Imiquimod:A potential option for inhibition of repigmentation of congenital melanocytic nevus after laser ablation

Congenital melanocytic nevi(CMN) are common skin tumors. Large and specially located nevi cannot be completely removed by surgery, posing the risks of both cosmetic deformities and potential malignancy.Nonsurgical treatments, such as laser therapy and physical dermabrasion, can overcome the limitations of surgery;however, the high rate of repigmentation remains an unresolved global challenge. We conducted a self-controlled observational study of a patient with a nevus on the chest. Two areas of the lesion were treated with an Er:YAG laser and 5% imiquimod cream was applied to one of these areas. After nearly 7-months of follow-up, we observed a significant difference in color between the two areas, suggesting that topical imiquimod may inhibit repigmentation and significantly enhance the effectiveness of laser treatment.

Comprehensive identification and potential application of genetic alteration-driven enhancer RNAs for eRNA-targeted therapy in breast cancer

Enhancer RNAs(eRNAs)are a class of non-coding RNA,which play a critical role in tumor progression.1 Previous studies have indicated abundant CpG methylation,somatic mutation,and copy number variation in eRNA regions in cancers.2,3 We constructed a landscape of genetic alteration-driven eRNAs and provided an integrative pipeline to identify drug candidates that affect eRNA activity.Furthermore,we explored the prognostic value of genetic alteration-driven eRNAs.

Clinical management of a rare melanoma case arising from congenital melanocytic nevus

Congenital melanocytic nevi(CMNs)are skin lesions characterized by benign melanocytic proliferations and present at birth or shortly thereafter.Large and giant CMNs,with a projected adult size≥20 cm and 40 cm in diameter respectively,are more likely to develop into malignant melanoma.In most cases,melanoma arising from congenital melanocytic nevus(CMN)is particularly aggressive.

Biallelic inactivation of SDHA results in comorbidity of pediatric recurrent neuroblastoma and gastric stromal tumor

Neuroblastoma(NB)is a common pediatric extracranial solid tumor that exhibits varied characteristics,clinical features,and prognosis.1 Totally 1%-2%of cases show familial history with genetic links like ALK,PHOX2B mutations,and1p36or11q14-23locusdeletions.Gastrointestinal stromal tumors(GISTs)are rare mesenchymal neoplasms of the gastrointestinal tract.

Aligned Organization of Synapses and Mitochondria in Auditory Hair Cells

Recent studies have revealed great functional and structural heterogeneity in the ribbon-type synapses at the basolateral pole of the isopotential inner hair cell(IHC).This feature is believed to be critical for audition over a wide dynamic range,but whether the spatial gradient of ribbon morphology is fine-tuned in each IHC and how the mitochondrial network is organized to meet local energy demands of synaptic transmission remain unclear.By means of three-dimensional electron microscopy and artificial intelligence-based algorithms,we demonstrated the cell-wide structural quantification of ribbons and mitochondria in mature mid-cochlear IHCs of mice.We found that adjacent IHCs in staggered pairs differ substantially in cell body shape and ribbon morphology gradient as well as mitochondrial organization.Moreover,our analysis argues for a location-specific arrangement of correlated ribbon and mitochondrial function at the basolateral IHC pole.

Toward a molecular mechanism-based prediction of CRISPR-Cas9 targeting effects

The CRISPR-Cas9 system,serving as a powerful genome-editing technology,has revolutionized the life sciences.However,it exhibits off-target activities that may present severe problems in clinical applications.Although a great number of in silico models have been developed to predict CRISPR targeting efficiency and specificity,they are running into a bottleneck with the lack of a mechanistic understanding of the on-and off-target activities of Cas9.

