Development of Mandarin Lexical Tone Identification in Noise and Its Relation With Working Memory.

PURPOSE: This study aimed to examine the developmental trajectory of Mandarin tone identification in quiet and two noisy conditions: speech-shaped noise (SSN) and multitalker babble noise. In addition, we evaluated the relationship between tonal identification development and working memory capacity. METHOD: Ninety-three typically developing children aged 5-8 years and 23 young adults completed categorical identification of two tonal continua (Tone 1-4 and Tone 2-3) in quiet, SSN, and babble noise. Their working memory was additionally measured using auditory digit span tests. Correlation analyses between digit span scores and boundary widths were performed. RESULTS: Six-year-old children have achieved the adultlike ability of categorical identification of Tone 1-4 continuum under both types of noise. Moreover, 6-year-old children could identify Tone 2-3 continuum as well as adults in SSN. Nonetheless, the child participants, even 8-year-olds, performed worse when tokens from Tone 2-3 continuum were masked by babble noise. Greater working memory capacity was associated with better tone identification in noise for preschoolers aged 5-6 years; however, for school-age children aged 7-8 years, such correlation only existed in Tone 2-3 continuum in SSN. CONCLUSIONS: Lexical tone perception might take a prolonged time to achieve adultlike competence in babble noise relative to SSN. Moreover, a significant interaction between masking type and stimulus difficulty was found, as indicated by Tone 2-3 being more susceptible to interference from babble noise than Tone 1-4. Furthermore, correlations between working memory capacity and tone perception in noise varied with developmental stage, stimulus difficulty, and masking type.

Statistical Information Affects Spoken Word Recognition of Tone Languages in Stutterers: Evidence From an Auditory-Perceptual Gating Study.

PURPOSE: Previous studies have shown that individuals who stutter exhibit abnormal speech perception in addition to disfluent production as compared with their nonstuttering peers. This study investigated whether adult Chinese-speaking stutterers are still able to use knowledge of statistical regularities embedded in their native language to recognize spoken words and, if so, how much acoustic information is needed to trigger this information. METHOD: Seventeen stutterers and 20 typical, nonstuttering controls participated in a gating experiment. All participants listened to monosyllabic words that consisted of syllables and lexical tones and were segmented into eight successive gates. These words differed in syllable token frequency and syllable-tone co-occurrence probability in line with a Chinese spoken word corpus. The correct syllable-only, correct tone-only, correct syllable-tone word, and correct syllable-incorrect tone responses were analyzed between the two groups using mixed-effects models. RESULTS: Stutterers were less accurate overall than controls, with fewer correct syllables, tones, and their combination as words. However, stutterers showed consistent and reliable perceptual patterns triggered by statistical information of speech, as reflected by more accurate responses to high-frequency syllables, high-probability tones, and tone errors all in manners similar to those of nonstuttering controls. CONCLUSIONS: Stutterers' atypical speech perception is not due to a lack of statistical learning. Stutterers were able to perceive spoken words with phonological tones based on statistical regularities embedded in their native speech. This finding echoes previous production studies of stuttering and lends some support for a link between perception and production. Implications of pathological, diagnostic, and therapeutic conditions of stuttering are discussed.

Tone Deafness in Music Does Not Preclude Distributional Learning of Nonnative Tonal Languages in Individuals With Congenital Amusia.

PURPOSE: Previous studies have shown that individuals with congenital amusia exhibit deficient pitch processing across music and language domains. This study investigated whether adult Chinese-speaking listeners with amusia were still able to learn Thai lexical tones based on stimulus frequency of statistical distribution via distributional learning, despite their degraded lexical tone perception. METHOD: Following a pretest-training-posttest design, 21 amusics and 23 typical, musically intact listeners were assigned into bimodal and unimodal distribution conditions. Listeners were asked to discriminate minimal pairs of Thai mid-level tone and falling tone superimposed on variable base syllables and uttered by different speakers. The perceptual accuracy for each test session and improvement from pretest to posttest were collected and analyzed between the two groups using generalized mixed-effects models. RESULTS: When discriminating Thai lexical tones, amusics were less accurate than typical listeners. Nonetheless, similarly to control listeners, perceptual gains from pretest to posttest were observed in bimodally rather than unimodally trained amusics, as evidenced by both trained and nontrained test words. CONCLUSIONS: Amusics are able to learn lexical tones in a second or foreign context of speech. This extends previous research by showing that amusics' distributional learning of linguistic pitch remains largely preserved despite their degraded pitch processing. It is thus likely that manifestations of amusia in speech could not result from their abnormal statistical learning mechanism. This study meanwhile provides a heuristic approach for future studies to apply this paradigm into amusics' treatment to mitigate their pitch-processing disorder.

