Anteromedial thalamus gates the selection and stabilization of long-term memories.

Memories initially formed in hippocampus gradually stabilize to cortex over weeks-to-months for long-term storage. The mechanistic details of this brain re-organization remain poorly understood. We recorded bulk neural activity in circuits that link hippocampus and cortex as mice performed a memory-guided virtual-reality task over weeks. We identified a prominent and sustained neural correlate of memory in anterior thalamus, whose inhibition substantially disrupted memory consolidation. More strikingly, gain amplification enhanced consolidation of otherwise unconsolidated memories. To gain mechanistic insights, we developed a technology for simultaneous cellular-resolution imaging of hippocampus, thalamus, and cortex throughout consolidation. We found that whereas hippocampus equally encodes multiple memories, the anteromedial thalamus preferentially encodes salient memories, and gradually increases correlations with cortex to facilitate tuning and synchronization of cortical ensembles. We thus identify a thalamo-cortical circuit that gates memory consolidation and propose a mechanism suitable for the selection and stabilization of hippocampal memories into longer-term cortical storage.

Novice nurses' transition shock and professional identity: The chain mediating roles of self-efficacy and resilience.

AIMS AND OBJECTIVES: The aim of this study was to explore the association between transition shocks and professional identity and the mediating roles of self-efficacy and resilience among Chinese novice nurses. BACKGROUND: Novice nurses experience transition shock when they start their careers, which might lead to decreased professional identity and ultimately turnover. By contrast, self-efficacy and resilience are excellent psychological resources that may be associated with higher professional identity. It is unclear how transition shock affects professional identity by influencing these two internal resources. DESIGN: A cross-sectional survey. METHODS: The STROBE guidelines were followed to report this study. Convenience sampling was used to recruit participants, and 252 novice nurses completed the Transition Shock of Novice Nurses Scale, the Professional Identity Assessment Scale, the General Self-Efficacy Scale and the Connor-Davidson Resilience Scale between April 2022 and May 2022. Influencing factors were primarily identified using independent-sample t-tests and a one-way ANOVA. Structural equation modelling was used to detect the mediating effects of self-efficacy and resilience. RESULTS: Differences in novice nurses' levels of professional identity were found across age groups, hospitals and departments. Transition shock was negatively related to professional identity. Self-efficacy and resilience mediated the complete chain relationship between transition shock and professional identity. CONCLUSION: To our knowledge, this study is the first to explore the mediating effect of self-efficacy and resilience on transition shock and professional identity. Higher transition shock may lead to lower professional identity by reducing self-efficacy and resilience. RELEVANCE TO CLINICAL PRACTICE: Nursing managers ought to emphasise the significant role of psychological resources in the work adaptation process of novice nurses. It may be more effective to improve professional identity and maintain the stability of the health care system. PATIENT OR PUBLIC CONTRIBUTION: Nursing administrators working at seven preselected hospitals actively assisted us in the process of collecting self-report questionnaires from novice nurses, such as by booking appointments and providing access for questionnaire administration. In addition, the participants were actively involved in the data collection process.

The mediating role of cognitive emotion regulation in the relationship between self-concealment and quality of life among breast cancer chemotherapy patients.

PURPOSE: This study aimed to explore whether self-concealment (SC) affects the quality of life (QOL), and whether cognitive emotion regulation (CER) mediates the relationship between SC and QOL among breast cancer chemotherapy patients. METHODS: This cross-sectional study was conducted among 228 breast cancer chemotherapy patients from November 2021 to March 2022 in Anhui Province, China. Data were collected using the Self-Concealment Scale, Cognitive Emotion Regulation Questionnaire, and Short Form 36 Questionnaire. Descriptive statistics, independent-sample t test, one-way analysis of variance, and structural equation modeling were used to explore associations among SC, CER, and QOL. RESULTS: QOL levels differed significantly by participant age, monthly per capita household income and home location. SC was negatively correlated with QOL. SSC was negatively correlated with adaptive-CER strategies and positively correlated with maladaptive-CER strategies. Adaptive-CER strategies were positively correlated with QOL. Maladaptive-CER strategies were negatively correlated with QOL. CER fully mediated the association between SC and QOL in breast cancer chemotherapy patients. CONCLUSION: Nursing staff should help breast cancer chemotherapy patients reduce the use of maladaptive-CER strategies in the care of patients in the future. Helping patients reduce SC is more conductive to improving the QOL of breast cancer chemotherapy patients.

