Chronic pain, psychological distress, and quality of life in males with Duchenne muscular dystrophy.

AIM: To describe chronic pain in Duchenne muscular dystrophy (DMD) from children's/adolescents' perspectives, explore patient variables associated with self-reported pain, and examine the relationship between chronic pain, psychological functioning, and health-related quality of life (HRQoL). METHOD: This observational study included a paediatric cohort (aged 8-18 years; median age 9 years 4 months) with DMD under multidisciplinary care (n = 45). Clinical data of the latest visit were extracted from the electronic health record and assessment of pain, psychological distress, and HRQoL were performed during the same visit. RESULTS: Thirty-two patients reported pain during the previous 4 weeks, and 18 reported persistent or recurrent chronic pain. Average pain intensity of chronic pain was mild, with regions of the legs (n = 12), lower back (n = 6), hips (n = 6), and shoulder (n = 6) most frequently affected. Older age, higher body mass index, being non-ambulatory, wheelchair dependency, and spinal deformities were contextual variables related to the presence of chronic pain. Furthermore, chronic pain was significantly associated with psychological distress and reduced HRQoL in paediatric patients with DMD. INTERPRETATION: Chronic pain in paediatric DMD is frequent and widespread, highlighting the need for pain to be addressed in the routine care of affected young people. Chronic pain may make a significant contribution to psychological distress and impaired HRQoL in paediatric patients with DMD. WHAT THIS PAPER ADDS: Chronic pain differs in aetiology, scope, and nature compared with acute pain in paediatric Duchenne muscular dystrophy (DMD). Older age, higher body mass index, being non-ambulatory, wheelchair dependency, and spinal deformities are important patient variables. Chronic pain is significantly associated with psychological distress and reduced health-related quality of life in paediatric DMD.

Rasch analysis of the 32-item motor function measure in ambulant patients with Duchenne muscular dystrophy.

OBJECTIVE: This study analyzed the 32-item Motor Function Measure in a cohort of ambulatory patients with Duchenne muscular dystrophy using Rasch measurement methods. DESIGN: This is a psychometric study. SETTING: Rehabilitation centre of a large public children's hospital in Shenzhen, China. PARTICIPANTS: Data from 176 genetically confirmed ambulant patients with Duchenne muscular dystrophy (mean age 7.3 years, SD 2.3 years, range 3.1-13.1 years) were analyzed. RESULTS: Rasch analyses supported the Motor Function Measure domain D1 as a reliable (person reliability = 0.88, person separation index = 2.71) and valid (acceptable targeting, little misfit, minimal category disordering) measure in ambulant patients with Duchenne muscular dystrophy. Remodelling the domain D1 by collapsing item 25 from 4 to 3 response categories addressed the problematic disordered thresholds, resulting in a rebuilt domain D1 with enhanced measurement properties. However, findings for domains D2 and D3 did not fulfil most Rasch model expectations. There were disordered thresholds for most items in domains D2 and D3, with low reliability coefficients, item mistargeting and misfit, and large ceiling effects. CONCLUSION: Rasch analyses confirmed that the Motor Function Measure domain D1 was reliable and valid and provided a unidimensional measure for motor function in ambulant Duchenne muscular dystrophy patients. Accuracy of measurement had been enhanced through remodelling, and a rebuilt domain D1 with category collapsing for item 25 was proposed. The analysis revealed multiple limitations of the domains D2 and D3 that certain essential psychometrics were poorly met and, therefore, should be used with caution in this patient group.

A novel method to identify gene interaction patterns.

BACKGROUND: Gene interaction patterns, including modules and motifs, can be used to identify cancer specific biomarkers and to reveal the mechanism of tumorigenesis. Most of the existing module network inferencing methods focus on gene independent functional patterns, while the studies of overlapping characteristics between modules are lacking. The objective of this study was to reveal the functional overlapping patterns in gene modules, helping elucidate the regulatory relationship between overlapping genes and communities, as well as to explore cancer formation and progression. RESULTS: We analyzed six cancer datasets from The Cancer Genome Atlas and obtained three kinds of gene functional modules for each cancer, including Independent-Community, Dependent-Community and Merged-Community. In the six cancers, 59(3.5%) Independent-Communities were identified, while 1631(96.5%) Dependent-Communities were acquired. Compared with Lemon-Tree and K-Means, the gene communities identified by our method were enriched in more known GO categories with lower p-values. Meanwhile, those identified distinguishing communities can significantly distinguish the survival prognostic of patients by Kaplan-Meier analysis. Furthermore, identified driver genes in the gene communities can be considered as biomarkers which can accurately distinguish the tumour or normal samples for each cancer type. CONCLUSIONS: In all identified communities, Dependent-Communities are the majority. Our method is more effective than the other two methods which do not consider the overlapping characteristics of modules. This indicates that overlapping genes are located in different specific functional groups, and a communication bridge is established between the communities to construct a comprehensive carcinogenesis.

