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It has been suggested that our perception of the internal milieu, or the body's internal state, is shaped by our beliefs and previous knowledge about the body's expected state, rather than being solely based on actual interoceptive experiences. This study investigated whether heartbeat perception could be illusorily distorted towards prior subjective beliefs, such that threat expectations suffice to induce a misperception of heartbeat frequency. Participants were instructed to focus on their cardiac activity and report their heartbeat, either tapping along to it (Experiment 1) or silently counting (Experiment 2) while ECG was recorded. While completing this task, different cues provided valid predictive information about the intensity of an upcoming cutaneous stimulation (high- vs. low- pain). Results showed that participants expected a heart rate increase over the anticipation of high- vs. low-pain stimuli and that this belief was perceptually instantiated, as suggested by their interoceptive reports. Importantly, the perceived increase was not mirrored by the real heart rate. Perceptual modulations were absent when participants executed the same task but with an exteroceptive stimulus (Experiment 3). The findings reveal, for the first time, an interoceptive illusion of increased heartbeats elicited by threat expectancy and shed new light on interoceptive processes through the lenses of Bayesian predictive processes, providing tantalizing insights into how such illusory phenomena may intersect with the recognition and regulation of people's internal states., Competing Interests: Declaration of competing interest The authors declare no competing financial or academic interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Respiration and cardiac activity intricately interact through complex physiological mechanisms. The heartbeat-evoked potential (HEP) is an EEG fluctuation reflecting the cortical processing of cardiac signals. We recently found higher HEP amplitude during exhalation than inhalation during a task involving attention to cardiac sensations. This may have been due to reduced cardiac perception during inhalation and heightened perception during exhalation through attentional mechanisms. To investigate relationships between HEP, attention, and respiration, we introduced an experimental setup that included tasks related to cardiac and respiratory interoceptive and exteroceptive attention. Results revealed HEP amplitude increases during the interoceptive tasks over fronto-central electrodes. When respiratory phases were taken into account, HEP increases were primarily driven by heartbeats recorded during exhalation, specifically during the cardiac interoceptive task, while inhalation had minimal impact. These findings emphasize the role of respiration in cardiac interoceptive attention and could have implications for respiratory interventions to fine-tune cardiac interoception., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Respiration and heartbeat continuously interact within the living organism at many different levels, representing two of the main oscillatory rhythms of the body and providing major sources of interoceptive information to the brain. Despite the modulatory effect of respiration on exteroception and cognition has been recently established in humans, its role in shaping interoceptive perception has been scarcely investigated so far. In two independent studies, we investigated the effect of spontaneous breathing on cardiac interoception by assessing the Heartbeat Evoked Potential (HEP) in healthy humans. In Study 1, we compared HEP activity for heartbeats occurred during inhalation and exhalation in 40 volunteers at rest. We found higher HEP amplitude during exhalation, compared to inhalation, over fronto-centro-parietal areas. This suggests increased brain-heart interactions and improved cortical processing of the heartbeats during exhalation. Further analyses revealed that this effect was moderated by heart rate changes. In Study 2, we tested the respiratory phase-dependent modulation of HEP activity in 20 volunteers during Exteroceptive and Interoceptive conditions of the Heartbeat Detection (HBD) task. In these conditions, participants were requested to tap at each heartbeat, either listened to or felt, respectively. Results showed higher HEP activity and higher detection accuracy at exhalation than inhalation in the Interoceptive condition only. Direct comparisons of Interoceptive and Exteroceptive conditions confirmed stronger respiratory phase-dependent modulation of HEP and accuracy when attention was directed towards the interoceptive stimuli. Moreover, HEP changes during the Interoceptive condition were independent of heart physiology, but were positively correlated with higher detection accuracy at exhalation than inhalation. This suggests a link between optimization of cortical processing of cardiac signals and detection of heartbeats across the respiratory cycle. Overall, we provide data showing that respiration shapes cardiac interoception at the neurophysiological and behavioural levels. Specifically, exhalation may allow attentional shift towards the internal bodily states., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2022. Published by Elsevier Inc.)

