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With the development of wearable electronic technology, the flexible photodetectors have attracted widespread attention, and it is of great significance to develop flexible, eco‐friendly and low‐cost photodetectors. Cellulose paper, as a flexible, eco‐friendly, low‐cost, lightweight, customizable, biodegradable and renewable material, has received enthusiastic attention and rapid development in the field of photodetectors in recent years. In this review, it is focused on the research progress of paper‐based (PB) photodetectors. First, the fabrication methods of PB photodetectors are discussed, including electrode materials and optoelectronic functional materials. Then, this review systematically summarizes and analyzes the achievements of PB photodetectors on photoelectric performances (spectral response range, responsivity, detectivity, response/recovery times and on/off ratio) and flexibility characteristics (bending angle and bending cycle). In terms of key performance indicators, the PB photodetectors reported so far can detect multiple wavelengths of light from UV to near‐infrared with the maximum detectivity of 1013 Jones. In addition, the various applications of PB photodetectors is reviewed and discussed. Finally, it is look forward to the future development of PB photodetectors in terms of fabrication methods, photoelectric and flexible performances, and applications. With this review, it is hope that it will promoted the future development of PB photodetectors. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to determine the effects of iRoot BP Plus on receptor activator of nuclear factor‐κB ligand (RANKL)‐induced osteoclastogenesis in vitro and inflammation‐mediated bone resorption in vivo and investigated the underlying molecular mechanisms. Methodology: CCK‐8 was performed to test cell viability in RANKL‐induced RAW 264.7 cells and BMDMs in response to iRoot BP Plus. The effect of iRoot BP Plus on osteoclastogenesis was determined using TRAP staining and phalloidin staining, respectively. Pit formation assay was conducted to measure osteoclast resorptive capacity. Western blot and qPCR were performed to examine osteoclast‐related proteins and gene expression, respectively. Western blot was also used to investigate the signalling pathways involved. For in vivo experiments, an LPS‐induced mouse calvarial bone resorption model was established to analyse the effect of iRoot BP Plus on bone resorption (n = 6 per group). At 7 days, mouse calvaria were collected and prepared for histological analysis. Results: We identified that iRoot BP Plus extracts significantly attenuated RANKL‐induced osteoclastogenesis, reduced sealing zone formation, restrained osteolytic capacity and decreased osteoclast‐specific gene expression (p <.01). Mechanistically, iRoot BP Plus extracts reduced TRAF6 via proteasomal degradation, then suppressed the phosphorylation of mitogen‐activated protein kinases (MAPKs), blocked the nuclear translocation of c‐Fos and diminished nuclear factor‐κB (NF‐κB) p65 and NFATc1 accumulation. Consistent with the in vitro results, iRoot BP Plus extracts attenuated osteoclast activity thus protecting against inflammatory bone resorption in vivo (p <.05), which was accompanied by a suppression of TRAF6, c‐Fos, NFATc1 and cathepsin K expression. Conclusion: These findings provide valuable insights into the signalling mechanisms underlying nanoparticulate bioceramic putty‐mediated bone homeostasis. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidence supports the involvement of adaptive immunity in the development of radiation‐induced brain injury (RIBI). Our previous work has emphasized the cytotoxic function of CD8+ T cells in RIBI. In this study, we aimed to investigate the presence and potential roles of cytotoxic CD4+ T cells (CD4+ CTLs) in RIBI to gain a more comprehensive understanding of adaptive immunity in this context. Main Text: Utilizing single‐cell RNA sequencing (scRNA‐seq), we analyzed 3934 CD4+ T cells from the brain lesions of four RIBI patients and identified six subclusters within this population. A notable subset, the cytotoxic CD4+ T cells (CD4+ CTLs), was marked with high expression of cytotoxicity‐related genes (NKG7, GZMH, GNLY, FGFBP2, and GZMB) and several chemokine and chemokine receptors (CCL5, CX3CR1, and CCL4L2). Through in‐depth pseudotime analysis, which simulates the development of CD4+ T cells, we observed that the CD4+ CTLs exhibited signatures of terminal differentiation. Their functions were enriched in protein serine/threonine kinase activity, GTPase regulator activity, phosphoprotein phosphatase activity, and cysteine‐type endopeptidase activity involved in the apoptotic signaling pathway. Correspondingly, mice subjected to gamma knife irradiation on the brain showed a time‐dependent infiltration of CD4+ T cells, an increase of MHCII+ cells, and the existence of CD4+ CTLs in lesions, along with an elevation of apoptotic‐related proteins. Finally, and most crucially, single‐cell T‐cell receptor sequencing (scTCR‐seq) analysis at the patient level determined a large clonal expansion of CD4+ CTLs in lesion tissues of RIBI. Transcriptional factor‐encoding genes TBX21, RORB, and EOMES showed positive correlations with the cytotoxic functions of CD4+ T cells, suggesting their potential to distinguish RIBI‐related CD4+ CTLs from other subsets. Conclusion: The present study enriches the understanding of the transcriptional landscape of adaptive immune cells in RIBI patients. It provides the first description of a clonally expanded CD4+ CTL subset in RIBI lesions, which may illuminate new mechanisms in the development of RIBI and offer potential biomarkers or therapeutic targets for the disease. [ABSTRACT FROM AUTHOR]