Effectiveness and learning experience from undergraduate nursing students in surgical nursing skills course: a quasi- experimental study about blended learning.

BACKGROUND: Blended learning is increasingly being adopted, and yet a gap remains in the related literature pertaining to its skill performance, learning engagement and inner experience in undergraduate surgical nursing skills course. OBJECTIVES: To investigate the changes in skills performance and learning engagement in the application of blended learning, and what it actually brings to nursing students. DESIGN: The study uses a historical control, two-armed, mixed and quasi-experimental design. METHODS: The blended learning version of the course was offered to the 2019 class of 334 nursing undergraduates. Quantitative and qualitative data were collected after the course to obtain a comprehensive understanding of the course effects compared with the 304 nursing undergraduates of grade 2017 who adapted traditional learning. Quantitative data were analyzed by descriptive and inferential statistics using IBM SPSS 26.0, and qualitative data were encoded using Nvivo11.0. RESULTS: There were significant differences in skill performance and learning engagement between the class of 2017 and 2019 (p < 0.001). Combined with further analysis of the interview data, 3 first-level nodes and 8 secondary nodes were determined. Students' opinions, comments and suggestions on the application of blended learning are refreshing. CONCLUSION: Moving forward with blended learning: opportunities and challenges go hand in hand. Researchers need to continually modify their research designs to respond to variable educational environments.

Discovery of triterpenoids as potent dual inhibitors of pancreatic lipase and human carboxylesterase 1.

Pancreatic lipase (PL) is a well-known key target for the prevention and treatment of obesity. Human carboxylesterase 1A (hCES1A) has become an important target for the treatment of hyperlipidaemia. Thus, the discovery of potent dual-target inhibitors based on PL and hCES1A hold great potential for the development of remedies for treating related metabolic diseases. In this study, a series of natural triterpenoids were collected and the inhibitory effects of these triterpenoids on PL and hCES1A were determined using fluorescence-based biochemical assays. It was found that oleanolic acid (OA) and ursolic acid (UA) have the excellent inhibitory effects against PL and hCES1A, and highly selectivity over hCES2A. Subsequently, a number of compounds based on the OA and UA skeletons were synthesised and evaluated. Structure-activity relationship (SAR) analysis of these compounds revealed that the acetyl group at the C-3 site of UA (compound 41) was very essential for both PL and hCES1A inhibition, with IC50 of 0.75 µM and 0.014 µM, respectively. In addition, compound 39 with 2-enol and 3-ketal moiety of OA also has strong inhibitory effects against both PL and hCES1A, with IC50 of 2.13 µM and 0.055 µM, respectively. Furthermore, compound 39 and 41 exhibited good selectivity over other human serine hydrolases including hCES2A, butyrylcholinesterase (BChE) and dipeptidyl peptidase IV (DPP-IV). Inhibitory kinetics and molecular docking studies demonstrated that both compounds 39 and 41 were effective mixed inhibitors of PL, while competitive inhibitors of hCES1A. Further investigations demonstrated that both compounds 39 and 41 could inhibit adipocyte adipogenesis induced by mouse preadipocytes. Collectively, we found two triterpenoid derivatives with strong inhibitory ability on both PL and hCES1A, which can be served as promising lead compounds for the development of more potent dual-target inhibitors targeting on PL and hCES1A.

RepLong: de novo repeat identification using long read sequencing data.