The necessity to improve in vitro cell screening assays is becoming ever more important. Pharmaceutical companies, research laboratories and hospitals require technologies that help to speed up conventional screening and therapeutic procedures to produce more data in a short time in a realistic and reliable manner. The design of new solutions for test biomaterials and active molecules is one of the urgent problems of preclinical screening and the limited correlation between in vitro and in vivo data remains one of the major issues. The establishment of the most suitable in vitro model provides reduction in times, costs and, last but not least, in the number of animal experiments as recommended by the 3Rs (replace, reduce, refine) ethical guiding principles for testing involving animals. Although two-dimensional (2D) traditional cell screening assays are generally cheap and practical to manage, they have strong limitations, as cells, within the transition from the three-dimensional (3D) in vivo to the 2D in vitro growth conditions, do not properly mimic the real morphologies and physiology of their native tissues. In the study of human pathologies, especially, animal experiments provide data closer to what happens in the target organ or apparatus, but they imply slow and costly procedures and they generally do not fully accomplish the 3Rs recommendations, i.e., the amount of laboratory animals and the stress that they undergo must be minimized. Microfluidic devices seem to offer different advantages in relation to the mentioned issues. This review aims to describe the critical issues connected with the conventional cells culture and screening procedures, showing what happens in the in vivo physiological micro and nano environment also from a physical point of view. During the discussion, some microfluidic tools and their components are described to explain how these devices can circumvent the actual limitations described in the introduction.

Heart regeneration is an unmet clinical need, hampered by limited renewal of adult cardiomyocytes and fibrotic scarring. Pluripotent stem cell-based strategies are emerging, but unravelling cellular dynamics of host-graft crosstalk remains elusive. Here, by combining lineage tracing and single-cell transcriptomics in injured non-human primate heart biomimics, we uncover the coordinated action modes of human progenitor-mediated muscle repair. Chemoattraction via CXCL12/CXCR4 directs cellular migration to injury sites. Activated fibroblast repulsion targets fibrosis by SLIT2/ROBO1 guidance in organizing cytoskeletal dynamics. Ultimately, differentiation and electromechanical integration lead to functional restoration of damaged heart muscle. In vivo transplantation into acutely and chronically injured porcine hearts illustrated CXCR4-dependent homing, de novo formation of heart muscle, scar-volume reduction and prevention of heart failure progression. Concurrent endothelial differentiation contributed to graft neovascularization. Our study demonstrates that inherent developmental programmes within cardiac progenitors are sequentially activated in disease, enabling the cells to sense and counteract acute and chronic injury., (© 2022. The Author(s).)