Although gene/genome duplications in the early stage of vertebrates have been thought to provide major resources of raw genetic materials for evolutionary innovations, it is unclear whether they continuously contribute to the evolution of morphological complexity during the course of vertebrate evolution, such as the evolution from two heart chambers (fishes) to four heart chambers (mammals and birds). We addressed this issue by our heart RNA‐Seq experiments combined with published data, using 13 vertebrates and one invertebrate (sea squirt, as an outgroup). Our evolutionary transcriptome analysis showed that number of ancient paralogous genes expressed in heart tends to increase with the increase of heart chamber number along the vertebrate phylogeny, in spite that most of them were duplicated at the time near to the origin of vertebrates or even more ancient. Moreover, those paralogs expressed in heart exert considerably different functions from heart‐expressed singletons: the former are functionally enriched in cardiac muscle and muscle contraction‐related categories, whereas the latter play more basic functions of energy generation like aerobic respiration. These findings together support the notion that recruiting anciently paralogous genes that are expressed in heart is associated with the increase of chamber number in vertebrate evolution. Research Highlights: Correlation between the expression of paralogous genes and heart chamber complexity.Paralogs expressed in heart exert considerably different functions from heart‐expressed singletons.Paralogous genes expressed in heart is associated with the increase of chamber number in evolution. [ABSTRACT FROM AUTHOR]

For sustainable wearable applications, triboelectric nanogenerators (TENGs) should have the features of flexibility, robustness, biocompatibility, and integration. For this purpose, flexible TENGs were proposed using thermoplastic polyurethane (TPU) film with a porous structure and multi‐walled carbon nanotubes (MWCNT) was incorporated to enhance the output performance by forming microcapatitors. The conductive fabric was embedded in the friction layer as electrodes, convenient for integration and wearing. Benefiting from the porous structure and microcapatitor effect, the results showed that the output voltage and current of TENG based on the MWCNT@TPU porous composite film increased to 41 V, and 12.4 μA when the concentration of TPU was 18 wt% and the concentration of MWCNT was 0.3 wt%, from the original 9 V and 1.5 μA for TENG with dense TPU film. The harvested electric energy was enough to light up 148 LEDs or 18 COBs, as well as charging capacitors for powering micro‐electronics. In addition, the TENG could be used for sensing emergency situations and identifying objects. Generally, the designed TENG provides new insights into investigating porous materials with flexibility for high performance energy harvesters. Highlights: A wearable, integratable and durable triboelectric layer was developed.The triboelectric layer was optimized by incorporating carbon nanotubes.The outputs of TENG were improved by porous structure and microcapatitor effect.The TENG had a great potential in energy harvesting and protective alarm system. [ABSTRACT FROM AUTHOR]

Osteoclasts are bone‐resorbing polykaryons responsible for skeletal remodeling during health and disease. Coincident with their differentiation from myeloid precursors, osteoclasts undergo extensive transcriptional and metabolic reprogramming in order to acquire the cellular machinery necessary to demineralize bone and digest its interwoven extracellular matrix. While attempting to identify new regulatory molecules critical to bone resorption, we discovered that murine and human osteoclast differentiation is accompanied by the expression of Zeb1, a zinc‐finger transcriptional repressor whose role in normal development is most frequently linked to the control of epithelial‐mesenchymal programs. However, following targeting, we find that Zeb1 serves as an unexpected regulator of osteoclast energy metabolism. In vivo, Zeb1‐null osteoclasts assume a hyperactivated state, markedly decreasing bone density due to excessive resorptive activity. Mechanistically, Zeb1 acts in a rheostat‐like fashion to modulate murine and human osteoclast activity by transcriptionally repressing an ATP‐buffering enzyme, mitochondrial creatine kinase 1 (MtCK1), thereby controlling the phosphocreatine energy shuttle and mitochondrial respiration. Together, these studies identify a novel Zeb1/MtCK1 axis that exerts metabolic control over bone resorption in vitro and in vivo. Synopsis: Osteoporosis and similar bone‐wasting conditions can be caused by an increase in osteoclast‐mediated bone resorption. Here, we learn that both murine and human osteoclasts are activated by a Zeb1‐dependent regulation of mitochondrial energy metabolism.The transcription factor Zeb1 is a negative regulator of giant multinucleated osteoclast‐mediated skeletal remodeling.Zeb1 regulates mitochondrial energy metabolism in myeloid lineage‐derived osteoclasts.The mitochondrial creatine kinase MtCK1 is a transcriptional target of Zeb1 that enables bone resorption by buffering ATP availability. [ABSTRACT FROM AUTHOR]