Single-cell RNA-Seq reveals transcriptional regulatory networks directing the development of mouse maxillary prominence

During vertebrate embryonic development,neural crest-derived ectomesenchyme within the maxillary prominences undergoes precisely coordinated proliferation and differentiation to give rise to diverse craniofacial structures,such as tooth and palate.However,the transcriptional regulatory networks underpinning such an intricate process have not been fully elucidated.Here,we perform single-cell RNA-Seq to comprehensively characterize the transcriptional dynamics during mouse maxillary development from embryonic day(E)10.5eE14.5.Our single-cell transcriptome atlas of~28,000 cells uncovers mesenchymal cell populations representing distinct differentiating states and reveals their developmental trajectory,suggesting that the segregation of dental from the palatal mesenchyme occurs at E11.5.Moreover,we identify a series of key transcription factors(TFs)associated with mesenchymal fate transitions and deduce the gene regulatory networks directed by these TFs.Collectively,our study provides important resources and insights for achieving a systems-level understanding of craniofacial morphogenesis and abnormality.

Upregulation of RIN3 induces endosomal dysfunction in Alzheimer’s disease

Background In Alzheimer’s Disease(AD),about one-third of the risk genes identified by GWAS encode proteins that function predominantly in the endocytic pathways.Among them,the Ras and Rab Interactor 3(RIN3)is a guanine nucleotide exchange factor(GEF)for the Rab5 small GTPase family and has been implicated to be a risk factor for both late onset AD(LOAD)and sporadic early onset AD(sEOAD).However,how RIN3 is linked to AD pathogenesis is currently undefined.Methods Quantitative PCR and immunoblotting were used to measure the RIN3 expression level in mouse brain tissues and cultured basal forebrain cholinergic neuron(BFCNs).Immunostaining was used to define subcellular localization of RIN3 and to visualize endosomal changes in cultured primary BFCNs and PC12 cells.Recombinant flag-tagged RIN3 protein was purified from HEK293T cells and was used to define RIN3-interactomes by mass spectrometry.RIN3-interacting partners were validated by co-immunoprecipitation,immunofluorescence and yeast two hybrid assays.Live imaging of primary neurons was used to examine axonal transport of amyloid precursor protein(APP)andβ-secretase 1(BACE1).Immunoblotting was used to detect protein expression,processing of APP and phosphorylated forms of Tau.Results We have shown that RIN3 mRNA level was significantly increased in the hippocampus and cortex of APP/PS1 mouse brain.Basal forebrain cholinergic neurons(BFCNs)cultured from E18 APP/PS1 mouse embryos also showed increased RIN3 expression accompanied by early endosome enlargement.In addition,via its proline rich domain,RIN3 recruited BIN1(bridging integrator 1)and CD2AP(CD2 associated protein),two other AD risk factors,to early endosomes.Interestingly,overexpression of RIN3 or CD2AP promoted APP cleavage to increase its carboxyl terminal fragments(CTFs)in PC12 cells.Upregulation of RIN3 or the neuronal isoform of BIN1 increased phosphorylated Tau level.Therefore,upregulation of RIN3 expression promoted accumulation of APP CTFs and increased phosphorylated Tau.These effects by RIN3 was rescued by the expression of a dominant negative Rab5(Rab5S34N)construct.Our study has thus pointed to that RIN3 acts through Rab5 to impact endosomal trafficking and signaling.Conclusion RIN3 is significantly upregulated and correlated with endosomal dysfunction in APP/PS1 mouse.Through interacting with BIN1 and CD2AP,increased RIN3 expression alters axonal trafficking and procession of APP.Together with our previous studies,our current work has thus provided important insights into the role of RIN3 in regulating endosomal signaling and trafficking.

The genomic,transcriptomic,and immunological profiles of perineural invasion in pancreatic ductal adenocarcinoma

Dear Editor,Cancer neuroscience is an emerging topic in cancer research(Monje et al.,2020;Shi et al.,2022).Perineural invasion(PNI),defined as the neoplastic invasion of tumor cells into or surrounding the different layers of nervous fibers(epineural,perineural,and endoneural spaces of the neuronal sheath),is associated with aggressive tumor behavior.