Objective: To report outcomes on patients with multiple sclerosis (MS) and related disorders with coronavirus disease 2019 (COVID-19) illness., Methods: From March 16 to April 30, 2020, patients with MS or related disorders at NYU Langone MS Comprehensive Care Center were identified with laboratory-confirmed or suspected COVID-19. The diagnosis was established using a standardized questionnaire or by review of in-patient hospital records., Results: We identified 76 patients (55 with relapsing MS, of which 9 had pediatric onset; 17 with progressive MS; and 4 with related disorders). Thirty-seven underwent PCR testing and were confirmed positive. Of the entire group, 64 (84%) patients were on disease-modifying therapy (DMT) including anti-CD20 therapies (n = 34, 44.7%) and sphingosine-1-phosphate receptor modulators (n = 10, 13.5%). The most common COVID-19 symptoms were fever and cough, but 21.1% of patients had neurologic symptom recrudescence preceding or coinciding with the infection. A total of 18 (23.7%) were hospitalized; 8 (10.5%) had COVID-19 critical illness or related death. Features more common among those hospitalized or with critical illness or death were older age, presence of comorbidities, progressive disease, and a nonambulatory status. No DMT class was associated with an increased risk of hospitalization or fatal outcome., Conclusions: Most patients with MS with COVID-19 do not require hospitalization despite being on DMTs. Factors associated with critical illness were similar to the general at-risk patient population. DMT use did not emerge as a predictor of poor COVID-19 outcome in this preliminary sample., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Neuroimaging and EEG studies have shown that passive observation of the full body and of specific body parts is associated with 1 ) activity of an occipito-temporal region named the extrastriate body area (EBA), 2 ) amplitude modulations of a specific posterior event-related potential (ERP) component (N1/N190), and 3 ) a theta-band (4-7 Hz) synchronization recorded from occipito-temporal electrodes compatible with the location of EBA. To characterize the functional role of the occipito-temporal theta-band increase during the processing of body-part stimuli, we recorded EEG from healthy participants while they were engaged in an identification task (match-to-sample) of images of hands and nonbody control images (leaves). In addition to confirming that occipito-temporal electrodes show a larger N1 for hand images compared with control stimuli, cluster-based analysis revealed an occipito-temporal cluster showing an increased theta power when hands are presented (compared with leaves) and show that this theta increase is higher for identified hands compared with nonidentified ones while not being significantly different between not identified nonhand stimuli. Finally, single trial multivariate pattern analysis revealed that time-frequency modulation in the theta band is a better marker for classifying the identification of hand images than the ERP modulation. The present results support the notion that theta activity over the occipito-temporal cortex is an informative marker of hand visual processing and may reflect the activity of a network coding for stimulus identity. NEW & NOTEWORTHY Hands provide crucial information regarding the identity of others, which is a key information for social processes. We recorded EEG activity of healthy participants during the visual identification of hand images. The combination of univariate and multivariate pattern analysis in time- and time-frequency domain highlights the functional role of theta (4-7 Hz) activity over visual areas during hand identification and emphasizes the robustness of this neuromarker in occipito-temporal visual processing dynamics.

This work presents a disposable passive microfluidic system, allowing chemotaxis studies, through the generation of a concentration gradient. The device can handle liquid flows without an external supply of pressure or electric gradients, but simply using gravity force. It is able to ensure flow rates of 10 µL/h decreasing linearly with 2.5% in 24 h. The device is made of poly(methylmethacrylate) (PMMA), a biocompatible material, and it is fabricated by micro-milling and solvent assisted bonding. It is assembled into a mini incubator, designed properly for cell biology studies in passive microfluidic devices, which provides control of temperature and humidity levels, a contamination-free environment for cells with air and 5% of CO 2 . Furthermore, the mini incubator can be mounted on standard inverted optical microscopes. By using our microfluidic device integrated into the mini incubator, we are able to evaluate and follow in real-time the migration of any cell line to a chemotactic agent. The device is validated by showing cell migration at a rate of 0.36 µm/min, comparable with the rates present in scientific literature.

Background: The phenotypic presentation of multiple sclerosis (MS) may predict long-term outcomes and little is known about factors contributing to heterogeneity at MS onset. Given temporality, it is likely MS risk factors also influence presentation of the disease near onset., Methods: Using a retrospective cross-sectional study of MS cases, we investigated: age of onset (AOO), number of impaired functional domains (NIFDs), time to second relapse (TT2R), and early relapse activity (ERA). Machine learning variable selection was applied to epidemiologic data for each outcome, followed by multivariable regression models. The models were further adjusted for HLA-DRB1*15:01 carrier status and a MS genetic risk score (GRS). The TT2R and ERA analyses were restricted to relapsing remitting MS cases., Results: HLA-DRB1*15:01, GRS, and smoking were associated with earlier AOO. Cases who were male, obese, had lower education, or had primary progressive MS were older at onset. For NIFDs, those with relapsing remitting MS and of lower SES had increased NIFDs. Among relapsing remitting cases, those who were older at onset, obese, and had polyfocal presentation had shorter TT2R, while ERA was greater among those younger at onset and who were obese., Conclusion: Individual characteristics including age, genetic profiles, obesity, and smoking status contribute to heterogeneity in disease presentation and modulate early disease course evolution., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Human pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells, hold enormous promise for many biomedical applications, such as regenerative medicine, drug testing, and disease modeling. Although induced pluripotent stem cells resemble embryonic stem cells both morphologically and functionally, the extent to which these cell lines are truly equivalent, from a molecular point of view, remains controversial., Methods: Principal component analysis and K-means cluster analysis of collected Raman spectroscopy data were used for a comparative study of the biochemical fingerprint of human induced pluripotent stem cells and human embryonic stem cells. The Raman spectra analysis results were further validated by conventional biological assays., Results: Raman spectra analysis revealed that the major difference between human embryonic stem cells and induced pluripotent stem cells is due to the nucleic acid content, as shown by the strong positive peaks at 785, 1098, 1334, 1371, 1484, and 1575 cm -1 , which is enriched in human induced pluripotent stem cells., Conclusions: Here, we report a nonbiological approach to discriminate human induced pluripotent stem cells from their native embryonic stem cell counterparts.