c.3G>A mutation in the CRYAB gene that causes fatal infantile hypertonic myofibrillar myopathy in the Chinese population.

Infantile hypertonic myofibrillar myopathy is characterized by the rapid development of rigid muscles and respiratory insufficiency soon after birth, with very high mortality. It is extremely rare, and only a few cases having been reported until now. Here we report four Chinese infants with fatal neuromuscular disorders characterized by abdominal and trunk skeletal muscle stiffness and rapid respiratory insufficiency progression. Electromyograms showed increased insertion activities and profuse fibrillation potentials with complex repetitive discharges. Immunohistochemistry staining of muscle biopsies showed accumulations of desmin in the myocytes. Powdery Z-bands with dense granules across sarcomeres were observed in muscle fibers using electron microscopy. All patients carry a homozygous c.3G>A mutation in the CRYAB gene, which resulted in the loss of the initiating methionine and the absence of protein. This study's findings help further understand the disease and highlight a founder mutation in the Chinese population.

[Clinical features of sleep-disordered breathing in children with neuromuscular disease].

OBJECTIVE: To study the clinical features of sleep-disordered breathing (SDB) in children with neuromuscular disease (NMD). METHODS: A retrospective analysis was performed on the medical data of 18 children who were diagnosed with NMD and underwent polysomnography (PSG) (NMD group). Eleven children without NMD who had abnormal sleeping habit and normal sleep structure on PSG were enrolled as the control group. The two groups were compared in terms of the daily and nocturnal symptoms of SDB, incidence rate of obstructive sleep apnea (OSA), pulmonary function, end-tidal partial pressure of carbon dioxide (PetCO2), features of sleep structure, and sleep respiratory events. RESULTS: In the NMD group, 16 children (89%) had related daily and nocturnal symptoms of SDB, and the youngest age was 1 year at the onset of such symptoms. Compared with the control group, the NMD group had significant reductions in total sleep time and sleep efficiency (P < 0.05), a significant reduction in the proportion of rapid eye movement (REM) sleep (P < 0.05), significant increases in obstructive apnea and hypopnea events (P < 0.05) and oxygen reduction events during REM sleep (P < 0.05), and a significant reduction in blood oxygen saturation during REM sleep (P < 0.05). In the NMD group, 17 children (94%) were diagnosed with OSA, and all children had normal lung function and PetCO2. CONCLUSIONS: There is a high proportion of children with SDB among the children with NMD, and SDB can be observed in the early stage of NMD, which results in the damage of sleep structure and the reduction in sleep efficiency. Respiratory events are mainly obstructive events, and oxygen reduction events are mainly observed during REM sleep.

DMCM: a Data-adaptive Mutation Clustering Method to identify cancer-related mutation clusters.

Motivation: Functional somatic mutations within coding amino acid sequences confer growth advantage in pathogenic process. Most existing methods for identifying cancer-related mutations focus on the single amino acid or the entire gene level. However, gain-of-function mutations often cluster in specific protein regions instead of existing independently in the amino acid sequences. Some approaches for identifying mutation clusters with mutation density on amino acid chain have been proposed recently. But their performance in identification of mutation clusters remains to be improved. Results: Here we present a Data-adaptive Mutation Clustering Method (DMCM), in which kernel density estimate (KDE) with a data-adaptive bandwidth is applied to estimate the mutation density, to find variable clusters with different lengths on amino acid sequences. We apply this approach in the mutation data of 571 genes in over twenty cancer types from The Cancer Genome Atlas (TCGA). We compare the DMCM with M2C, OncodriveCLUST and Pfam Domain and find that DMCM tends to identify more significant clusters. The cross-validation analysis shows DMCM is robust and cluster cancer type enrichment analysis shows that specific cancer types are enriched for specific mutation clusters. Availability and implementation: DMCM is written in Python and analysis methods of DMCM are written in R. They are all released online, available through https://github.com/XinguoLu/DMCM. Supplementary information: Supplementary data are available at Bioinformatics online.