Distributional learning of musical pitch despite tone deafness in individuals with congenital amusia.

Congenital amusia is an innate and lifelong deficit of music processing. This study investigated whether adult listeners with amusia were still able to learn pitch-related musical chords based on stimulus frequency of statistical distribution, i.e., via distributional learning. Following a pretest-training-posttest design, 18 amusics and 19 typical, musically intact listeners were assigned to bimodal and unimodal conditions that differed in distribution of the stimuli. Participants' task was to discriminate chord minimal pairs, which were transposed to a novel microtonal scale. Accuracy rates for each test session were collected and compared between the two groups using generalized mixed-effects models. Results showed that amusics were less accurate than typical listeners at all comparisons, thus corroborating previous findings. Importantly, amusics-like typical listeners-demonstrated perceptual gains from pretest to posttest in the bimodal condition (but not the unimodal condition). The findings reveal that amusics' distributional learning of music remains largely preserved despite their deficient music processing. Implications of the results for statistical learning and intervention programs to mitigate amusia are discussed.

SRTsim: spatial pattern preserving simulations for spatially resolved transcriptomics.

Spatially resolved transcriptomics (SRT)-specific computational methods are often developed, tested, validated, and evaluated in silico using simulated data. Unfortunately, existing simulated SRT data are often poorly documented, hard to reproduce, or unrealistic. Single-cell simulators are not directly applicable for SRT simulation as they cannot incorporate spatial information. We present SRTsim, an SRT-specific simulator for scalable, reproducible, and realistic SRT simulations. SRTsim not only maintains various expression characteristics of SRT data but also preserves spatial patterns. We illustrate the benefits of SRTsim in benchmarking methods for spatial clustering, spatial expression pattern detection, and cell-cell communication identification.

Musical Training Enhances Categorical Perception of Speech in Preschoolers: Training Duration and Musical Program Matter.

PURPOSE: Previous research has indicated the beneficial effects of musical training on speech perception in children. However, little has been known about whether musical training exerts transfer effects on fine-grained perception of linguistic pitch and time information. This study aimed to investigate the effects of different musical training programs and training duration on preschoolers' categorical perception (CP) of lexical tones and voice onset time (VOT) in Mandarin Chinese, which utilize pitch and time changes, respectively, to convey phonemic contrasts. METHOD: Sixty-one Mandarin-speaking children aged 4 years were randomly assigned to pitch-based musical training (carillon group), rhythm-based musical training (drum group), or handcraft learning (control group). Children completed the tests designed to assess their musical abilities, CP of lexical tones and VOT, IQ, and working memory at three time-points. Repeated-measures analyses of variance were conducted to evaluate the training-related effects in various tasks. Correlation analyses were used to infer the relationships between musical abilities and CP performance of speech. RESULTS: The carillon group demonstrated advantages over the drum and control groups in music pitch processing and CP of lexical tones; besides, the drum group performed better in the music time processing and CP of VOT than the control group. Moreover, positive correlations were found between musical gains and improvements on CP of speech. CONCLUSIONS: These results provide evidence that transfer effects occur in CP of lexical tones and VOT in preschoolers. Our findings highlight the selectivity of musical advantages driven by different components of training programs and suggest that long-term musical training could be a means of early speech rehabilitation in children with communication disorders.

Audiovisual Mandarin Lexical Tone Perception in Quiet and Noisy Contexts: The Influence of Visual Cues and Speech Rate.

