warrants a high index of suspicion in men with endovascular prosthetic material. The new Duke-ISCVID criteria and molecular techniques are useful for its diagnosis. Considering a significant complication rate, cardiac surgery and removal of CIEDs play a key role in reducing mortality.

Neuroanatomical correlates of musicianship in left-handers.

BACKGROUND: Left-handedness is a condition that reverses the typical left cerebral dominance of motor control to an atypical right dominance. The impact of this distinct control - and its associated neuroanatomical peculiarities - on other cognitive functions such as music processing or playing a musical instrument remains unexplored. Previous studies in right-handed population have linked musicianship to a larger volume in the (right) auditory cortex and a larger volume in the (right) arcuate fasciculus. RESULTS: In our study, we reveal that left-handed musicians (n = 55), in comparison to left-handed non-musicians (n = 75), exhibit a larger gray matter volume in both the left and right Heschl's gyrus, critical for auditory processing. They also present a higher number of streamlines across the anterior segment of the right arcuate fasciculus. Importantly, atypical hemispheric lateralization of speech (notably prevalent among left-handers) was associated to a rightward asymmetry of the AF, in contrast to the leftward asymmetry exhibited by the typically lateralized. CONCLUSIONS: These findings suggest that left-handed musicians share similar neuroanatomical characteristics with their right-handed counterparts. However, atypical lateralization of speech might potentiate the right audiomotor pathway, which has been associated with musicianship and better musical skills. This may help explain why musicians are more prevalent among left-handers and shed light on their cognitive advantages.

A description of risk associated with use of antipsychotics among community dwelling older adults: A descriptive cross-sectional study.

The objective of this research was to analyze the risk of adverse effects in patients older than 65 years with dementia and in concomitant treatment with antidementia and antipsychotic drugs and who are cared for by community nurses. A retrospective cross-sectional descriptive study was carried out. A total of 332 patients who were cared for by primary care teams participated. Most of the patients were women, totally dependent for the basic activities of daily living and residing in the family home. They were polymedicated and there was poor therapeutic adherence. The risk of adverse effects was higher in polymedicated patients who had been taking antipsychotics for longer periods and in those who had a main caregiver. However, those patients who had been assessed by the community nurse were protected from suffering adverse effects. This study demonstrates how integrated and continuous nursing care can reduce adverse effects in this type of patient.

Infective endocarditis in children and adolescents: a different profile with clinical implications.

BACKGROUND: Our aim was to compare pediatric infective endocarditis (IE) with the clinical profile and outcomes of IE in adults. METHODS: Prospective multicenter registry in 31 Spanish hospitals including all patients with a diagnosis of IE from 2008 to 2020. RESULTS: A total of 5590 patients were included, 49 were <18 years (0.1%). Congenital heart disease (CHD) was present in 31 children and adolescents (63.2%). Right-sided location was more common in children/adolescents than in adults (46.9% vs. 6.3%, P < 0.001). Pediatric pulmonary IE was more frequent in patients with CHD (48.4%) than in those without (5.6%), P = 0.004. Staphylococcus aureus etiology tended to be more common in pediatric patients (32.7%) than in adults (22.3%), P = 0.082. Heart failure was less common in pediatric patients than in adults, due to the lower rate of heart failure in children/adolescents with CHD (9.6%) with respect to those without CHD (44.4%), P = 0.005. Inhospital mortality was high in both children, and adolescents and adults (16.3% vs. 25.9%; P = 0.126). CONCLUSIONS: Most IE cases in children and adolescents are seen in patients with CHD that have a more common right-sided location and a lower prevalence of heart failure than patients without CHD. IE in children and adolescents without CHD has a more similar profile to IE in adults. IMPACT: Infective endocarditis (IE) in children and adolescents is often seen in patients with congenital heart disease (CHD). Right-sided location is the most common in patients with CHD and heart failure is less common as a complication compared with patients without CHD. Infective endocarditis (IE) in children/adolescents without CHD has a more similar profile to IE in adults. In children/adolescents without CHD, locations were similar to adults, including a predominance of left-sided IE. Acute heart failure was the most frequent complication, seen mainly in adults, and in children/adolescents without CHD.

