A lineage tree-based hidden Markov model quantifies cellular heterogeneity and plasticity.

Individual cells can assume a variety of molecular and phenotypic states and recent studies indicate that cells can rapidly adapt in response to therapeutic stress. Such phenotypic plasticity may confer resistance, but also presents opportunities to identify molecular programs that could be targeted for therapeutic benefit. Approaches to quantify tumor-drug responses typically focus on snapshot, population-level measurements. While informative, these methods lack lineage and temporal information, which are particularly critical for understanding dynamic processes such as cell state switching. As new technologies have become available to measure lineage relationships, modeling approaches will be needed to identify the forms of cell-to-cell heterogeneity present in these data. Here we apply a lineage tree-based adaptation of a hidden Markov model that employs single cell lineages as input to learn the characteristic patterns of phenotypic heterogeneity and state transitions. In benchmarking studies, we demonstrated that the model successfully classifies cells within experimentally-tractable dataset sizes. As an application, we analyzed experimental measurements in cancer and non-cancer cell populations under various treatments. We find evidence of multiple phenotypically distinct states, with considerable heterogeneity and unique drug responses. In total, this framework allows for the flexible modeling of single cell heterogeneity across lineages to quantify, understand, and control cell state switching.

Multi-sensory feedback improves spatially compatible sensori-motor responses.

To interact with machines, from computers to cars, we need to monitor multiple sensory stimuli, and respond to them with specific motor actions. It has been shown that our ability to react to a sensory stimulus is dependent on both the stimulus modality, as well as the spatial compatibility of the stimulus and the required response. However, the compatibility effects have been examined for sensory modalities individually, and rarely for scenarios requiring individuals to choose from multiple actions. Here, we compared response time of participants when they had to choose one of several spatially distinct, but compatible, responses to visual, tactile or simultaneous visual and tactile stimuli. We observed that the presence of both tactile and visual stimuli consistently improved the response time relative to when either stimulus was presented alone. While we did not observe a difference in response times of visual and tactile stimuli, the spatial stimulus localization was observed to be faster for visual stimuli compared to tactile stimuli.

Interacting humans use forces in specific frequencies to exchange information by touch.

Object-mediated joint action is believed to be enabled by implicit information exchange between interacting individuals using subtle haptic signals within their interaction forces. The characteristics of these haptic signals have, however, remained unclear. Here we analyzed the interaction forces during an empirical dyadic interaction task using Granger-Geweke causality analysis, which allowed us to quantify the causal influence of each individual's forces on their partner's. We observed that the inter-partner influence was not the same at every frequency. Specifically, in the frequency band of [2.15-7] Hz, we observed inter-partner differences of causal influence that were invariant of the movement frequencies in the task and present only when information exchange was indispensable for task performance. Moreover, the inter-partner difference in this frequency band was observed to be correlated with the task performance by the dyad. Our results suggest that forces in the [2.15-7] Hz band constitute task related information exchange between individuals during physical interactions.

Tissue-specific and repeat length-dependent somatic instability of the X-linked dystonia parkinsonism-associated CCCTCT repeat.

X-linked dystonia-parkinsonism (XDP) is a progressive adult-onset neurodegenerative disorder caused by insertion of a SINE-VNTR-Alu (SVA) retrotransposon in the TAF1 gene. The SVA retrotransposon contains a CCCTCT hexameric repeat tract of variable length, whose length is inversely correlated with age at onset. This places XDP in a broader class of repeat expansion diseases, characterized by the instability of their causative repeat mutations. Here, we observe similar inverse correlations between CCCTCT repeat length with age at onset and age at death and no obvious correlation with disease duration. To gain insight into repeat instability in XDP we performed comprehensive quantitative analyses of somatic instability of the XDP CCCTCT repeat in blood and in seventeen brain regions from affected males. Our findings reveal repeat length-dependent and expansion-based instability of the XDP CCCTCT repeat, with greater levels of expansion in brain than in blood. The brain exhibits regional-specific patterns of instability that are broadly similar across individuals, with cerebellum exhibiting low instability and cortical regions exhibiting relatively high instability. The spectrum of somatic instability in the brain includes a high proportion of moderate repeat length changes of up to 5 repeats, as well as expansions of ~ 20- > 100 repeats and contractions of ~ 20-40 repeats at lower frequencies. Comparison with HTT CAG repeat instability in postmortem Huntington's disease brains reveals similar brain region-specific profiles, indicating common trans-acting factors that contribute to the instability of both repeats. Analyses in XDP brains of expansion of a different SVA-associated CCCTCT located in the LIPG gene, and not known to be disease-associated, reveals repeat length-dependent expansion at overall lower levels relative to the XDP CCCTCT repeat, suggesting that expansion propensity may be modified by local chromatin structure. Together, the data support a role for repeat length-dependent somatic expansion in the process(es) driving the onset of XDP and prompt further investigation into repeat dynamics and the relationship to disease.