PURPOSE: Armed with the theory of embodied cognition proposing tight interactions between perception, motor, and cognition, this study aimed to test the hypothesis that speech rate-altered Mandarin lexical tone perception in quiet and noisy environments could be affected by the bodily dynamic cross-modal information. METHOD: Fifty-three adult listeners completed a Mandarin tone perception task with 720 tone stimuli in auditory-only (AO), auditory-facial (AF), and auditory-facial-plus-gestural (AFG) modalities, at fast, normal, and slow speech rates under quiet and noisy conditions. In AF and AFG modalities, both congruent and incongruent audiovisual information were designed and presented. Generalized linear mixed-effects models were constructed to analyze the accuracy of tone perception across different conditions. RESULTS: In Mandarin tone perception, the magnitude of enhancement of AF and AFG cues across three speech rates was significantly higher than that of the AO cue in the adverse context of noise, yet additional metaphoric gestures did not show significant differences from the facial information. Furthermore, the performance of auditory tone perception at the fast speech rate was significantly better than that at the normal speech rate when the inputs were incongruent between auditory and visual channels in quiet. CONCLUSIONS: This study provided compelling evidence showing that integrated audiovisual information plays a vital role not only in improving lexical tone perception in noise but also in modulating the effects of speech rate on Mandarin tone perception in quiet for native listeners. Our findings, supporting the theory of embodied cognition, are implicational for speech and hearing rehabilitation among both young and old clinical populations.

Structural and mechanistic basis for recognition of alternative tRNA precursor substrates by bacterial ribonuclease P.

Binding of precursor tRNAs (ptRNAs) by bacterial ribonuclease P (RNase P) involves an encounter complex (ES) that isomerizes to a catalytic conformation (ES*). However, the structures of intermediates and the conformational changes that occur during binding are poorly understood. Here, we show that pairing between the 5' leader and 3'RCCA extending the acceptor stem of ptRNA inhibits ES* formation. Cryo-electron microscopy single particle analysis reveals a dynamic enzyme that becomes ordered upon formation of ES* in which extended acceptor stem pairing is unwound. Comparisons of structures with alternative ptRNAs reveals that once unwinding is completed RNase P primarily uses stacking interactions and shape complementarity to accommodate alternative sequences at its cleavage site. Our study reveals active site interactions and conformational changes that drive molecular recognition by RNase P and lays the foundation for understanding how binding interactions are linked to helix unwinding and catalysis.

Neuregulin 4 suppresses NASH-HCC development by restraining tumor-prone liver microenvironment.

The mammalian liver comprises heterogeneous cell types within its tissue microenvironment that undergo pathophysiological reprogramming in disease states, such as non-alcoholic steatohepatitis (NASH). Patients with NASH are at an increased risk for the development of hepatocellular carcinoma (HCC). However, the molecular and cellular nature of liver microenvironment remodeling that links NASH to liver carcinogenesis remains obscure. Here, we show that diet-induced NASH is characterized by the induction of tumor-associated macrophage (TAM)-like macrophages and exhaustion of cytotoxic CD8+ T cells in the liver. The adipocyte-derived endocrine factor Neuregulin 4 (NRG4) serves as a hormonal checkpoint that restrains this pathological reprogramming during NASH. NRG4 deficiency exacerbated the induction of tumor-prone liver immune microenvironment and NASH-related HCC, whereas transgenic NRG4 overexpression elicited protective effects in mice. In a therapeutic setting, recombinant NRG4-Fc fusion protein exhibited remarkable potency in suppressing HCC and prolonged survival in the treated mice. These findings pave the way for therapeutic intervention of liver cancer by targeting the NRG4 hormonal checkpoint.

Modeling zero inflation is not necessary for spatial transcriptomics.

BACKGROUND: Spatial transcriptomics are a set of new technologies that profile gene expression on tissues with spatial localization information. With technological advances, recent spatial transcriptomics data are often in the form of sparse counts with an excessive amount of zero values. RESULTS: We perform a comprehensive analysis on 20 spatial transcriptomics datasets collected from 11 distinct technologies to characterize the distributional properties of the expression count data and understand the statistical nature of the zero values. Across datasets, we show that a substantial fraction of genes displays overdispersion and/or zero inflation that cannot be accounted for by a Poisson model, with genes displaying overdispersion substantially overlapped with genes displaying zero inflation. In addition, we find that either the Poisson or the negative binomial model is sufficient for modeling the majority of genes across most spatial transcriptomics technologies. We further show major sources of overdispersion and zero inflation in spatial transcriptomics including gene expression heterogeneity across tissue locations and spatial distribution of cell types. In particular, when we focus on a relatively homogeneous set of tissue locations or control for cell type compositions, the number of detected overdispersed and/or zero-inflated genes is substantially reduced, and a simple Poisson model is often sufficient to fit the gene expression data there. CONCLUSIONS: Our study provides the first comprehensive evidence that excessive zeros in spatial transcriptomics are not due to zero inflation, supporting the use of count models without a zero inflation component for modeling spatial transcriptomics.

The Phonological Development of Mandarin Voiceless Affricates in Three- to Five-Year-Old Children.