Biomedical articles share annotations with their citation neighbors.

BACKGROUND: Numerous efforts have been poured into annotating the wealth of knowledge contained in biomedical articles. Thanks to such efforts, it is now possible to quantitatively explore relations between these annotations and the citation network at large scale. RESULTS: With the aid of several large and small annotation databases, this study shows that articles share annotations with their citation neighborhood to the point that the neighborhood's most common annotations are likely to be those appearing in the article. CONCLUSIONS: These findings posit that an article's citation neighborhood defines to a large extent the article's annotated content. Thus, citations should be considered as a foundation for future knowledge management and annotation of biomedical articles.

Characteristics and Outcome of Acute Heart Failure in Infective Endocarditis: Focus on Cardiogenic Shock.

BACKGROUND: Studies investigating the impact of cardiogenic shock (CS) on endocarditis are lacking. METHODS: Prospectively collected cohort from 35 Spanish centers (2008-2018). Logistic regression analyses were performed to identify risk factors for developing CS and predictors of mortality. RESULTS: Among 4856 endocarditis patients, 1652 (34%) had acute heart failure (AHF) and 244 (5%) CS. Compared with patients without AHF and AHF but no CS, patients with CS presented higher rates of surgery (40.5%, 52.5%, and 68%; P < .001) and in-hospital mortality (16.3%, 39.1%, and 52.5%). Compared with patients with septic shock, CS patients presented higher rates of surgery (42.5% vs 68%; P < .001) and lower rates of in-hospital and 1-year mortality (62.3% vs 52.5%, P = .008, and 65.3% vs 57.4%, P = .030). Severe aortic and mitral regurgitation (OR [95% CI], 2.47 [1.82-3.35] and 3.03 [2.26-4.07]; both P < .001), left-ventricle ejection fraction <60% (1.72; 1.22-2.40; P = .002), heart block (2.22; 1.41-3.47; P = .001), tachyarrhythmias (5.07; 3.13-8.19; P < .001), and acute kidney failure (2.29; 1.73-3.03; P < .001) were associated with higher likelihood of developing CS. Prosthetic endocarditis (2.03; 1.06 -3.88; P = .032), Staphylococcus aureus (3.10; 1.16 -8.30; P = .024), tachyarrhythmias (3.09; 1.50-10.13; P = .005), and not performing cardiac surgery (11.40; 4.83-26.90; P < .001) were associated with a higher risk of mortality. CONCLUSIONS: AHF is common among patients with endocarditis. CS is associated with high mortality and should be promptly identified and assessed for cardiac surgery.

bigSCale: an analytical framework for big-scale single-cell data.

Single-cell RNA sequencing (scRNA-seq) has significantly deepened our insights into complex tissues, with the latest techniques capable of processing tens of thousands of cells simultaneously. Analyzing increasing numbers of cells, however, generates extremely large data sets, extending processing time and challenging computing resources. Current scRNA-seq analysis tools are not designed to interrogate large data sets and often lack sensitivity to identify marker genes. With bigSCale, we provide a scalable analytical framework to analyze millions of cells, which addresses the challenges associated with large data sets. To handle the noise and sparsity of scRNA-seq data, bigSCale uses large sample sizes to estimate an accurate numerical model of noise. The framework further includes modules for differential expression analysis, cell clustering, and marker identification. A directed convolution strategy allows processing of extremely large data sets, while preserving transcript information from individual cells. We evaluated the performance of bigSCale using both a biological model of aberrant gene expression in patient-derived neuronal progenitor cells and simulated data sets, which underlines the speed and accuracy in differential expression analysis. To test its applicability for large data sets, we applied bigSCale to assess 1.3 million cells from the mouse developing forebrain. Its directed down-sampling strategy accumulates information from single cells into index cell transcriptomes, thereby defining cellular clusters with improved resolution. Accordingly, index cell clusters identified rare populations, such as reelin (Reln)-positive Cajal-Retzius neurons, for which we report previously unrecognized heterogeneity associated with distinct differentiation stages, spatial organization, and cellular function. Together, bigSCale presents a solution to address future challenges of large single-cell data sets.