Promise and challenges of dystonia brain banking: establishing a human tissue repository for studies of X-Linked Dystonia-Parkinsonism.

X-Linked Dystonia-Parkinsonism (XDP) is a neurodegenerative disease affecting individuals with ancestry to the island of Panay in the Philippines. In recent years there has been considerable progress at elucidating the genetic basis of XDP and candidate disease mechanisms in patient-derived cellular models, but the neural substrates that give rise to XDP in vivo are still poorly understood. Previous studies of limited XDP postmortem brain samples have reported a selective dropout of medium spiny neurons within the striatum, although neuroimaging of XDP patients has detected additional abnormalities in multiple brain regions beyond the basal ganglia. Given the need to fully define the CNS structures that are affected in this disease, we created a brain bank in Panay to serve as a tissue resource for detailed studies of XDP-related neuropathology. Here we describe this platform, from donor recruitment and consent to tissue collection, processing, and storage, that was assembled within a predominantly rural region of the Philippines with limited access to medical and laboratory facilities. Thirty-six brains from XDP individuals have been collected over an initial 4 years period. Tissue quality was assessed based on histologic staining of cortex, RNA integrity scores, detection of neuronal transcripts in situ by fluorescent hybridization chain reaction, and western blotting of neuronal and glial proteins. The results indicate that this pipeline preserves tissue integrity to an extent compatible with a range of morphologic, molecular, and biochemical analyses. Thus the algorithms that we developed for working in rural communities may serve as a guide for establishing similar brain banks for other rare diseases in indigenous populations.

Combined assessment of DYRK1A, BDNF and homocysteine levels as diagnostic marker for Alzheimer's disease.

Early identification of Alzheimer's disease (AD) risk factors would aid development of interventions to delay the onset of dementia, but current biomarkers are invasive and/or costly to assess. Validated plasma biomarkers would circumvent these challenges. We previously identified the kinase DYRK1A in plasma. To validate DYRK1A as a biomarker for AD diagnosis, we assessed the levels of DYRK1A and the related markers brain-derived neurotrophic factor (BDNF) and homocysteine in two unrelated AD patient cohorts with age-matched controls. Receiver-operating characteristic curves and logistic regression analyses showed that combined assessment of DYRK1A, BDNF and homocysteine has a sensitivity of 0.952, a specificity of 0.889 and an accuracy of 0.933 in testing for AD. The blood levels of these markers provide a diagnosis assessment profile. Combined assessment of these three markers outperforms most of the previous markers and could become a useful substitute to the current panel of AD biomarkers. These results associate a decreased level of DYRK1A with AD and challenge the use of DYRK1A inhibitors in peripheral tissues as treatment. These measures will be useful for diagnosis purposes.

To bridge or not to bridge the multisensory time gap: bimanual coordination to sound and touch with temporal lags.

Living in a complex and multisensory environment involves constant interaction between perception and action. There is evidence that multisensory integration is governed by temporal factors, such as physiological synchrony between cross-modal stimuli favouring multisensory benefit, and the existence of a range of asynchrony between the stimuli which affords their binding (the temporal window of integration). These factors were examined in this study in a bimanual sensorimotor synchronization task with cross-modal stimuli. Participants synchronized each hand to a pair of audio-tactile stimuli, in which the asynchrony between onsets of auditory and tactile stimuli was systematically manipulated. In cross-modal conditions, they were instructed to tap either to the auditory stimuli or to tactile stimuli. The results reported a temporal window of integration of 160 ms centred around 40 and 80 ms (tactile first). Moreover, the temporal interval between the auditory and tactile stimuli affected the stability of bimanual coordination and of synchronization exclusively when participants were instructed to synchronize with tactile stimuli. Overall, the results indicate that both physiological asynchrony and temporal window of integration apply to cross-modal integration in a bimanual synchronization task. In addition, it shows the effect of auditory dominance onto multisensory temporal processes. This study sheds light on the role of temporal factors in multisensory processes when perception and actions are rhythmic and coupled.

[Reconciliating neurology and psychiatry: The prototypical case of frontotemporal dementia]. / Rapprochement entre neurologie et psychiatrie : le cas prototypique de la dégénérescence frontotemporale.