Clinical utilization of olaparib,a PARP inhibitor,in BRCA1-mutant metastatic acral melanoma

Acral melanoma(AM)is a rare subtype of cutaneous melanoma linked to poor prognosis,largely due to a lacking of effective targeted therapeutic strategies.Whole-genome sequencing(WGS)data revealed that AM showed a different mutation landscape from cutaneous melanoma.1 BRCA1 and BRCA2 mutations appear in about 3%–16%of AMs.2,3 Pharmacologic inhibition of the DNA repair enzyme PARP has been approved by the FDA as monotherapy in patients with deleterious germline BRCA1/2 mutated advanced ovarian cancer,and the usage has been expanded to metastatic breast cancer,pancreatic cancer,and prostate cancer with homologous recombination repair(HRR)gene defects.4 However,whether AM with BRCA mutations is also sensitive to PARP inhibition is unknown.We identified a stageⅣAM patient with a germline BRCA1 frameshift mutation(BRAC1 G1384Nfs∗7)who was resistant to anti-PD1 therapy.Both patient-derived xenograft and cells(PDX/PDC)models from the same AM patient were established.PARP inhibitor olaparib significantly decreased cell proliferation and slowed tumor growth by increasing DNA double-strand breakage in AM cancer cells.Administration of olaparib to the patient achieved stable disease for 3 months.This study provides preclinical and clinical evidence that PARP inhibitors can slow tumor growth in BRCA1-mutant advanced acral melanoma.

An Injectable silk-based hydrogel as a novel biomineralization seedbed for critical-sized bone defect regeneration

The healing process of critical-sized bone defects urges for a suitable biomineralization environment. However, the unsatisfying repair outcome usually results from a disturbed intricate milieu and the lack of in situ mineralization resources. In this work, we have developed a composite hydrogel that mimics the natural bone healing processes and serves as a seedbed for bone regeneration. The oxidized silk fibroin and fibrin are incorporated as rigid geogrids, and amorphous calcium phosphate (ACP) and platelet-rich plasma serve as the fertilizers and loam, respectively. Encouragingly, the seedbed hydrogel demonstrates excellent mechanical and biomineralization properties as a stable scaffold and promotes vascularized bone regeneration in vivo. Additionally, the seedbed serves a succinate-like function via the PI3K-Akt signaling pathway and subsequently orchestrates the mitochondrial calcium uptake, further converting the exogenous ACP into endogenous ACP. Additionally, the seedbed hydrogel realizes the succession of calcium resources and promotes the evolution of the biotemplate from fibrin to collagen. Therefore, our work has established a novel silk-based hydrogel that functions as an in-situ biomineralization seedbed, providing a new insight for critical-sized bone defect regeneration.

The single-cell landscape reveals unique tumor subsets and microenvironments associated with poor clinical outcomes in primary testicular diffuse large B-cell lymphoma

Diffuse large B cell lymphoma(DLBCL)is one of the most prevalent lymphoid malignancies.The current standard of care can cure about two-thirds of DLBCL patients.1 Primary testicular diffuse large B-cell lymphoma(PT-DLBCL)is a rare but highly aggressive form of mature B-cell lymphoma that accounts for approximately 1%-9%of testicular malignancies.Different from nodal DLBCL,PT-DLBCL has a markedly worse prognosis because of inferior response to the current treatment regimens and significant extranodal tropism.2 Three main questions remained unresolved in the field of PT-DLBCL research.

Advancements in understanding chickencoccidiosis:from Eimeria biology to innovativecontrol strategies

Coccidiosis,an intestinal disease caused by Eimeria protozoan parasites,affects various animal species,and espe-cially poses a significant threat to the poultry industry.The current primary control methods include anticoccidial drugs and vaccines.However,emerging challenges such as drug resistance and vaccine efficacy issues are rooted in the complex life cycle and species diversification of Eimeria.In this review,we first consolidate recent breakthroughs in understanding Eimeria biology,focusing on the parasite development and its intricate interactions with the host,notably its relationships with host immune cells and the gut microbiota.Furthermore,we provide an extensive sum-mary of current control strategies for Eimeria infections.This includes an in-depth analysis of anticoccidial drugs,their mechanisms of resistance,and the increasing utilization of diverse anticoccidial vaccines to combat these challenges.Finally,we highlight the latest innovative strategies leading the way in coccidiosis control.Through an exploration of cutting-edge techniques,we also provide insights into future directions for effectively combating this disease.In conclusion,the future of coccidiosis control lies in the use of a multifaceted approach,integrating advanced bio-logical insights with innovative therapeutic strategies.This review not only serves to enhance our understanding of Eimeria biology but also provides a valuable resource for researchers involved in developing and implementing strategies to manage and control coccidiosis,ensuring the health and productivity of poultry worldwide.