The manifestation of individual differences in sensitivity to punishment during resting state is modulated by eye state.

Structural and functional neuroimaging studies have shown that brain areas associated with fear and anxiety (defensive system areas) are modulated by individual differences in sensitivity to punishment (SP). However, little is known about how SP is related to brain functional connectivity and the factors that modulate this relationship. In this study, we investigated whether a simple methodological manipulation, such as performing a resting state with eyes open or eyes closed, can modulate the manifestation of individual differences in SP. To this end, we performed an exploratory fMRI resting state study in which a group of participants (n = 88) performed a resting state with eyes closed and another group (n = 56) performed a resting state with eyes open. All participants completed the Sensitivity to Punishment and Sensitivity to Reward Questionnaire. Seed-based functional connectivity analyses were performed in the amygdala, hippocampus, and periaqueductal gray (PAG). Our results showed that the relationship between SP and left amygdala-precuneus and left hippocampus-precuneus functional connectivity was modulated by eye state. Moreover, in the eyes open group, SP was negatively related to the functional connectivity between the PAG and amygdala and between the PAG and left hippocampus, and it was positively related to the functional connectivity between the amygdala and hippocampus. Together, our results may suggest underlying differences in the connectivity between anxiety-related areas based on eye state, which in turn would affect the manifestation of individual differences in SP.

Semantic persistence of ambiguous biomedical names in the citation network.

MOTIVATION: Name ambiguity has long been a central problem in biomedical text mining. To tackle it, it has been usually assumed that names present only one meaning within a given text. It is not known whether this assumption applies beyond the scope of single documents. RESULTS: Using a new method that leverages large numbers of biomedical annotations and normalized citations, this study shows that ambiguous biomedical names mentioned in scientific articles tend to present the same meaning in articles that cite them or that they cite, and, to a lesser extent, two steps away in the citation network. Citations, therefore, can be regarded as semantic connections between articles and the citation network should be considered for tasks such as automatic name disambiguation, entity linking and biomedical database annotation. A simple experiment shows the applicability of these findings to name disambiguation. AVAILABILITY AND IMPLEMENTATION: The code used for this analysis is available at: https://github.com/raroes/one-sense-per-citation-network.

Sustained and transient gray matter volume changes after n-back training: A VBM study.

Working memory training causes functional adaptations in the brain, which include changes in activation and functional connectivity that remain stable over time. Few studies have investigated gray matter (GM) changes after working memory training, and they have produced heterogeneous results without clarifying the stable effects of training. The present study was designed to test for sustained and transient anatomic changes after only 200 min of working memory training. The voxel-based morphometry technique was used in order to investigate the GM changes produced by a brief single n-back training, immediately and 5 weeks after finishing it. The sample was composed by 59 human participants who underwent MRI scanning and were assigned to either a training group or a passive control group. Results showed sustained GM volume enlargement in the right superior parietal cortex and a transient GM decrease in the right putamen. The brain adaptation in the right superior parietal cortex was stronger in individuals who showed greater improvements in performance. The results provide further evidence that a brief working memory training is able to produce brain plasticity in structures related to the trained task.

Hippo signaling controls cell cycle and restricts cell plasticity in planarians.

The Hippo pathway plays a key role in regulating cell turnover in adult tissues, and abnormalities in this pathway are consistently associated with human cancers. Hippo was initially implicated in the control of cell proliferation and death, and its inhibition is linked to the expansion of stem cells and progenitors, leading to larger organ size and tumor formation. To understand the mechanism by which Hippo directs cell renewal and promotes stemness, we studied its function in planarians. These stem cell-based organisms are ideal models for the analysis of the complex cellular events underlying tissue renewal in the whole organism. hippo RNA interference (RNAi) in planarians decreased apoptotic cell death, induced cell cycle arrest, and could promote the dedifferentiation of postmitotic cells. hippo RNAi resulted in extensive undifferentiated areas and overgrowths, with no effect on body size or cell number. We propose an essential role for hippo in controlling cell cycle, restricting cell plasticity, and thereby preventing tumoral transformation.