Craniosynostosis is a congenital anomaly characterized by the premature fusion of cranial sutures. Sutures are a critical connective tissue that regulates bone growth; their aberrant fusion results in abnormal shapes of the head and face. The molecular and cellular mechanisms have been investigated for a long time, but knowledge gaps remain between genetic mutations and mechanisms of pathogenesis for craniosynostosis. We previously demonstrated that the augmentation of bone morphogenetic protein (BMP) signaling through constitutively active BMP type 1A receptor (caBmpr1a) in neural crest cells (NCCs) caused the development of premature fusion of the anterior frontal suture, leading to craniosynostosis in mice. In this study, we demonstrated that ectopic cartilage forms in sutures prior to premature fusion in caBmpr1a mice. The ectopic cartilage is subsequently replaced by bone nodules leading to premature fusion with similar but unique fusion patterns between two neural crest‐specific transgenic Cre mouse lines, P0‐Cre and Wnt1‐Cre mice, which coincides with patterns of premature fusion in each line. Histologic and molecular analyses suggest that endochondral ossification in the affected sutures. Both in vitro and in vivo observations suggest a greater chondrogenic capacity and reduced osteogenic capability of neural crest progenitor cells in mutant lines. These results suggest that the augmentation of BMP signaling alters the cell fate of cranial NCCs toward a chondrogenic lineage to prompt endochondral ossification to prematurely fuse cranial sutures. By comparing P0‐Cre;caBmpr1a and Wnt1‐Cre;caBmpr1a mice at the stage of neural crest formation, we found more cell death of cranial NCCs in P0‐Cre;caBmpr1a than Wnt1‐Cre;caBmpr1a mice at the developing facial primordia. These findings may provide a platform for understanding why mutations of broadly expressed genes result in the premature fusion of limited sutures. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

As omics technologies, including genomics, epigenomics, transcriptomics, T cell receptor‐repertorie profiling, proteomics, metabolomics and microbiomics, have provided valuable insights into CAR T cell therapy, in our recent review, we discuss these multidimensional profiling technologies in CAR T cell research, and their potential to identify tumor‐specific antigens and molecular characteristics associated with anti‐tumour effects and toxicities. [ABSTRACT FROM AUTHOR]

Background: The effects of seasonal factors on sensitive skin (SS) have been reported intensively, but the mechanisms still remain poorly understood. Objective: To investigate the effects of seasonal factors on SS, by comparing the physiological changes in the healthy skin and different subgroups of SS with seasonal variation. Methods: Through a questionnaire survey, lactic acid sting test, and capsaicin test, qualified subjects were classified into four groups: healthy skin, only lactic acid sting test positive (LAST(+)/CAT(−)), only capsaicin test positive (LAST(−)/CAT(+)), and both positive (LAST(+)/CAT(+)). Skin physiological parameters were measured in winter and summer. Results: A total of 140 subjects completed the study. Significant differences were found in transepidermal water loss (TEWL), skin pH, and cutaneous blood flow (CBF) between winter and summer in the four groups. There were significant differences in stratum corneum hydration (SCH) of the LAST(+)/CAP(−) and LAST(+)/CAP(+) groups, current perception threshold (CPT) at 250 Hz of the LAST(+)/CAT(+) group, and epidermal density of the healthy skin group between the two seasons. Sum of the scores of sting (SSS) showed a close correlation with TEWL, SCH, pH, CPT at 250 Hz, and epidermal density. Sum of the scores of burning (SSB) showed a strong correlation with TEWL, pH, CPT at 250 Hz and 5 Hz, and epidermal density. Conclusions: Seasonal variation influences the skin barrier function of different types of sensitive skin at different levels. We therefore strongly suggest that, with seasonal variation, different treatments will be undertaken for different subgroups of sensitive skin. [ABSTRACT FROM AUTHOR]