Motivation: The identification of repetitive elements is important in genome assembly and phylogenetic analyses. The existing de novo repeat identification methods exploiting the use of short reads are impotent in identifying long repeats. Since long reads are more likely to cover repeat regions completely, using long reads is more favorable for recognizing long repeats. Results: In this study, we propose a novel de novo repeat elements identification method namely RepLong based on PacBio long reads. Given that the reads mapped to the repeat regions are highly overlapped with each other, the identification of repeat elements is equivalent to the discovery of consensus overlaps between reads, which can be further cast into a community detection problem in the network of read overlaps. In RepLong, we first construct a network of read overlaps based on pair-wise alignment of the reads, where each vertex indicates a read and an edge indicates a substantial overlap between the corresponding two reads. Secondly, the communities whose intra connectivity is greater than the inter connectivity are extracted based on network modularity optimization. Finally, representative reads in each community are extracted to form the repeat library. Comparison studies on Drosophila melanogaster and human long read sequencing data with genome-based and short-read-based methods demonstrate the efficiency of RepLong in identifying long repeats. RepLong can handle lower coverage data and serve as a complementary solution to the existing methods to promote the repeat identification performance on long-read sequencing data. Availability and implementation: The software of RepLong is freely available at https://github.com/ruiguo-bio/replong. Contact: ywsun@szu.edu.cn or zhuzx@szu.edu.cn. Supplementary information: Supplementary data are available at Bioinformatics online.

Magnetic Separation-Assistant Fluorescence Resonance Energy Transfer Inhibition for Highly Sensitive Probing of Nucleolin.

For the widely used "off-on" fluorescence (or phosphorescence) resonance energy transfer (FRET or PRET) system, the separation of donors and acceptors species was vital for enhancing the sensitivity. To date, separation of free donors from FRET/PRET inhibition systems was somewhat not convenient, whereas separation of the target-induced far-between acceptors has hardly been reported yet. We presented here a novel magnetic separation-assistant fluorescence resonance energy transfer (MS-FRET) inhibition strategy for highly sensitive detection of nucleolin using Cy5.5-AS1411 as the donor and Fe3O4-polypyrrole core-shell (Fe3O4@PPY) nanoparticles as the NIR quenching acceptor. Due to hydrophobic interaction and π-π stacking of AS1411 and PPY, Cy5.5-AS1411 was bound onto the surface of Fe3O4@PPY, resulting in 90% of fluorescence quenching of Cy5.5-AS1411. Owing to the much stronger specific interaction of AS1411 and nucleolin, the presence of nucleolin could take Cy5.5-AS1411 apart from Fe3O4@PPY and restore the fluorescence of Cy5.5-AS1411. The superparamagnetism of Fe3O4@PPY enabled all separations and fluorescence measurements complete in the same quartz cell, and thus allowed the convenient but accurate comparison of the sensitivity and fluorescence recovery in the cases of separation or nonseparation. Compared to nonseparation FRET inhibition, the separation of free Cy5.5-AS1411 from Cy5.5-AS1411-Fe3O4@PPY solution (the first magnetic separation, MS-1) had as high as 25-fold enhancement of the sensitivity, whereas further separation of the nucleolin-inducing far-between Fe3O4@PPY from the FRET inhibition solution (the second magnetic separation, MS-2) could further enhance the sensitivity to 35-fold. Finally, the MS-FRET inhibition assay displayed the linear range of 0.625-27.5 µg L(-1) (8.1-359 pM) and detection limit of 0.04 µg L(-1) (0.05 pM) of nucleolin. The fluorescence intensity recovery (the percentage ratio of the final restoring fluorescence intensity to the quenched fluorescence intensity of Cy5.5-AS1411 solution by 0.09 g L(-1) Fe3O4@PPY) was enhanced from 36% (for nonseparation) to 56% (for two magnetic separations). This is the first accurate evaluation for the effect of separating donor/acceptor species on the FRET inhibition assay.

Ionic strength assay via polyacrylate-ferriferrous oxide magnetic photonic crystals.