Usefulness of the Hybrid RFR-FFR Approach: Results of a Prospective and Multicenter Analysis of Diagnostic Agreement between RFR and FFR-The RECOPA (REsting Full-Cycle Ratio Comparation versus Fractional Flow Reserve (A Prospective Validation)) Study.

BACKGROUND: The resting full-cycle ratio (RFR) is a novel resting index which in contrast to the gold standard (fractional flow reserve (FFR)) does not require maximum hyperemia induction. The objectives of this study were to evaluate the agreement between RFR and FFR with the currently recommended thresholds and to design a hybrid RFR-FFR ischemia detection strategy, allowing a reduction of coronary vasodilator use. MATERIALS AND METHODS: Patients subjected to invasive physiological study in 9 Spanish centers were prospectively recruited between April 2019 and March 2020. Sensitivity and specificity studies were made to assess diagnostic accuracy between the recommended levels of RFR ≤0.89 and FFR ≤0.80 (primary objective) and to determine the RFR "grey zone" in order to define a hybrid strategy with FFR affording 95% global agreement compared with FFR alone (secondary objective). RESULTS: A total of 380 lesions were evaluated in 311 patients. Significant correlation was observed (R 2 = 0.81; P < 0.001) between the two techniques, with 79% agreement between RFR ≤ 0.89 and FFR ≤ 0.80 (positive predictive value, 68%, and negative predictive value, 80%). The hybrid RFR-FFR strategy, administering only adenosine in the "grey zone" (RFR: 0.86 to 0.92), exhibited an agreement of over 95% with FFR, with high predictive values (positive predictive value, 91%, and negative predictive value, 92%), reducing the need for vasodilators by 58%. CONCLUSIONS: Dichotomous agreement between RFR and FFR with the recommended thresholds is significant but limited. The adoption of a hybrid RFR-FFR strategy affords very high agreement, with minimization of vasodilator use.

Left-handed musicians show a higher probability of atypical cerebral dominance for language.

Music processing and right hemispheric language lateralization share a common network in the right auditory cortex and its frontal connections. Given that the development of hemispheric language dominance takes place over several years, this study tested whether musicianship could increase the probability of observing right language dominance in left-handers. Using a classic fMRI language paradigm, results showed that atypical lateralization was more predominant in musicians (40%) than in nonmusicians (5%). Comparison of left-handers with typical left and atypical right lateralization revealed that: (a) atypical cases presented a thicker right pars triangularis and more gyrified left Heschl's gyrus; and (b) the right pars triangularis of atypical cases showed a stronger intra-hemispheric functional connectivity with the right angular gyrus, but a weaker interhemispheric functional connectivity with part of the left Broca's area. Thus, musicianship is the first known factor related to a higher prevalence of atypical language dominance in healthy left-handed individuals. We suggest that differences in the frontal and temporal cortex might act as shared predisposing factors to both musicianship and atypical language lateralization.

Neural stem cell therapy of foetal onset hydrocephalus using the HTx rat as experimental model.

Foetal onset hydrocephalus is a disease starting early in embryonic life; in many cases it results from a cell junction pathology of neural stem (NSC) and neural progenitor (NPC) cells forming the ventricular zone (VZ) and sub-ventricular zone (SVZ) of the developing brain. This pathology results in disassembling of VZ and loss of NSC/NPC, a phenomenon known as VZ disruption. At the cerebral aqueduct, VZ disruption triggers hydrocephalus while in the telencephalon, it results in abnormal neurogenesis. This may explain why derivative surgery does not cure hydrocephalus. NSC grafting appears as a therapeutic opportunity. The present investigation was designed to find out whether this is a likely possibility. HTx rats develop hereditary hydrocephalus; 30-40% of newborns are hydrocephalic (hyHTx) while their littermates are not (nHTx). NSC/NPC from the VZ/SVZ of nHTx rats were cultured into neurospheres that were then grafted into a lateral ventricle of 1-, 2- or 7-day-old hyHTx. Once in the cerebrospinal fluid, neurospheres disassembled and the freed NSC homed at the areas of VZ disruption. A population of homed cells generated new multiciliated ependyma at the sites where the ependyma was missing due to the inherited pathology. Another population of NSC homed at the disrupted VZ differentiated into ßIII-tubulin+ spherical cells likely corresponding to neuroblasts that progressed into the parenchyma. The final fate of these cells could not be established due to the protocol used to label the grafted cells. The functional outcomes of NSC grafting in hydrocephalus remain open. The present study establishes an experimental paradigm of NSC/NPC therapy of foetal onset hydrocephalus, at the etiologic level that needs to be further explored with more analytical methodologies.