This study investigates the phonological development of Mandarin voiceless affricates produced by Mandarin-speaking children. Thirty-six monolingual Mandarin-speaking children and twelve adults participated in a speech production task. Auditory-based transcription analysis and acoustic analysis were utilized to quantify the relative order of affricate acquisition. Both methods yielded earlier acquisition of alveopalatal affricates at age three than retroflex and alveolar affricates, whereas they differed in the acquisition order of retroflex and alveolar affricates. The former revealed that both retroflex and alveolar affricates were acquired at age five, regardless of aspiration, while the latter yielded earlier acquisition of retroflex than alveolar affricates. Possible reasons for the discrepancy are discussed in relation to the different nature of the two methods. Overall, the observed acquisition order of Mandarin voiceless affricates suggests that child speech development is a complex process, and is influenced by various factors including oromotor maturation and language-specific phoneme frequencies in the ambient language.

A novel nonparametric computational strategy for identifying differential methylation regions.

BACKGROUND: DNA methylation has long been known as an epigenetic gene silencing mechanism. For a motivating example, the methylomes of cancer and non-cancer cells show a number of methylation differences, indicating that certain features characteristics of cancer cells may be related to methylation characteristics. Robust methods for detecting differentially methylated regions (DMRs) could help scientists narrow down genome regions and even find biologically important regions. Although some statistical methods were developed for detecting DMR, there is no default or strongest method. Fisher's exact test is direct, but not suitable for data with multiple replications, while regression-based methods usually come with a large number of assumptions. More complicated methods have been proposed, but those methods are often difficult to interpret. RESULTS: In this paper, we propose a three-step nonparametric kernel smoothing method that is both flexible and straightforward to implement and interpret. The proposed method relies on local quadratic fitting to find the set of equilibrium points (points at which the first derivative is 0) and the corresponding set of confidence windows. Potential regions are further refined using biological criteria, and finally selected based on a Bonferroni adjusted t-test cutoff. Using a comparison of three senescent and three proliferating cell lines to illustrate our method, we were able to identify a total of 1077 DMRs on chromosome 21. CONCLUSIONS: We proposed a completely nonparametric, statistically straightforward, and interpretable method for detecting differentially methylated regions. Compared with existing methods, the non-reliance on model assumptions and the straightforward nature of our method makes it one competitive alternative to the existing statistical methods for defining DMRs.

Individuals With Congenital Amusia Show Degraded Speech Perception but Preserved Statistical Learning for Tone Languages.

PURPOSE: Individuals with congenital amusia exhibit degraded speech perception. This study examined whether adult Chinese Mandarin listeners with amusia were still able to extract the statistical regularities of Mandarin speech sounds, despite their degraded speech perception. METHOD: Using the gating paradigm with monosyllabic syllable-tone words, we tested 19 Mandarin-speaking amusics and 19 musically intact controls. Listeners heard increasingly longer fragments of the acoustic signal across eight duration-blocked gates. The stimuli varied in syllable token frequency and syllable-tone co-occurrence probability. The correct syllable-tone word, correct syllable-only, correct tone-only, and correct syllable-incorrect tone responses were compared respectively between the two groups using mixed-effects models. RESULTS: Amusics were less accurate than controls in terms of the correct word, correct syllable-only, and correct tone-only responses. Amusics, however, showed consistent patterns of top-down processing, as indicated by more accurate responses to high-frequency syllables, high-probability tones, and tone errors all in manners similar to those of the control listeners. CONCLUSIONS: Amusics are able to learn syllable and tone statistical regularities from the language input. This extends previous work by showing that amusics can track phonological segment and pitch cues despite their degraded speech perception. The observed speech deficits in amusics are therefore not due to an abnormal statistical learning mechanism. These results support rehabilitation programs aimed at improving amusics' sensitivity to pitch.

The Development of Categorical Perception of Segments and Suprasegments in Mandarin-Speaking Preschoolers.