Mammalian cells utilize Akt‐dependent signaling to deploy intracellular Glut4 toward cell surface to facilitate glucose uptake. Low‐density lipoprotein receptor (LDLR) is the cargo receptor mediating endocytosis of apolipoprotein B‐containing lipoproteins. However, signaling‐controlled regulation of intracellular LDLR trafficking remains elusive. Here, we describe a unique amino acid stress response, which directs the deployment of intracellular LDLRs, causing enhanced LDL endocytosis, likely via Ca2+ and calcium/calmodulin‐dependent protein kinase II‐mediated signalings. This response is independent of induction of autophagy. Amino acid stress‐induced increase in LDL uptake in vitro is comparable to that by pravastatin. In vivo, acute AAS challenge for up to 72 h enhanced the rate of hepatic LDL uptake without changing the total expression level of LDLR. Reducing dietary amino acids by 50% for 2 to 4 weeks ameliorated high fat diet‐induced hypercholesterolemia in heterozygous LDLR‐deficient mice, with reductions in both LDL and VLDL fractions. We suggest that identification of signaling‐controlled regulation of intracellular LDLR trafficking has advanced our understanding of the LDLR biology, and may benefit future development of additional therapeutic strategies for treating hypercholesterolemia. Synopsis: At the cellular level, amino acid starvation triggers translocation of intracellular LDLRs to the cell surface, causing enhanced LDL endocytosis. At the systemic level, dietary amino acid restriction enhances clearance of LDL cholesterol from the circulation. Removal of extracellular amino acids promotes LDLR trafficking to the cell surface, leading to enhanced LDL endocytosisThis response is mediated by Ca2+‐ and CaMKII‐dependent signaling which redistributes intracellular LDLRs to the fast recycling routeIn heterozygous LDLR+/− mice, dietary amino acid restriction ameliorates high fat‐induced hypercholesterolemia [ABSTRACT FROM AUTHOR]

The cranial base is a critical structure in the head, which is composed of endoskeletal and dermal skeletal. The braincase floor, part of the cranial base, is a midline structure of the head. Because it is a midline structure connecting the posterior skull with the facial region, braincase floor is critical for the orientation of the facial structure. Shortened braincase floor leads to mid‐facial hypoplasia and malocclusions. During embryonic development, elongation of the braincase floor occurs through endochondral ossification in the parachordal cartilage, hypophyseal cartilage, and trabecular cartilage, which leads to formation of basioccipital (BO), basisphenoid (BS), and presphenoid (PS) bones, respectively. Currently, little is known about whether maturation of parachordal cartilage, hypophyseal cartilage, and trabecular cartilage occurs in a simultaneous or sequential manner and if the formation of one impacts the others. Our previous studies demonstrated that loss of function of ciliary protein Evc2 leads to premature fusion in the intersphenoid synchondrosis (ISS). In this study, we take advantage of Evc2 mutant mice to delineate the mechanism governing synchondrosis formation. Our analysis supports a cascade mechanism on the spatiotemporal regulation of the braincase floor development that the hypertrophy of parachordal cartilage (posterior side) impacts the hypertrophy of hypophyseal cartilage (middle) and trabecular cartilage (anterior side) in a sequential manner. The cascade mechanism well explains the premature fusion of the ISS in Evc2 mutant mice and is instructive to understand the specifically shortened anterior end of the braincase floor in various types of genetic syndromes. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

This bioequivalence study was conducted to determine the pharmacokinetics and safety profiles of an originator and a generic avanafil formulation in Chinese male subjects under fed and fasting conditions. Each eligible subject was initially randomly given avanafil (200 mg) in a test‐reference or reference‐test order, before being switched to another study drug sequence after 7 drug‐free days. The bioequivalence of test and reference avanafil were determined if the 90%CIs of the geometric mean ratio (GMR) for the area under plasma concentration‐time curve (AUC) from time 0 to infinity (AUC0‐∞), AUC from time 0 to the last detectable concentration (AUC0‐t), and the maximum plasma concentration (Cmax) fell within the range 80%‐125%. Under fasting/fed conditions, the 90%CIs of GMR for AUC0‐∞, AUC0‐t, and Cmax were 98.9% to 109.5%/96.0% to 101.2%, 99.6% to 110.3%/96.6% to 102.4%, and 99.3% to 116.8%/94.3% to 106.7%, respectively, which were all within the 80%‐125% range. Adverse events (AEs) occurred in 20.8% of subjects under fasting conditions and 20.7% of subjects under fed conditions, with a severity of grade 1. No significant difference was found in the rate of occurrence of AEs and drug‐related AEs in the test and reference‐avanafil groups (all P >.05). We concluded that the test and reference avanafil were bioequivalent in healthy Chinese male subjects under fasting and fed conditions. [ABSTRACT FROM AUTHOR]