The subcommissural organ and the Reissner fiber: old friends revisited.

The subcommissural organ (SCO) is an ancient and conserved brain gland secreting into cerebrospinal fluid (CSF) glycoproteins that form the Reissner fiber (RF). The present investigation was designed to further investigate the dynamic of the biosynthetic process of RF glycoproteins prior and after their release into the CSF, to identify the RF proteome and N-glycome and to clarify the mechanism of assembly of RF glycoproteins. Various methodological approaches were used: biosynthetic labelling injecting 35S-cysteine and 3H-galactose into the CSF, injection of antibodies against galectin-1 into the cerebrospinal fluid, light and electron microscopical methods; isolated bovine RF was used for proteome analyses by mass spectrometry and glycome analysis by xCGE-LIF. The biosynthetic labelling study further supported that a small pool of SCO-spondin molecules rapidly enter the secretory pathways after its synthesis, while most of the SCO-spondin molecules are stored in the rough endoplasmic reticulum for hours or days before entering the secretory pathway and being released to assemble into RF. The proteomic analysis of RF revealed clusterin and galectin-1 as partners of SCO-spondin; the in vivo use of anti-galectin-1 showed that this lectin is essential for the assembly of RF. Galectin-1 is not secreted by the SCO but evidence was obtained that it would be secreted by multiciliated ependymal cells lying close to the SCO. Further, a surprising variety and complexity of glycan structures were identified in the RF N-glycome that further expands the potential functions of RF to a level not previously envisaged. A model of the macromolecular organization of Reissner fiber is proposed.

Separate Contribution of Striatum Volume and Pitch Discrimination to Individual Differences in Music Reward.

Individual differences in the level of pleasure induced by music have been associated with the response of the striatum and differences in functional connectivity between the striatum and the auditory cortex. In this study, we tested whether individual differences in music reward are related to the structure of the striatum and the ability to discriminate pitch. We acquired a 3-D magnetization-prepared rapid-acquisition gradient-echo image for 32 musicians and 26 nonmusicians who completed a music-reward questionnaire and a test of pitch discrimination. The analysis of both groups together showed that sensitivity to music reward correlated negatively with the volume of both the caudate and nucleus accumbens and correlated positively with pitch-discrimination abilities. Moreover, musicianship, pitch discrimination, and caudate volume significantly predicted individual differences in music reward. These results are consistent with the proposal that individual differences in music reward depend on the interplay between auditory abilities and the reward network.

Evaluation of the immunogenicity and efficacy of BCG and MTBVAC vaccines using a natural transmission model of tuberculosis.

Effective vaccines against tuberculosis (TB) are needed in order to prevent TB transmission in human and animal populations. Evaluation of TB vaccines may be facilitated by using reliable animal models that mimic host pathophysiology and natural transmission of the disease as closely as possible. In this study, we evaluated the immunogenicity and efficacy of two attenuated vaccines, BCG and MTBVAC, after each was given to 17 goats (2 months old) and then exposed for 9 months to goats infected with M. caprae. In general, MTBVAC-vaccinated goats showed higher interferon-gamma release than BCG vaccinated goats in response to bovine protein purified derivative and ESAT-6/CFP-10 antigens and the response was significantly higher than that observed in the control group until challenge. All animals showed lesions consistent with TB at the end of the study. Goats that received either vaccine showed significantly lower scores for pulmonary lymph nodes and total lesions than unvaccinated controls. Both MTBVAC and BCG vaccines proved to be immunogenic and effective in reducing severity of TB pathology caused by M. caprae. Our model system of natural TB transmission may be useful for evaluating and optimizing vaccines.