This study investigated the developmental trajectories of categorical perception (CP) of segments (i.e., stops) and suprasegments (i.e., lexical tones) in an attempt to examine the perceptual development of phonological categories and whether CP of suprasegments develops in parallel with that of segments. Forty-seven Mandarin-speaking monolingual preschoolers aged four to six years old, and fourteen adults completed both identification and discrimination tasks of the Tone 1-2 continuum and the /pa/-/pha/ continuum. Results revealed that children could perceive both lexical tones and aspiration of stops in a categorical manner by age four. The boundary position did not depend on age, with children having similar positions to adults regardless of speech continuum types. The boundary width, on the other hand, reached the adult-like level at age six for lexical tones, but not for stops. In addition, the within-category discrimination score did not differ significantly between children and adults for both continua. The between-category discrimination score improved with age and achieved the adult-like level at age five for lexical tones, but still not for stops even at age six. It suggests that the fine-grained perception of phonological categories is a protracted process, and the improvement and varying timeline of the development of segments and suprasegments are discussed in relation to statistical learning of the regularities of speech sounds in ambient language, ongoing maturation of perceptual systems, the memory mechanism underlying perceptual learning, and the intrinsic nature of speech elements.

SPARK-X: non-parametric modeling enables scalable and robust detection of spatial expression patterns for large spatial transcriptomic studies.

Spatial transcriptomic studies are becoming increasingly common and large, posing important statistical and computational challenges for many analytic tasks. Here, we present SPARK-X, a non-parametric method for rapid and effective detection of spatially expressed genes in large spatial transcriptomic studies. SPARK-X not only produces effective type I error control and high power but also brings orders of magnitude computational savings. We apply SPARK-X to analyze three large datasets, one of which is only analyzable by SPARK-X. In these data, SPARK-X identifies many spatially expressed genes including those that are spatially expressed within the same cell type, revealing new biological insights.

Effects of Amateur Musical Experience on Categorical Perception of Lexical Tones by Native Chinese Adults: An ERP Study.

Music impacting on speech processing is vividly evidenced in most reports involving professional musicians, while the question of whether the facilitative effects of music are limited to experts or may extend to amateurs remains to be resolved. Previous research has suggested that analogous to language experience, musicianship also modulates lexical tone perception but the influence of amateur musical experience in adulthood is poorly understood. Furthermore, little is known about how acoustic information and phonological information of lexical tones are processed by amateur musicians. This study aimed to provide neural evidence of cortical plasticity by examining categorical perception of lexical tones in Chinese adults with amateur musical experience relative to the non-musician counterparts. Fifteen adult Chinese amateur musicians and an equal number of non-musicians participated in an event-related potential (ERP) experiment. Their mismatch negativities (MMNs) to lexical tones from Mandarin Tone 2-Tone 4 continuum and non-speech tone analogs were measured. It was hypothesized that amateur musicians would exhibit different MMNs to their non-musician counterparts in processing two aspects of information in lexical tones. Results showed that the MMN mean amplitude evoked by within-category deviants was significantly larger for amateur musicians than non-musicians regardless of speech or non-speech condition. This implies the strengthened processing of acoustic information by adult amateur musicians without the need of focused attention, as the detection of subtle acoustic nuances of pitch was measurably improved. In addition, the MMN peak latency elicited by across-category deviants was significantly shorter than that by within-category deviants for both groups, indicative of the earlier processing of phonological information than acoustic information of lexical tones at the pre-attentive stage. The results mentioned above suggest that cortical plasticity can still be induced in adulthood, hence non-musicians should be defined more strictly than before. Besides, the current study enlarges the population demonstrating the beneficial effects of musical experience on perceptual and cognitive functions, namely, the effects of enhanced speech processing from music are not confined to a small group of experts but extend to a large population of amateurs.

Genome-Wide Differentially Methylated Region Analysis to Reveal Epigenetic Differences of Articular Cartilage in Kashin-Beck Disease and Osteoarthritis.

Kashin-Beck disease (KBD) is a degenerative osteoarticular disorder, and displays the significant differences with osteoarthritis (OA) regarding the etiology and molecular changes in articular cartilage. However, the underlying dysfunctions of molecular mechanisms in KBD and OA remain unclear. Here, we primarily performed the various genome-wide differential methylation analyses to reveal the distinct differentially methylated regions (DMRs) in conjunction with corresponding differentially methylated genes (DMGs), and enriched functional pathways in KBD and OA. We identified a total of 131 DMRs in KBD vs. Control, and 58 DMRs in OA vs. Controls, and the results demonstrate that many interesting DMRs are linked to DMGs, such as SMOC2 and HOXD3, which are all key genes to regulate cartilage/skeletal physiologic and pathologic process, and are further enriched in skeletal system and limb-associated pathways. Our DMR analysis indicates that KBD-associated DMRs has higher proportion than OA-associated DMRs in gene body regions. KBD-associated DMGs were enriched in wounding and coagulation-related functional pathways that may be stimulated by trace elements. The identified molecular features provide novel clues for understanding the pathogenetic and therapeutic studies of both KBD and OA.