Rapid rescue response has the highest priority in case of emergency randomly happening on the freeway network, which allows rescue vehicles to have many trajectory options. Searching for the fastest way is not easy within a short time after traffic accident happens especially for the mountainous area with special characteristics such as limited traffic capacity, enclosed internal space and so on. Here, road segment model is proposed to determine smallest road segment covering possible rescue ways. Other than traditional optimal search methods, modified reinforcement‐leaning is introduced to find the optimal road trajectory. The proposed methods are tested in the freeway of Qinling Tunnel group, Xihan Freeway of Shaanxi province, China as a case study. Compared with traditional shortest path method, the rescue vehicle arrival time to the accident location is shortened from 22.9 to 6.5 min and dissipation time is also shortened from 52.4 to 25.6 min. Both of them show the proposed road trajectory could improve the rescue effectiveness and reduce the influence to road network. Successful application of these case study shows they could probably extend to use to other scenarios and contribute to improve the intelligence transportation system. [ABSTRACT FROM AUTHOR]

Lithium‐sulfur (Li‐S) batteries are one of the most promising high‐energy‐density storage systems. However, serious capacity attenuation and poor cycling stability induced by the shuttle effect of polysulfide intermediates can impede the practical application of Li‐S batteries. Herein we report a novel sulfur cathode by intertwining multi‐walled carbon nanotubes (CNTs) and porous boron nitride fibers (BNFs) for the subsequent loading of sulfur. This structural design enables trapping of active sulfur and serves to localize the soluble polysulfide within the cathode region, leading to low active material loss. Compared with CNTs/S, CNTs/BNFs/S cathodes deliver a high initial capacity of 1222 mAh g−1 at 0.1 C. Upon increasing the current density to 4 C, the cell retained a capacity of 482 mAh g−1 after 500 cycles with a capacity decay of only 0.044 % per cycle. The design of CNTs/BNFs/S gives new insight on how to optimize cathodes for Li‐S batteries. [ABSTRACT FROM AUTHOR]

Aim: To analyze the heterogeneity of fibroblasts isolated from the fibrous capsules of radicular cysts and explore the effects of fibroblast subsets on bone destruction. Methodology: Radicular cysts were divided into groups according to varying perilesional sclerosis identified by radiograph. Colony‐forming units (CFUs) were isolated from the fibrous capsules of cysts, by which Trap + MNCs were induced, and the expression of osteoclastogenesis‐related genes was compared among groups by real‐time PCR. The variances in gene profiles of CFUs were identified by principal component analysis, and then, CFUs were divided into subsets using cluster analysis. The induction of Trap + MNCs and related gene expression was compared among subsets, and osteoclastogenic induction was blocked by IST‐9 or bevacizumab. The fibroblast subsets in cysts were investigated by retrospective immunostaining with IST‐9, VEGF‐A, and CD34. A fibroblast subset that underwent gene editing by CRISPR/Cas was injected into the site of bone defects in animal models, and the in vivo effects on osteoclastogenesis were investigated. Results: The fibroblast CFUs isolated from radicular cysts with perilesional unsclerotized cysts induced more Trap + MNCs than those with perilesional sclerotic cysts (p <.05). Most fibroblast CFUs from unsclerotized cysts belonged to Cluster 2, which induced more Trap + MNCs (p <.05) and highly expressed genes facilitating osteoclastogenesis; these results were different from those of Cluster 1 (p <.05), in which most CFUs were isolated from perilesional sclerotic cysts or controls (p <.05). The high expression of EDA + FN and VEGF‐A was investigated in both the fibroblasts of Cluster 2 and the fibrous capsules of unsclerotized cysts (p <.05), and the number of Trap + MNCs induced by Cluster 2 was decreased by treatment with IST‐9 and bevacizumab (p <.05). Consistently, EDA exon exclusion significantly decreased the osteoclastogenic induction of fibroblasts from Cluster 2 in vivo (p <.05). Conclusion: The fibrous capsules of radicular cysts contain heterogeneous fibroblasts that can form subsets exhibiting different effects on osteoclastogenesis. The subset, which depending on the autocrine effects of EDA + FN on VEGF‐A, mainly contributes to the osteoclastogenesis and bone destruction of radicular cysts. The regulation of the proportion of subsets is a possible strategy for artificially interfering with osteoclastogenesis. [ABSTRACT FROM AUTHOR]