Frontotemporal degeneration (FTD) in its behavioral variant (bvFTD) is probably one of the conditions that best illustrates the links between psychiatry and neurology. It is indeed admitted that between a third and half of patients with this condition, especially in early-onset forms, receive an initial diagnosis of psychiatric disorder (depression, schizophrenia, bipolar disorder) and are then referred to a psychiatric ward. BvFTD can thus be considered a neurological disorder with a psychiatric presentation. Among psychiatric symptoms reported in this disease, psychotic symptoms (hallucinations, delusions, especially of persecution), which have long been underestimated in bvFTD and are not part of the current diagnostic criteria, are present in about 20% of cases and may be inaugural. They are particularly common in the genetic forms related to a mutation in the C9orf72 gene (up to 50%), and to a lesser extent in the GRN gene (up to 25%). C9orf72 gene mutation is often associated with a family history of dementia or motor neuron disease but also of psychiatric disorders. It has also been described in sporadic presentation forms. Sometimes, the moderate degree of brain atrophy on MRI described in patients carrying this mutation may complicate the differential diagnosis with late-onset psychiatric diseases. In the present article, we underline the importance of considering that psychiatric - especially psychotic - symptoms are not rare in bvFTD, which should lead to a revision of the diagnostic criteria of this disease by taking greater account of this fact. We also propose a diagnostic chart, based on concerted evaluation by neurologists and psychiatrists for cases of atypical psychiatric symptoms (late-onset or pharmacoresistant troubles) leading to consider the possibility of a neurological disorder, in order to shed a new light on these difficult clinical situations. In the field of research, bvFTD may constitute a model to explore the neural basis of certain psychiatric disorders, and a possible molecular link between bvFTD and psychoses, which could eventually lead to new therapeutic approaches, has been recently suggested. Thus, bvFTD illustrates how the links between neurology and psychiatry are close and tend to evolve with the progress of scientific knowledge. It is necessary to strengthen collaboration between the two disciplines both to improve the care - diagnosis and management of these patients - and to promote the emergence of innovative clinical research.

Modifications of the endosomal compartment in peripheral blood mononuclear cells and fibroblasts from Alzheimer's disease patients.

Identification of blood-based biomarkers of Alzheimer's disease (AD) remains a challenge. Neuropathological studies have identified enlarged endosomes in post-mortem brains as the earliest cellular change associated to AD. Here the presence of enlarged endosomes was investigated in peripheral blood mononuclear cells from 48 biologically defined AD patients (25 with mild cognitive impairment and 23 with dementia (AD-D)), and 23 age-matched healthy controls using immunocytochemistry and confocal microscopy. The volume and number of endosomes were not significantly different between AD and controls. However, the percentage of cells containing enlarged endosomes was significantly higher in the AD-D group as compared with controls. Furthermore, endosomal volumes significantly correlated to [C(11)]PiB cortical index measured by positron emission tomography in the AD group, independently of the APOE genotype, but not to the levels of amyloid-beta, tau and phosphorylated tau measured in the cerebrospinal fluid. Importantly, we confirmed the presence of enlarged endosomes in fibroblasts from six unrelated AD-D patients as compared with five cognitively normal controls. This study is the first, to our knowledge, to report morphological alterations of the endosomal compartment in peripheral cells from AD patients correlated to amyloid load that will now be evaluated as a possible biomarker.

Plasma DYRK1A as a novel risk factor for Alzheimer's disease.

To determine whether apparent involvement of DYRK1A in Alzheimer's disease (AD) pathology makes it a candidate plasma biomarker for diagnosis, we developed a method to quantify plasma DYRK1A by immunoblot in transgenic mouse models having different gene dosages of Dyrk1a, and, consequently, different relative protein expression. Then, we measured plasma DYRK1A levels in 26 patients with biologically confirmed AD and 25 controls (negative amyloid imaging available on 13). DYRK1A was detected in transgenic mouse brain and plasma samples, and relative levels of DYRK1A correlated with the gene copy number. In plasma from AD patients, DYRK1A levels were significantly lower compared with controls (P<0.0001). Results were similar when we compared AD patients with the subgroup of controls confirmed by negative amyloid imaging. In a subgroup of patients with early AD (CDR=0.5), lower DYRK1A expression was confirmed. In contrast, no difference was found in levels of DYRK1B, the closest relative of DYRK1A, between AD patients and controls. Further, AD patients exhibited a positive correlation between plasma DYRK1A levels and cerebrospinal fluid tau and phosphorylated-tau proteins, but no correlation with amyloid-ß42 levels and Pittsburgh compound B cortical binding. DYRK1A levels detected in lymphoblastoid cell lines from AD patients were also lower when compared with cells from age-matched controls. These findings suggest that reduced DYRK1A expression might be a novel plasma risk factor for AD.