Frameshift mutations in the TTN gene encoding titin are a major cause for inherited forms of dilated cardiomyopathy (DCM), a heart disease characterized by ventricular dilatation, systolic dysfunction, and progressive heart failure. To date, there are no specific treatment options for DCM patients but heart transplantation. Here, we show the beneficial potential of reframing titin transcripts by antisense oligonucleotide (AON)-mediated exon skipping in human and murine models of DCM carrying a previously identified autosomal-dominant frameshift mutation in titin exon 326. Correction of TTN reading frame in patient-specific cardiomyocytes derived from induced pluripotent stem cells rescued defective myofibril assembly and stability and normalized the sarcomeric protein expression. AON treatment in Ttn knock-in mice improved sarcomere formation and contractile performance in homozygous embryos and prevented the development of the DCM phenotype in heterozygous animals. These results demonstrate that disruption of the titin reading frame due to a truncating DCM mutation can be restored by exon skipping in both patient cardiomyocytes in vitro and mouse heart in vivo, indicating RNA-based strategies as a potential treatment option for DCM., (© 2015 The Authors. Published under the terms of the CC BY 4.0 license.)

Human induced pluripotent stem cells (hiPSCs) represent a versatile tool to model genetic diseases and are a potential source for cell transfusion therapies. However, it remains elusive to which extent patient-specific hiPSC-derived cells functionally resemble their native counterparts. Here, we generated a hiPSC model of the primary platelet disease Glanzmann thrombasthenia (GT), characterized by dysfunction of the integrin receptor GPIIbIIIa, and compared side-by-side healthy and diseased hiPSC-derived platelets with peripheral blood platelets. Both GT-hiPSC-derived platelets and their peripheral blood equivalents showed absence of membrane expression of GPIIbIIIa, a reduction of PAC-1 binding, surface spreading and adherence to fibrinogen. We demonstrated that GT-hiPSC-derived platelets recapitulate molecular and functional aspects of the disease and show comparable behavior to their native counterparts encouraging the further use of hiPSC-based disease models as well as the transition towards a clinical application.

Several mutations in distinct genes, all coding for sarcomeric proteins, have been reported in unrelated kindreds with familial hypertrophic cardiomyopathy (FHC). We have identified nine individuals from three families harboring two distinct mutations in one copy of the β-myosin heavy chain (β-MHC) gene. In this study, the expression of the mutant β-myosin protein isoform, isolated from slow-twitch fibers of skeletal muscle, was demonstrated by Northern and Western blot analysis; this myosin showed a decreased in vitro motility activity and produced a lower actin-activated ATPase activity. Isometric tension, measured in single slow-twitch fibers isolated from the affected individuals, also showed a significant decrease. The degree of impairment of β-myosin function, as well as the loss in isometric tension development, were strictly dependent on the amount of the isoform transcribed from the mutated allele. Interestingly, a strong correlation was also demonstrated between mutant β-myosin content and clinical features of FHC. On the other hand, we were unable to detect any correlation between mutant β-myosin expression and degree of cardiac hypertrophy, thereby strengthening the hypothesis that hypertrophy, one of the hallmarks of FHC, might not necessarily be related to the clinical evolution of this disease. These findings lend support to the notion that additional factors rather than the mutated gene may play a pathogenetic role in cardiac wall thickening, whereas the prognosis appears to be strongly related to the amount of mutant protein., (Copyright © 2012 Wiley Periodicals, Inc.)