The Integrative Method Based on the Module-Network for Identifying Driver Genes in Cancer Subtypes.

With advances in next-generation sequencing(NGS) technologies, a large number of multiple types of high-throughput genomics data are available. A great challenge in exploring cancer progression is to identify the driver genes from the variant genes by analyzing and integrating multi-types genomics data. Breast cancer is known as a heterogeneous disease. The identification of subtype-specific driver genes is critical to guide the diagnosis, assessment of prognosis and treatment of breast cancer. We developed an integrated frame based on gene expression profiles and copy number variation (CNV) data to identify breast cancer subtype-specific driver genes. In this frame, we employed statistical machine-learning method to select gene subsets and utilized an module-network analysis method to identify potential candidate driver genes. The final subtype-specific driver genes were acquired by paired-wise comparison in subtypes. To validate specificity of the driver genes, the gene expression data of these genes were applied to classify the patient samples with 10-fold cross validation and the enrichment analysis were also conducted on the identified driver genes. The experimental results show that the proposed integrative method can identify the potential driver genes and the classifier with these genes acquired better performance than with genes identified by other methods.

A co-expression modules based gene selection for cancer recognition.

Gene expression profiles are used to recognize patient samples for cancer diagnosis and therapy. Gene selection is crucial to high recognition performance. In usual gene selection methods the genes are considered as independent individuals and the correlation among genes is not used efficiently. In this description, a co-expression modules based gene selection method for cancer recognition is proposed. First, in the cancer dataset a weighted correlation network is constructed according to the correlation between each pair of genes, different modules from this network are identified and the significant modules are selected for following exploration. Second, based on these informative modules information gain is applied to selecting the feature genes for cancer recognition. Then using LOOCV, the experiments with different classification algorithms are conducted and the results show that the proposed method makes better classification accuracy than traditional gene selection methods. At last, via gene ontology enrichment analysis the biological significance of the co-expressed genes in specific modules was verified.

δ-containing GABA A receptors on parvalbumin interneurons modulate neuronal excitability and network dynamics in the mouse medial prefrontal cortex.

In medial prefrontal cortex (mPFC), fast-spiking parvalbumin (PV) interneurons regulate excitability and microcircuit oscillatory activity important for cognition. Although PV interneurons inhibit pyramidal neurons, they themselves express δ subunits of GABAA receptors important for slow inhibition. However, the specific contribution of δ-containing GABAA receptors to the function of PV interneurons in mPFC is unclear. We explored cellular, synaptic, and local-circuit activity in PV interneurons and pyramidal neurons in mouse mPFC after selectively deleting δ subunits in PV interneurons (cKO mice). In current-clamp recordings, cKO PV interneurons exhibited a higher frequency of action potentials and higher input resistance than wild type (WT) PV interneurons. Picrotoxin increased firing and GABA decreased firing in WT PV interneurons but not in cKO PV interneurons. The δ-preferring agonist THIP reduced spontaneous inhibitory postsynaptic currents in WT pyramidal neurons but not in cKO pyramidal neurons. In WT slices, depolarizing the network with 400 nM kainate increased firing of pyramidal neurons but had little effect on PV interneuron firing. By contrast, in cKO slices kainate recruited PV interneurons at the expense of pyramidal neurons. At the population level, kainate induced broadband increases in local field potentials in WT but not cKO slices. These results on cells and the network can be understood through increased excitability of cKO PV interneurons. In summary, our study demonstrates that δ-containing GABAA receptors in mPFC PV interneurons play a crucial role in regulating their excitability and the phasic inhibition of pyramidal neurons, elucidating intricate mechanisms governing cortical circuitry. Significance statement: By selectively deleting δ-containing GABAA receptors in PV interneurons, we demonstrate the importance of these receptors on PV interneuron excitability, synaptic inhibition of pyramidal neurons, and circuit function.