Convenient reading out and/or determination of ionic strength (IS) is of great significance for both scientific research and real life applications. We presented here a novel method for the rapid and sensitive IS assay based on the electrolyte-induced sensitive wavelength blueshifts of the reflection spectra of polyacrylate capped Fe3O4 magnetic photonic crystals (PA-Fe3O4-MPCs). For HCl, MgSO4 and the common electrolytes corresponding to the salinity of seawater (including NaCl, KCl, MgCl2, CaCl2, Na2SO4 and their mixtures), the PA-Fe3O4-MPCs displayed wavelength blueshifts identical to the total IS of the aqueous solutions, regardless of the kind of above-mentioned electrolytes in the solutions. Besides, the PA-Fe3O4-MPCs exhibited relatively high sensitivity (an average of 294 nm L mmol(-1) in the range of 0.05-0.30 mmol L(-1), and an even higher value of 386 nm L mmol(-1) at 0.05-0.15 mmol L(-1)) and fast response (within 8 s) to the IS of aqueous solutions. The relative standard deviation (RSD) for IS (NaCl, 0.1 mmol L(-1)) was 4.4% (n = 5). The developed method was applied to determine the salinity of seawater samples, and the determined results were validated by the traditional standard chlorinity titration and electric conductimetry method. The recoveries were in the range of 92-104%. The proposed PA-Fe3O4-MPCs based reflectometry method would have great potential for IS and salinity assays.

Experience in developing innovative practical ability for Master of Nursing Specialist degree program in China: A qualitative descriptive study of postgraduates.

BACKGROUND: Nursing talent training should be adjusted in accordance with policies and regulations, the priority areas of health care, the development of nursing disciplines, and changes in nurses' roles. Experience from nursing education stakeholders indicates that postgraduate education faces numerous challenges. Thus, it is necessary to discuss postgraduates' experience in cultivating innovative practical ability. OBJECTIVES: To analyze the experiences of nursing specialist postgraduates in cultivating innovative practical ability to provide a reference for further improvement of the Master of Nursing Specialist program. DESIGN: A qualitative study. SETTING: A university and its three affiliated tertiary hospitals in H city, China. PARTICIPANTS AND METHODS: Individual, semi-structured interviews were conducted face-to-face with 12 postgraduates currently in clinical practice and six postgraduate nurses within two years of graduation between April and June 2022. All interviews were audio-recorded and transcribed verbatim, and the data were analyzed using the Colaizzi method. RESULTS: Three key themes emerged: (1) the cognition of innovative practical ability; (2) the experience of cultivating innovative practical ability at school; and (3) the experience of cultivating innovative practical ability in the hospital. CONCLUSIONS: With a full understanding of the training experience of postgraduates' innovative practical ability, policymakers and training units can clarify the shortcomings of the training model, make targeted improvements, and work together to build a more scientific and complete MNS training model. Our findings have the potential to inform faculty structure, catalyze curriculum reform, optimize clinical practice to facilitate the development of Master of Nursing Specialist programs, improve the quality of care, and promote patient recovery.

Anteromedial Thalamus Gates the Selection & Stabilization of Long-Term Memories.

Memories initially formed in hippocampus gradually stabilize to cortex, over weeks-to-months, for long-term storage. The mechanistic details of this brain re-organization process remain poorly understood. In this study, we developed a virtual-reality based behavioral task and observed neural activity patterns associated with memory reorganization and stabilization over weeks-long timescales. Initial photometry recordings in circuits that link hippocampus and cortex revealed a unique and prominent neural correlate of memory in anterior thalamus that emerged in training and persisted for several weeks. Inhibition of the anteromedial thalamus-to-anterior cingulate cortex projections during training resulted in substantial memory consolidation deficits, and gain amplification more strikingly, was sufficient to enhance consolidation of otherwise unconsolidated memories. To provide mechanistic insights, we developed a new behavioral task where mice form two memories, of which only the more salient memory is consolidated, and also a technology for simultaneous and longitudinal cellular resolution imaging of hippocampus, thalamus, and cortex throughout the consolidation window. We found that whereas hippocampus equally encodes multiple memories, the anteromedial thalamus forms preferential tuning to salient memories, and establishes inter-regional correlations with cortex, that are critical for synchronizing and stabilizing cortical representations at remote time. Indeed, inhibition of this thalamo-cortical circuit while imaging in cortex reveals loss of contextual tuning and ensemble synchrony in anterior cingulate, together with behavioral deficits in remote memory retrieval. We thus identify a thalamo-cortical circuit that gates memory consolidation and propose a mechanism suitable for the selection and stabilization of hippocampal memories into longer term cortical storage.