We report an Italian family in which molecular genetic analysis showed expansion of CAG repeats indicative of the SCA2 genotype. This family confirms that ataxia, ophthalmoparesis and sensory peripheral neuropathy are the salient features of the SCA2 phenotype. In the present cases, early onset and mental deterioration were important additional findings. Nerve biopsy findings were compatible with a chronic axonopathy. We found a direct correlation between length of triplet expansion and severity of the clinical symptoms. Of particular interest is the late-onset phenotypical expression in a patient with 34 repeats.

We report neuropathological findings in a 22-year-old man affected with neuronal intranuclear inclusion disease. The inclusions affected to different extents the various structures of the central nervous system, being more numerous in cerebral cortex, inferior olives, hypoglossal and oculomotor nuclei. They ultrastructurally differed from Marinesco bodies. In the neurons of the substantia nigra, we occasionally observed intranuclear inclusions resembling the so-called rodlets of Roncoroni. We did not observe inclusions in the extraneuronal tissues. There was no apparent correlation between frequency of the inclusions and neuronal loss. Intranuclear inclusions were found in many morphologically normal neurons. We suggest that the intranuclear inclusions are the marker of a distinctive disorder, even though their role in neuronal degeneration remains to be clarified.

We describe two brothers with an autosomal recessive syndrome characterized by neonatal onset, severe impairment of cognitive and motor functions, abnormal ocular movements and slight dystonic postures. Brain MR and CT scan showed a reduction in size of the cerebellum and to a lesser extent pons, accompanied by cerebral and cerebellar white matter abnormalities. These data suggest that they have a particular phenotype of pontocerebellar hypoplasia. Extensive laboratory investigation excluded known metabolic causes of pontocerebellar hypoplasia. We discuss the nosological status of pontocerebellar hypoplasia in relation to other early-onset pontocerebellar disorders.

We report the case of a boy with neuronal intranuclear inclusion disease in whom the diagnosis was made by examination of a rectal biopsy specimen. Intranuclear inclusions were observed in the Auerbach and Meissner plexuses. In an attempt to understand the physiopathology of this very rare disease, we performed polymerase chain reaction (PCR) and reverse transcriptase-PCR analysis for viral nucleic acids of human immunodeficiency virus type 1 (HIV-1), HIV-2, human cytomegalovirus and measles virus. No viral nucleic acids were detected in the biopsy specimen.

We describe an Italian male patient, deceased at 29 years of age, affected with a syndrome characterized by childhood-onset seizures, mental disorders, motor dysfunction and bilateral palatal myoclonus. Skeletal X-ray examination showed diffuse osteopenia of the tubular bones, and cyst-like lesions in the carpal, metacarpal and tarsal bones bilaterally and in the proximal end of the right femur. Skin biopsy showed subcutaneous and adipose tissue containing membranocystic structures. Cerebral MR and CT scans showed fronto-temporal atrophy, altered signal of the white matter and mineralization of the caudate and dentate nuclei. These findings strongly recall polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, but in the present case, bone alterations were not prominent; moreover, palatal myoclonus has never previously been described in this syndrome.

Muscle biopsy was performed in two patients with Hallervorden-Spatz disease and increased serum creatine kinase levels. Morphological analysis showed myopathic signs such as subsarcolemmal accumulation of myeloid structures, dense bodies and debris, endomysial macrophage activation, focal necrosis and fiber splitting. We emphasize the finding of muscle involvement in Hallervorden-Spatz disease, like in other forms of neuroacanthocytosis.