A role for δ subunit-containing GABA A receptors on parvalbumin positive neurons in maintaining electrocortical signatures of sleep states.

GABA A receptors containing δ subunits have been shown to mediate tonic/slow inhibition in the CNS. These receptors are typically found extrasynaptically and are activated by relatively low levels of ambient GABA in the extracellular space. In the mouse neocortex, δ subunits are expressed on the surface of some pyramidal cells as well as on parvalbumin positive (PV+) interneurons. An important function of PV+ interneurons is the organization of coordinated network activity that can be measured by EEG; however, it remains unclear what role tonic/slow inhibitory control of PV+ neurons may play in shaping oscillatory activity. After confirming a loss of functional δ mediated tonic currents in PV cells in cortical slices from mice lacking Gabrd in PV+ neurons (PV δcKO), we performed EEG recordings to survey network activity across wake and sleep states. PV δcKO mice showed altered spectral content of EEG during NREM and REM sleep that was a result of increased oscillatory activity in NREM and the emergence of transient high amplitude bursts of theta frequency activity during REM. Viral reintroduction of Gabrd to PV+ interneurons in PV δcKO mice rescued REM EEG phenotypes, supporting an important role for δ subunit mediated inhibition of PV+ interneurons for maintaining normal REM cortical oscillations. Significance statement: The impact on cortical EEG of inhibition on PV+ neurons was studied by deleting a GABA A receptor subunit selectively from these neurons. We discovered unexpected changes at low frequencies during sleep that were rescued by viral reintroduction.

NEXMIF variants are associated with epilepsy with or without intellectual disability.

OBJECTIVES: Variants in NEXMIF had been reported associated with intellectual disability (ID) without epilepsy or developmental epileptic encephalopathy (DEE). It is unkown whether NEXMIF variants are associated with epilepsy without ID. This study aims to explore the phenotypic spectrum of NEXMIF and the genotype-phenotype correlations. MATERIALS AND METHODS: Trio-based whole-exome sequencing was performed in patients with epilepsy. Previously reported NEXMIF variants were systematically reviewed to analyze the genotype-phenotype correlations. RESULTS: Six variants were identified in seven unrelated cases with epilepsy, including two de novo null variants and four hemizygous missense variants. The two de novo variants were absent in all populations of gnomAD and four hemizygous missense variants were absent in male controls of gnomAD. The two patients with de novo null variants exhibited severe developmental epileptic encephalopathy. While, the patients with hemizygous missense variants had mild focal epilepsy with favorable outcome. Analysis of previously reported cases revealed that males with missense variants presented significantly higher percentage of normal intellectual development and later onset age of seizure than those with null variants, indicating a genotype-phenotype correlation. CONCLUSION: This study suggested that NEXMIF variants were potentially associated with pure epilepsy with or without intellectual disability. The spectrum of epileptic phenotypes ranged from the mild epilepsy to severe developmental epileptic encephalopathy, where the epileptic phenotypes variability are potentially associated with patients' gender and variant type.

Association of FAT1 with focal epilepsy and correlation between seizure relapse and gene expression stage.

PURPOSE: The FAT1 gene encodes FAT atypical cadherin 1, which is essential for foetal development, including brain development. This study aimed to investigate the relationship between FAT1 variants and epilepsy. METHODS: Trio-based whole-exome sequencing was performed on a cohort of 313 patients with epilepsy. Additional cases with FAT1 variants were collected from the China Epilepsy Gene V.1.0 Matching Platform. RESULTS: Four pairs of compound heterozygous missense FAT1 variants were identified in four unrelated patients with partial (focal) epilepsy and/or febrile seizures, but without intellectual disability/developmental abnormalities. These variants presented no/very low frequencies in the gnomAD database, and the aggregate frequencies in this cohort were significantly higher than those in controls. Two additional compound heterozygous missense variants were identified in two unrelated cases using the gene-matching platform. All patients experienced infrequent (yearly/monthly) complex partial seizures or secondary generalised tonic-clonic seizures. They responded well toantiseizure medication, but seizures relapsed in three cases when antiseizure medication were decreased or withdrawn after being seizure-free for three to six years, which correlated with the expression stage of FAT1. Genotype-phenotype analysis showed that epilepsy-associated FAT1 variants were missense, whereas non-epilepsy-associated variants were mainly truncated. The relationship between FAT1 and epilepsy was evaluated to be "Strong" by the Clinical Validity Framework of ClinGen. CONCLUSIONS: FAT1 is a potential causative gene of partial epilepsy and febrile seizures. Gene expression stage was suggested to be one of the considerations in determining the duration ofantiseizure medication. Genotype-phenotype correlation helps to explain the mechanisms underlying phenotypic variation.