Neural activity ramps in frontal cortex signal extended motivation during learning.

Learning requires the ability to link actions to outcomes. How motivation facilitates learning is not well understood. We designed a behavioral task in which mice self-initiate trials to learn cue-reward contingencies and found that the anterior cingulate region of the prefrontal cortex (ACC) contains motivation-related signals to maximize rewards. In particular, we found that ACC neural activity was consistently tied to trial initiations where mice seek to leave unrewarded cues to reach reward-associated cues. Notably, this neural signal persisted over consecutive unrewarded cues until reward associated cues were reached, and was required for learning. To determine how ACC inherits this motivational signal we performed projection specific photometry recordings from several inputs to ACC during learning. In doing so, we identified a ramp in bulk neural activity in orbitofrontal cortex (OFC) -to-ACC projections as mice received unrewarded cues, which continued ramping across consecutive unrewarded cues, and finally peaked upon reaching a reward associated cue, thus maintaining an extended motivational state. Cellular resolution imaging of OFC confirmed these neural correlates of motivation, and further delineated separate ensembles of neurons that sequentially tiled the ramp. Together, these results identify a mechanism by which OFC maps out task structure to convey an extended motivational state to ACC to facilitate goal-directed learning.

Effectiveness of a professional identity promotion strategy for nursing students during the COVID-19 pandemic: A quasi-experimental study.

AIM: To evaluate the effectiveness of a professional identity promotion strategy (PIPS) on nursing students' professional identity and resilience. METHODS: This study was a quasi-experimental study with a random cluster sample of 103 sophomore undergraduate nursing students. One hundred students answered the questionnaires at both baseline and follow-up (51 of 53 in the intervention group and 49 of 50 in the control group). Intervention and control groups underwent 5 months PIPS and standard professional education from May 2 to September 27, respectively. Participants completed the professional identity questionnaire for nursing students (PIQNS) and Connor-Davidson resilience scale (CD-RISC). Data were collected at baseline (T0), after the intervention (T1) and 3 months after the intervention (T2), and analyzed using the Chi-squared test, Fisher's exact test, and repeated-measures analysis of variance. RESULTS: There were no significant differences between the two groups (p > .05) regarding demographic questions, professional identity, or resilience at baseline (p > .05). Significant differences were found in professional identity between groups (p < .001), measurement times (p = .026), and in the interaction between groups and measurement times (p = .018) from T0 to T2. Significant differences were found in resilience between groups (p < .001), measurement times (p = .007), and in the interaction between groups and measurement times (p = .035) from T0 to T2. CONCLUSIONS: The PIPS program improved nursing students' professional identity and resilience. Further long-term effectiveness of the program needs to be tested with implementation through various forms of mobile technology.

Screening for SH3TC2 variants in Charcot-Marie-Tooth disease in a cohort of Chinese patients.