High-frequency ultrasonography but not 930-nm optical coherence tomography reliably evaluates melanoma thickness in vivo: a prospective validation study.

BACKGROUND: Early diagnosis and rapid surgical excision are essential for improving the prognosis of patients with melanoma. Reflectance confocal microscopy has been validated as a feasible procedure for in vivo diagnosis of melanoma but cannot be used to measure tumour thickness. However, ultrasonography and optical coherence tomography may allow melanoma thickness to be measured in vivo. OBJECTIVES: To validate the accuracy and reliability of high-frequency ultrasonography (HFUS) and optical coherence tomography for assessing melanoma thickness in vivo. METHODS: We conducted a prospective study on 131 patients with at least one equivocal melanocytic lesion. Each lesion underwent optical coherence tomography and HFUS assessment, followed by excision and pathological examination. Histopathology was considered to be the gold standard for assessing melanoma thickness. Repeatability, inter- and intrarater reproducibility and reliability were evaluated for each imaging procedure. RESULTS: Ultrasonography showed a good level of agreement with histology [intraclass correlation coefficient (ICC) 0.807; 95% confidence interval (CI) 0.703-0.877] and excellent inter-rater reproducibility (G = 0.97), resulting in reliable in vivo assessment of melanoma thickness. The 930-nm optical coherence tomography showed a poor level of agreement with histopathology (ICC 0.0; 95% CI -0.2-0.2) and the inter-rater reproducibility was null (G = 0.00). CONCLUSIONS: HFUS is a reliable and reproducible noninvasive method for assessing melanoma thickness. Routine use of HFUS may allow single-step excision of equivocal melanocytic lesions, with surgical margins determined by in vivo assessment of tumour thickness.

Dual-parameter optimisation of the elastic properties of skin.

This paper presents a procedure for characterising the mechanical properties of skin using stochastic inverse identification. It is based on the minimisation of a cost function relative to the comparison between experimental suction experiments and their corresponding finite element models. Two different models are compared: a classical single-layer approach and a dual-layer medium which account for both the dermis and the hypodermis. Finite element results are used to construct the pre-optimisation database which is required for the inverse analysis. To compare the calculations, the entire identification is based on a dual-parameter optimisation procedure: for the single-layer approach a quadratic hyperelastic constitutive equation is used, whereas for the dual-layer medium a simple neo-Hookean potential is used. Theoretical conclusions, which are developed first, are then compared with actual case studies.

A European multicentre reappraisal of distal compound muscle action potential duration in chronic inflammatory demyelinating polyneuropathy.

BACKGROUND: The electrodiagnostic value of distal compound muscle action potential duration (DCMAPD) has been studied rarely in chronic inflammatory demyelinating polyneuropathy (CIDP). Cut-offs proposed have not been widely evaluated. The influence of low-cut EMG filter settings ≤ 10 Hz as used in Europe is uncertain. METHODS: We retrospectively reviewed records of 110 patients with typical, treatment-responsive CIDP, from Leicester, U.K., Paris and Angers, France. All fulfilled revised European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) clinical and electrodiagnostic criteria for typical CIDP (2010), before consideration of DCMAPD prolongation. Results were compared with those of 110 controls with chronic sensory/sensory-motor axonal neuropathy. We constructed receiver operating characteristic (ROC) curves for each nerve and derived cut-offs for DCMAPD prolongation, offering specificity of ≥ 98% vs. controls. RESULTS: DCMAPD was significantly greater in all nerves for CIDP patients, compared with controls (P < 0.001). ROC curves allowed derivation of cut-offs of sensitivities ranging from 27.1% (ulnar nerve) to 60% (tibial nerve). Using these cut-offs to define DCMAPD prolongation in any studied motor nerve offered a sensitivity of 69.1% for CIDP and specificity of 97.3% vs. controls. CONCLUSION: Cut-offs for DCMAPD are dependent on EMG filter settings. DCMAPD prolongation in any motor nerve, using our derived cut-offs, represents a sensitive and specific marker of CIDP in patients studied with EMG equipment with low-cut filter settings ≤ 10 Hz. Appropriate use of this parameter appears an essential criterion to consider in assessing suspected CIDP, which may be helpful in limiting extensiveness and duration of electrophysiological testing, thereby reducing patient discomfort.

[Petrous plasmacytoma revealed by a painful peripheral facial palsy]. / Plasmocytome du rocher révélé par une paralysie faciale périphérique douloureuse.