A Post-Marketing Surveillance Study of Nusinersen for Spinal Muscular Atrophy in Routine Medical Practice in China: Interim Results.

INTRODUCTION: Spinal muscular atrophy (SMA) is a rare, autosomal recessive, neuromuscular disease that leads to progressive muscular weakness and atrophy. Nusinersen, an antisense oligonucleotide, was approved for SMA in China in February 2019. We report interim results from a post-marketing surveillance phase 4 study, PANDA (NCT04419233), that collects data on the safety, efficacy, and pharmacokinetics of nusinersen in children with SMA in routine clinical practice in China. METHODS: Participants enrolled in PANDA will be observed for 2 years following nusinersen treatment initiation. The primary endpoint is the incidence of adverse events (AEs)/serious AEs (SAEs) during the treatment period. Efficacy assessments include World Health Organization (WHO) Motor Milestones assessment, the Hammersmith Infant Neurological Examination (HINE), and ventilation support. Plasma and cerebrospinal fluid (CSF) concentrations of nusinersen are measured at each dose visit. RESULTS: Fifty participants were enrolled as of the January 4, 2023, data cutoff: 10 with infantile-onset (≤ 6 months) and 40 with later-onset (> 6 months) SMA. All 50 participants have received at least one dose of nusinersen; 6 have completed the study. AEs were experienced by 45 (90%) participants and were mostly mild/moderate; no AEs led to nusinersen discontinuation or study withdrawal. Eleven participants experienced SAEs, most commonly pneumonia (n = 9); none were considered related to study treatment. Stability or gain of WHO motor milestone was observed and mean HINE-2 scores improved in both subgroups throughout the study. No serious respiratory events occurred, and no permanent ventilation support was initiated during the study. Pre-dose nusinersen CSF concentrations increased steadily through the loading-dose period, with no accumulation in plasma after multiple doses. CONCLUSION: Nusinersen was generally well tolerated with an acceptable overall safety profile, consistent with the known safety of nusinersen. Efficacy, safety, and nusinersen exposure are consistent with prior observations. These results support continuing PANDA and evaluation of nusinersen in Chinese participants with SMA. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04419233.

Efficacy and safety of perampanel as the first add-on therapy for children with epilepsy: A real-world multicenter prospective observational study.

OBJECTIVE: Perampanel (PER) is a new anti-seizure medication (ASM) with a novel mechanism of action. This study aimed to determine the efficacy and safety of PER when added to monotherapy in children and adolescents (age, 4-18 years) with epilepsy. METHOD: A multicenter prospective observational study was performed on children and adolescents (age, 4-18 years) with epilepsy who did not respond to ASM monotherapy between July 2021 and October 2022. PER was used as the first add-on therapy for the enrolled patients. Seizure-free rate, response rate, inefficacy rate, and drug retention rate were the main observation indicators during the 6 months of treatment. The patients were grouped based on treatment efficacy, and factors affecting efficacy were statistically analyzed. Adverse reactions were also recorded. RESULTS: In this study, 93 patients with epilepsy were enrolled; among them, 9 patients were lost to follow-up (attrition rate, 9.7 %), and 84 were included in the analysis. Five patients with unknown efficacy discontinued taking PER early due to intolerable adverse reactions, and 79 patients (48 males, 31 females; mean age, 11.0 ± 3.9 years) finally remained. Genetic epilepsy and structural epilepsy were found in 22 patients and 36 patients, respectively. The mean duration of epilepsy history at the time of PER initiation was 4.0 ± 3.8 years, and the mean maintenance dosage of add-on PER was 4.5 ± 1.8 mg/day (equivalent to 0.14 ± 0.07 mg/kg/day). Among the 79 patients, 28 patients were diagnosed with epilepsy syndrome, including 13 patients having self-limited epilepsy with centrotemporal spikes, among whom 9 patients were seizure-free after adding PER during the 6-month follow-up (seizure-free rate, 69.2 %). For these 79 patients, the seizure-free, response, and retention rates at the end of follow-up were 45.6 %, 74.7 %, and 82.1 %, respectively. Among the 84 patients included in the analyses, adverse reactions occurred in 20 patients, mainly dizziness (8 patients), somnolence (6 patients), and irritability (4 patients), and 4 patients developed two adverse reactions simultaneously. Univariate analyses revealed statistically significant differences in efficacy between groups with structural and non-structural epilepsy and between groups with different baseline concomitant ASMs, suggesting that these factors affected the efficacy of PER as the first add-on therapy. CONCLUSION: The overall response rate of PER as the first add-on therapy for children and adolescents with epilepsy who were followed up for 6 months was 74.7 %, indicating a relatively favorable safety and tolerability profile. The group of the baseline concomitant ASM administered and the etiological classification of epilepsy as either structural or non-structural were the factors influencing the efficacy of PER as the first add-on therapy.