Biphasic calcium phosphate (BCP) ceramics are the subject of much attention for use as bone replacement material. However, it remains a challenge to promote the degradation and osteoinductivity performances of BCP ceramics. In this work, novel BCP ceramic microspheres with good degradation and excellent osteoinductivity were prepared through high‐content strontium (Sr) doping. The in vitro results indicated that the Sr10‐BCP, Sr40‐BCP, and Sr80‐BCP microspheres all had their HA crystals partially transformed to the beta tricalcium phosphate phase following high‐temperature sintering because of Ca‐deficient HA formed by the partial substitution of Ca ions by Sr ions. In addition, the degradation rate was increased with the doping of increasing amounts of Sr. All prepared microspheres enhanced human bone marrow‐derived mesenchymal stem cells attachment and proliferation. Specifically, among these modified microspheres, the Sr40‐BCP microspheres showed the highest osteogenic potential. Furthermore, Sr40‐BCP and HA microspheres were implanted in a calvarial defect model of rat to evaluate the in vivo bone augmentation ability. The results indicated that Sr40‐BCP microspheres degraded more completely and significantly promoted new bone regeneration compared with HA microspheres. In conclusion, Sr40‐BCP microspheres have excellent potential for degradation and bone regeneration and are promising osteogenic materials. [ABSTRACT FROM AUTHOR]

Novel Eu3+-doped transparent oxyfluoride glass-ceramics containing BaLuF5 nanocrystals were successfully fabricated by melt-quenching technique for the first time. Analyses of XRD patterns prove that the new precipitated glass-ceramics are crystallized in cubic BaLuF5 based on isostructural BaGdF5. Intense red emissions observed in glass ceramics are attributed to the enrichment of Eu3+ ions into BaLuF5 nanocrystals. Besides, obvious stark splitting emissions, low forced electric dipole 5D0→7F2 transition, and long decay lifetimes of Eu3+ ions also evidence the partition of Eu3+ ions into BaLuF5 nanocrystals with low phonon energy. Such transparent material may find applications in photonics. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidence supports the involvement of adaptive immunity in the development of radiation-induced brain injury (RIBI). Our previous work has emphasized the cytotoxic function of CD8 + T cells in RIBI. In this study, we aimed to investigate the presence and potential roles of cytotoxic CD4 + T cells (CD4 + CTLs) in RIBI to gain a more comprehensive understanding of adaptive immunity in this context., Main Text: Utilizing single-cell RNA sequencing (scRNA-seq), we analyzed 3934 CD4 + T cells from the brain lesions of four RIBI patients and identified six subclusters within this population. A notable subset, the cytotoxic CD4 + T cells (CD4 + CTLs), was marked with high expression of cytotoxicity-related genes (NKG7, GZMH, GNLY, FGFBP2, and GZMB) and several chemokine and chemokine receptors (CCL5, CX3CR1, and CCL4L2). Through in-depth pseudotime analysis, which simulates the development of CD4 + T cells, we observed that the CD4 + CTLs exhibited signatures of terminal differentiation. Their functions were enriched in protein serine/threonine kinase activity, GTPase regulator activity, phosphoprotein phosphatase activity, and cysteine-type endopeptidase activity involved in the apoptotic signaling pathway. Correspondingly, mice subjected to gamma knife irradiation on the brain showed a time-dependent infiltration of CD4 + T cells, an increase of MHCII + cells, and the existence of CD4 + CTLs in lesions, along with an elevation of apoptotic-related proteins. Finally, and most crucially, single-cell T-cell receptor sequencing (scTCR-seq) analysis at the patient level determined a large clonal expansion of CD4 + CTLs in lesion tissues of RIBI. Transcriptional factor-encoding genes TBX21, RORB, and EOMES showed positive correlations with the cytotoxic functions of CD4 + T cells, suggesting their potential to distinguish RIBI-related CD4 + CTLs from other subsets., Conclusion: The present study enriches the understanding of the transcriptional landscape of adaptive immune cells in RIBI patients. It provides the first description of a clonally expanded CD4 + CTL subset in RIBI lesions, which may illuminate new mechanisms in the development of RIBI and offer potential biomarkers or therapeutic targets for the disease., (© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)