Mutations in the SH3TC2 gene cause Charcot-Marie-Tooth disease type 4C (CMT4C), characterized by inherited demyelinating peripheral neuropathy. CMT4C is a common form of CMT4/autosomal recessive (AR) CMT1. This study examined the SH3TC2 variants, investigated genotype-phenotype correlations and explored the frequency of CMT4C in Chinese patients. A total of 206 unrelated patients of Chinese Han descent clinically diagnosed with CMT were recruited. All patients underwent detailed history-taking, neurological examination, laboratory workups, and electrophysiological studies. Genetic analysis was performed via high-throughput target sequencing (NGS). Three patients, one male and two females, were found to carry five SH3TC2 mutations: patient 1 (c.3154C > T, p.R1054X; c.929G > A, p.G310E); Patient 2 (c.2872_2872del, p.S958fs; c.3710C > T, p.A1237V) and Patient 3 (c.2782C > T, p.Q928X; c.929G > A, p.G310E). The c.2872_2872del, c.3710C > T and c.2782C > T variants were not reported before. CMT4C caused by SH3TC2 mutation is a very common type of CMT4/AR CMT1. Three novel mutations, c.2872_2872del, c.3710C > T and c.2782C > T, were found in this study. Combination of clinical phenotype, nerve conduction studies, genetic analysis and bioinformatics analysis are of vital importance in patients suspected as CMT.

Contact heat evoked potentials in knowledge workers and unskilled labors.

BACKGROUND: Whether occupation has an impact on contact heat evoked potential (CHEP) results has not been investigated. In this study, we investigated the difference of CHEP parameters between knowledge workers and unskilled labors. METHODS: A total of 137 healthy participants were recruited between November 20, 2014 and December 31, 2016. All participants underwent neurologic examination, laboratory examination, and nerve conduction studies. CHEP was performed on four body sites: the upper border of the distal third of the volar forearm, the upper border of the distal third of the lateral leg, the spinous process of seventh cervical vertebrae (C7), and the spinous process of 12th thoracic vertebrae (T12). Independent t test and nonparametric test were performed using SPSS software to compare the difference of the CHEP parameters between knowledge workers and unskilled labors. RESULTS: The "N2 latency/height" (Z = -2.290, P = 0.022) and "P2 latency/height" (Z = -2.020, P = 0.043) on the volar forearm of unskilled labors significantly increased than those of knowledge workers. The "N2 latency/height" (F = 6.348, P = 0.016) and "P2 latency/height" (F = 5.920, P = 0.018) in the distal leg of unskilled labors significantly prolonged than those of knowledge workers. The N2-P2 amplitude (F = 5.797, P = 0.020) in the distal leg of unskilled labors significantly decreased than those of knowledge workers. CONCLUSIONS: Our study found that significantly prolonged N2 latency and P2 latency and significantly decreased N2-P2 amplitude in the distal leg and the volar forearm in unskilled labors as to knowledge workers.

Prognostic value of time to generalization in 71 Chinese patients with sporadic amyotrophic lateral sclerosis.

BACKGROUND: It is important to determine prognostic factors for the outcome of amyotrophic lateral sclerosis (ALS) at an early stage. The time taken for symptoms to spread from spinal or bulbar regions to both (time to generalization; TTG) is considered a strong predictor of survival; however, this has rarely been studied in Asian populations. The aim of this retrospective study was to evaluate potential factors affecting prognosis in Chinese patients with sporadic ALS, with a focus on the association between TTG and overall survival. METHODS: Seventy-one patients with sporadic ALS who were hospitalized at Chinese PLA General Hospital from 2009 to 2016 were followed up until December 2017. Survival analysis was performed using univariate Kaplan-Meier log-rank and multivariate Cox proportional hazards models. The clinical data of the patients were recorded and analyzed. Variables studied were age at symptom onset, sex, site of symptom onset, diagnostic latency, TTG, diagnostic category, ALS Functional Rating Scale-revised score, percent predicted forced vital capacity (FVC%), and disease progression rate (DPR) at diagnosis. RESULTS: The mean age at onset was 54 (SD = 10.2) years, and the median survival time from symptom onset was 41 months (95% confidence interval: 34-47). By univariate analysis, factors independently affecting survival were age at symptom onset (Log rank = 15.652, P < 0.0001), TTG (Log rank = 14.728, P < 0.0001), diagnostic latency (Log rank = 11.997, P = 0.001), and DPR (Log rank = 6.50, P = 0.011). In the Cox multivariate model, TTG had the strongest impact on survival time (hazard ratio = 0.926, P = 0.01). CONCLUSIONS: TTG can be used as an effective indicator of prognosis in patients with sporadic ALS.