Nusinersen effectiveness and safety in pediatric patients with 5q-spinal muscular atrophy: a multi-center disease registry in China.

OBJECTIVE: To evaluate the effectiveness and safety of nusinersen for the treatment of 5q-spinal muscular atrophy (SMA) among Chinese pediatric patients. METHODS: Using a longitudinal, multi-center registry, both prospective and retrospective data were collected from pediatric patients with 5q-SMA receiving nusinersen treatment across 18 centers in China. All patients fulfilling the eligibility criteria were included consecutively. Motor function outcomes were assessed post-treatment by SMA type. Safety profile was evaluated among patients starting nusinersen treatment post-enrollment. Descriptive analyses were used to report baseline characteristics, effectiveness, and safety results. RESULTS: As of March 2nd, 2023, 385 patients were included. Most patients demonstrated improvements or stability in motor function across all SMA types. Type II patients demonstrated mean changes [95% confidence interval (CI)] of 4.4 (3.4-5.4) and 4.1 (2.8-5.4) in Hammersmith Functional Motor Scale-Expanded (HFMSE), and 2.4 (1.7-3.1) and 2.3 (1.2-3.4) in Revised Upper Limb Module (RULM) scores at months 6 and 10. Type III patients exhibited mean changes (95% CI) of 3.9 (2.5-5.3) and 4.3 (2.6-6.0) in HFMSE, and 2.1 (1.2-3.0) and 1.5 (0.0-3.0) in RULM scores at months 6 and 10. Of the 132 patients, 62.9% experienced adverse events (AEs). Two patients experienced mild AEs (aseptic meningitis and myalgia) considered to be related to nusinersen by the investigator, with no sequelae. CONCLUSIONS: These data underscore the significance of nusinersen in Chinese pediatric patients with SMA regarding motor function improvement or stability, and support recommendations on nusinersen treatment by Chinese SMA guidelines and continuous coverage of nusinersen by basic medical insurance.

Allopregnanolone Effects on Inhibition in Hippocampal Parvalbumin Interneurons.

Allopregnanolone (AlloP) is a neurosteroid that potentiates ionotropic GABAergic (GABAA) inhibition and is approved for treating postpartum depression in women. Although the antidepressant mechanism of AlloP is largely unknown, it could involve selective action at GABAA receptors containing the δ subunit. Despite previous evidence for selective effects of AlloP on α4/δ-containing receptors of hippocampal dentate granule cells (DGCs), other recent results failed to demonstrate selectivity at these receptors (Lu et al., 2020). In contrast to DGCs, hippocampal fast-spiking parvalbumin (PV) interneurons express an unusual variant partnership of δ subunits with α1 subunits. Here, we hypothesized that native α1/δ receptors in hippocampal fast-spiking interneurons may provide a preferred substrate for AlloP. Contrary to the hypothesis, electrophysiology from genetically tagged PV interneurons in hippocampal slices from male mice showed that 100 nm AlloP promoted phasic inhibition by increasing the sIPSC decay, but tonic inhibition was not detectably altered. Co-application of AlloP with 5 µm GABA did augment tonic current, which was not primarily through δ-containing receptors. Furthermore, AlloP decreased the membrane resistance and the number of action potentials of DGCs, but the impact on PV interneurons was weaker than on DGCs. Thus, our results indicate that hippocampal PV interneurons possess low sensitivity to AlloP and suggest they are unlikely contributors to mood-altering effects of neurosteroids through GABA effects.