Network-based Transcriptome-wide Expression Study for Postmenopausal Osteoporosis.

PURPOSE: Menopause is a crucial physiological transition during a woman's life, and it occurs with growing risks of health issues like osteoporosis. To identify postmenopausal osteoporosis-related genes, we performed transcriptome-wide expression analyses for human peripheral blood monocytes (PBMs) using Affymetrix 1.0 ST arrays in 40 Caucasian postmenopausal women with discordant bone mineral density (BMD) levels. METHODS: We performed multiscale embedded gene coexpression network analysis (MEGENA) to study functionally orchestrating clusters of differentially expressed genes in the form of functional networks. Gene sets net correlations analysis (GSNCA) was applied to assess how the coexpression structure of a predefined gene set differs in high and low BMD groups. Bayesian network (BN) analysis was used to identify important regulation patterns between potential risk genes for osteoporosis. A small interfering ribonucleic acid (siRNA)-based gene silencing in vitro experiment was performed to validate the findings from BN analysis. RESULT: MEGENA showed that the "T cell receptor signaling pathway" and the "osteoclast differentiation pathway" were significantly enriched in the identified compact network, which is significantly correlated with BMD variation. GSNCA revealed that the coexpression structure of the "Signaling by TGF-beta receptor complex pathway" is significantly different between the 2 BMD discordant groups; the hub genes in the postmenopausal low and high BMD group are FURIN and SMAD3 respectively. With siRNA in vitro experiments, we confirmed the regulation relationship of TGFBR2-SMAD7 and TGFBR1-SMURF2. MAIN CONCLUSION: The present study suggests that biological signals involved in monocyte recruitment, monocyte/macrophage lineage development, osteoclast formation, and osteoclast differentiation might function together in PBMs that contribute to the pathogenesis of postmenopausal osteoporosis.

Statistical analysis of spatial expression patterns for spatially resolved transcriptomic studies.

Identifying genes that display spatial expression patterns in spatially resolved transcriptomic studies is an important first step toward characterizing the spatial transcriptomic landscape of complex tissues. Here we present a statistical method, SPARK, for identifying spatial expression patterns of genes in data generated from various spatially resolved transcriptomic techniques. SPARK directly models spatial count data through generalized linear spatial models. It relies on recently developed statistical formulas for hypothesis testing, providing effective control of type I errors and yielding high statistical power. With a computationally efficient algorithm, which is based on penalized quasi-likelihood, SPARK is also scalable to datasets with tens of thousands of genes measured on tens of thousands of samples. Analyzing four published spatially resolved transcriptomic datasets using SPARK, we show it can be up to ten times more powerful than existing methods and disclose biological discoveries that otherwise cannot be revealed by existing approaches.

Accuracy, robustness and scalability of dimensionality reduction methods for single-cell RNA-seq analysis.

BACKGROUND: Dimensionality reduction is an indispensable analytic component for many areas of single-cell RNA sequencing (scRNA-seq) data analysis. Proper dimensionality reduction can allow for effective noise removal and facilitate many downstream analyses that include cell clustering and lineage reconstruction. Unfortunately, despite the critical importance of dimensionality reduction in scRNA-seq analysis and the vast number of dimensionality reduction methods developed for scRNA-seq studies, few comprehensive comparison studies have been performed to evaluate the effectiveness of different dimensionality reduction methods in scRNA-seq. RESULTS: We aim to fill this critical knowledge gap by providing a comparative evaluation of a variety of commonly used dimensionality reduction methods for scRNA-seq studies. Specifically, we compare 18 different dimensionality reduction methods on 30 publicly available scRNA-seq datasets that cover a range of sequencing techniques and sample sizes. We evaluate the performance of different dimensionality reduction methods for neighborhood preserving in terms of their ability to recover features of the original expression matrix, and for cell clustering and lineage reconstruction in terms of their accuracy and robustness. We also evaluate the computational scalability of different dimensionality reduction methods by recording their computational cost. CONCLUSIONS: Based on the comprehensive evaluation results, we provide important guidelines for choosing dimensionality reduction methods for scRNA-seq data analysis. We also provide all analysis scripts used in the present study at www.xzlab.org/reproduce.html.