INTRODUCTION: The classical hypothesis of Bell's palsy, tempting in cases of peripheral facial palsy of rapid onset, must nevertheless be evoked with caution particularly if an intense pain is present, which should lead to search for a tumor of the skull base, especially the petrous bone. CASE REPORT: A 43-year-old man presented a peripheral facial palsy of rapidly progressive onset. A petrous bone tumor was diagnosed on the CT scan, which revealed an aspect of a glomic tumor or a metastatic lesion. The final histological diagnosis was plasmacytoma. DISCUSSION: This type of tumor has been rarely reported in this location. The radiological features are not specific at all, underlying the importance of searching for some associated signs such as a monoclonal protein and performing a histological examination when the firm diagnosis of a systemic disease like multiple myeloma has not been possible.

Neuropsychological disorders induced by cerebellar damage.

INTRODUCTION: Motor coordination disorders caused by cerebellar dysfunction are well known. However, the less known cerebellar neuropsychological disorders also merit attention, since they occur more frequently than one might imagine. CASE REPORT: We describe a 66-year-old patient with severe cerebellar damage caused by hemorrhagic stroke and associated with cognitive impairments (including impaired executive function, reasoning and judgment). A review of the literature on these neuropsychological disorders revealed a set of clinical, anatomical and functional imaging arguments that prompted us to broaden our vision of the cerebellum's role by acknowledging the presence of a cognitive component as well as the well-known motility component. In fact, there is good evidence of altered executive function (including mental flexibility, scheduling capacities and verbal working memory) in cerebellar patients. Visuospatial capacities are also affected, with disorders of visual memory and construction abilities having been reported. In terms of language, we noted reports of hypospontaneity and agrammatism with syntax problems. Memory (especially verbal memory), learning (both associative and procedural), judgment and reasoning also seem to be affected. In terms of emotion, various types of abnormal behavior and psychiatric disorders have been described and range from depression to true psychoses. Even though these data are controversial and must be confirmed, they prompt us to reconsider and deepen our understanding of the cerebellum's role and the functioning and improve our approach to (and management of) patients with cerebellar damage.

Mutations of the noggin (NOG) and of the activin A type I receptor (ACVR1) genes in a series of twenty-seven French fibrodysplasia ossificans progressiva (FOP) patients.

Fibrodysplasia ossificans progressiva (FOP) is a rare but very severe disease, characterised by congenital malformations of the toes and by progressive heterotopic ossification of muscles and joints. Two genes, the noggin (NOG) gene and the activin A type I receptor (ACVRI) gene, are involved in FOP. In this study we have searched for the NOG and the 617G>A (ACVR1) mutations in a well characterized series of twenty-seven French FOP patients. Five NOG mutations (delta 42, 274G>C, 275G>A, 276G>A, and 283G>A) have been found in seven (26%) of our FOP patients. The 617G>A mutation in the ACVR1 gene is found in fourteen (52%) of the patients. With one exception (patient number 22), 617G>A and NOG mutations are mutually exclusive in patients. Mutations 274G>C, 283G>A and 617G>A segregate with the trait in five different FOP families, some members of them being partially affected by the disease.

Human immunodeficiency virus atropy induces modification of subcutaneous adipose tissue architecture: in vivo visualization by high-resolution magnetic resonance imaging.

BACKGROUND: Human immunodeficiency virus (HIV) infection generally induces lipodystrophy. For targeted treatment a better understanding of its development is necessary. The utility of high-resolution magnetic resonance imaging (MRI) is explored. OBJECTIVES: The present study presents a way to visualize the adipose tissue architecture in vivo and to inspect modifications associated with the atrophy. METHODS: High-resolution MRI scans with surface coils were performed on the calf and at the lumbar region of three groups of patients: HIV patients with lipoatrophy, HIV patients without lipoatrophy and healthy volunteers. All patients underwent a clinical examination. In addition, dual energy X-ray absorptiometry (DEXA) measurements were taken. On the MRI scans adipose tissue thickness and adipose nodule size were measured. Results High-resolution MRI enabled identification of a clear disorganization of adipose tissue in patients with lipoatrophy. In addition, these patients presented a very small adipose tissue thickness on the calf and a very small nodule size. RESULTS: led to the hypothesis that adipose tissue disorganization appears before changes in DEXA measurements or clinically visible modifications. CONCLUSIONS: High-resolution MRI enabled visualization in vivo of precise changes in tissue organization due to HIV lipoatrophy. This imaging technique should be very informative for better monitoring of the atrophy.