TARSL: Triple-attention cross-network representation learning to predict synthetic lethality for anti-cancer drug discovery.

Cancer is a multifaceted disease that results from co-mutations of multi biological molecules. A promising strategy for cancer therapy involves in exploiting the phenomenon of Synthetic Lethality (SL) by targeting the SL partner of cancer gene. Since traditional methods for SL prediction suffer from high-cost, time-consuming and off-targets effects, computational approaches have been efficient complementary to these methods. Most of existing approaches treat SL associations as independent of other biological interaction networks, and fail to consider other information from various biological networks. Despite some approaches have integrated different networks to capture multi-modal features of genes for SL prediction, these methods implicitly assume that all sources and levels of information contribute equally to the SL associations. As such, a comprehensive and flexible framework for learning gene cross-network representations for SL prediction is still lacking. In this work, we present a novel Triple-Attention cross-network Representation learning for SL prediction (TARSL) by capturing molecular features from heterogeneous sources. We employ three-level attention modules to consider the different contribution of multi-level information. In particular, feature-level attention can capture the correlations between molecular feature and network link, node-level attention can differentiate the importance of various neighbors, and network-level attention can concentrate on important network and reduce the effects of irrelated networks. We perform comprehensive experiments on human SL datasets and these results have proven that our model is consistently superior to baseline methods and predicted SL associations could aid in designing anti-cancer drugs.

MAGCN: A Multiple Attention Graph Convolution Networks for Predicting Synthetic Lethality.

Synthetic lethality (SL) is a potential cancer therapeutic strategy and drug discovery. Computational approaches to identify synthetic lethality genes have become an effective complement to wet experiments which are time consuming and costly. Graph convolutional networks (GCN) has been utilized to such prediction task as be good at capturing the neighborhood dependency in a graph. However, it is still a lack of the mechanism of aggregating the complementary neighboring information from various heterogeneous graphs. Here, we propose the Multiple Attention Graph Convolution Networks for predicting synthetic lethality (MAGCN). First, we obtain the functional similarity features and topological structure features of genes from different data sources respectively, such as Gene Ontology data and Protein-Protein Interaction. Then, graph convolutional network is utilized to accumulate the knowledge from neighbor nodes according to synthetic lethal associations. Meanwhile, we propose a multiple graphs attention model and construct a multiple graphs attention network to learn the contribution factors of different graphs to generate embedded representation by aggregating these graphs. Finally, the generated feature matrix is decoded to predict potential synthetic lethal interaction. Experimental results show that MAGCN is superior to other baseline methods. Case study demonstrates the ability of MAGCN to predict human SL gene pairs.

Chronic striatal cholinergic interneuron excitation induces clinically-relevant dystonic behavior in mice.

Dystonia is common, debilitating, often medically refractory, and difficult to diagnose. The gold standard for both clinical and mouse model dystonia evaluation is subjective assessment, ideally by expert consensus. However, this subjectivity makes translational quantification of clinically-relevant dystonia metrics across species nearly impossible. Many mouse models of genetic dystonias display abnormal striatal cholinergic interneuron excitation, but few display subjectively dystonic features. Therefore, whether striatal cholinergic interneuron pathology causes dystonia remains unknown. To address these critical limitations, we first demonstrate that objectively quantifiable leg adduction variability correlates with leg dystonia severity in people. We then show that chemogenetic excitation of striatal cholinergic interneurons in mice causes comparable leg adduction variability in mice. This clinically-relevant dystonic behavior in mice does not occur with acute excitation, but rather develops after 14 days of ongoing striatal cholinergic interneuron excitation. This requirement for prolonged excitation recapitulates the clinically observed phenomena of a delay between an inciting brain injury and subsequent dystonia manifestation and demonstrates a causative link between chronic striatal cholinergic interneuron excitation and clinically-relevant dystonic behavior in mice. Therefore, these results support targeting striatal ChIs for dystonia drug development and suggests early treatment in the window following injury but prior to dystonia onset. One Sentence Summary: Chronic excitation of dorsal striatal cholinergic interneuron causes clinically-relevant dystonic phenotypes in mice.