LncRNA-Disease Association Prediction Using Two-Side Sparse Self-Representation.

Evidences increasingly indicate the involvement of long non-coding RNAs (lncRNAs) in various biological processes. As the mutations and abnormalities of lncRNAs are closely related to the progression of complex diseases, the identification of lncRNA-disease associations has become an important step toward the understanding and treatment of diseases. Since only a limited number of lncRNA-disease associations have been validated, an increasing number of computational approaches have been developed for predicting potential lncRNA-disease associations. However, how to predict potential associations precisely through computational approaches remains challenging. In this study, we propose a novel two-side sparse self-representation (TSSR) algorithm for lncRNA-disease association prediction. By learning the self-representations of lncRNAs and diseases from known lncRNA-disease associations adaptively, and leveraging the information provided by known lncRNA-disease associations and the intra-associations among lncRNAs and diseases derived from other existing databases, our model could effectively utilize the estimated representations of lncRNAs and diseases to predict potential lncRNA-disease associations. The experiment results on three real data sets demonstrate that our TSSR outperforms other competing methods significantly. Moreover, to further evaluate the effectiveness of TSSR in predicting potential lncRNAs-disease associations, case studies of Melanoma, Glioblastoma, and Glioma are carried out in this paper. The results demonstrate that TSSR can effectively identify some candidate lncRNAs associated with these three diseases.

Lung motion estimation using dynamic point shifting: An innovative model based on a robust point matching algorithm.

PURPOSE: Image-guided radiotherapy is an advanced 4D radiotherapy technique that has been developed in recent years. However, respiratory motion causes significant uncertainties in image-guided radiotherapy procedures. To address these issues, an innovative lung motion estimation model based on a robust point matching is proposed in this paper. METHODS: An innovative robust point matching algorithm using dynamic point shifting is proposed to estimate patient-specific lung motion during free breathing from 4D computed tomography data. The correspondence of the landmark points is determined from the Euclidean distance between the landmark points and the similarity between the local images that are centered at points at the same time. To ensure that the points in the source image correspond to the points in the target image during other phases, the virtual target points are first created and shifted based on the similarity between the local image centered at the source point and the local image centered at the virtual target point. Second, the target points are shifted by the constrained inverse function mapping the target points to the virtual target points. The source point set and shifted target point set are used to estimate the transformation function between the source image and target image. RESULTS: The performances of the authors' method are evaluated on two publicly available DIR-lab and POPI-model lung datasets. For computing target registration errors on 750 landmark points in six phases of the DIR-lab dataset and 37 landmark points in ten phases of the POPI-model dataset, the mean and standard deviation by the authors' method are 1.11 and 1.11 mm, but they are 2.33 and 2.32 mm without considering image intensity, and 1.17 and 1.19 mm with sliding conditions. For the two phases of maximum inhalation and maximum exhalation in the DIR-lab dataset with 300 landmark points of each case, the mean and standard deviation of target registration errors on the 3000 landmark points of ten cases by the authors' method are 1.21 and 1.04 mm. In the EMPIRE10 lung registration challenge, the authors' method ranks 24 of 39. According to the index of the maximum shear stretch, the authors' method is also efficient to describe the discontinuous motion at the lung boundaries. CONCLUSIONS: By establishing the correspondence of the landmark points in the source phase and the other target phases combining shape matching and image intensity matching together, the mismatching issue in the robust point matching algorithm is adequately addressed. The target registration errors are statistically reduced by shifting the virtual target points and target points. The authors' method with consideration of sliding conditions can effectively estimate the discontinuous motion, and the estimated motion is natural. The primary limitation of the proposed method is that the temporal constraints of the trajectories of voxels are not introduced into the motion model. However, the proposed method provides satisfactory motion information, which results in precise tumor coverage by the radiation dose during radiotherapy.