Mutations in CCIN cause teratozoospermia and male infertility

Teratozoospermia is usually associated with defective spermiogenesis and is a disorder with considerable genetic heterogeneity. Although previous studies have identified several teratozoospermia-associated genes, the etiology remains unknown for a majority of affected men. Here, we identified a homozygous missense mutation and a compound heterozygous mutation of CCIN in patients suffering from teratozoospermia. CCIN encodes the cytoskeletal protein Calicin that is involved in the formation and maintenance of the highly regular organization of the calyx of mammalian spermatozoa, and has been proposed to play a role in sperm head structure remodeling during the process of spermiogenesis. Our morphological and ultrastructural analyses of the spermatozoa obtained from all three men harboring deleterious CCIN mutants reveal severe head malformation. Further immunofluorescence assays unveil markedly reduced levels of Calicin in spermatozoa. These patient phenotypes are successfully recapitulated in mouse models expressing the disease-associated variants, confirming the role of Calicin in male fertility.Notably, all mutant spermatozoa from mice and human patients fail to adhere to the zona mass, which likely is the major mechanistic reason for CCIN-mutant sperm-derived infertility. Finally, the use of intracytoplasmic sperm injections(ICSI) successfully makes mutated mice and two couples with CCIN variants have healthy offspring. Taken together, our findings identify the role of Calicin in sperm head shaping and male fertility, providing important guidance for genetic counseling and assisted reproduction treatments.

细胞间线粒体成分转移触发缺血性心肌纤维化

心肌纤维化是引发心源性猝死的重要原因.心肌缺血/再灌注(MI/R)损伤可导致心肌细胞损伤甚至死亡,而成纤维细胞却出现激活并导致纤维化.目前,导致这一矛盾现象的细胞间通讯机制仍不清楚.小细胞外囊泡(small extracellular vesicles,sEVs)在细胞间通讯中起重要作用.但是,sEVs是否介导以及如何介导MI/R后心肌细胞和成纤维细胞间的通讯尚不清楚.本研究通过在体MI/R模型和细胞学实验发现,MI/R损伤情况下存在一种心肌细胞来源的sEV(Myo-sEV^(I/R)),其内容物富含线粒体成分.Myo-sEV^(I/R)被成纤维细胞摄取并触发纤维化.通过生物信息学筛选和实验验证,新发现Ambra1是Myo-sEV^(I/R)中的关键组分和潜在标志物.并且证实,Ambra1+-Myo-sEVs的释放是由MI/R损伤后心肌细胞的分泌型自噬所驱动,而不是经典的降解型自噬.在缺血和缺血周边区域,Ambra1^(+)-Myo-sEVs被成纤维细胞内吞导致跨细胞线粒体成分传递;线粒体DNA(mtDNA)激活cGAS-STING通路,促进成纤维细胞的活化和增殖.此外,数据显示,Ambral定位于Myo-sEV^(I/R)表面,心脏特异性的下调Ambral可抑制Ambral^(+)-Myo-sEVs的释放和成纤维细胞摄取,有效抑制缺血后心肌纤维化.本研究新证实了心肌分泌型自噬可介导缺血后心肌纤维化发生过程中的细胞间通讯.Ambral是Myo-sEVs的潜在标志物和特征分子,并具有重要的生物活性.本研究为缺血后心脏重塑提供了新的治疗靶点.

Structural and functional insights into R-loop prevention and m RNA export by budding yeast THO-Sub2 complex

During eukaryotic transcription,the nascent RNA molecules are processed and packed into RNA-protein particles,termed messenger ribonucleoparticles(mRNPs)[1].Precise mRNP assembly is essential for efficient messenger RNA(mRNA)processing and export[2].A conserved protein complex called TREX(transcription export complex)plays an important role in mRNP biogenesis[3-6].

Isogenic human pluripotent stem cell disease models reveal ABRA deficiency underlies cTnT mutation-induced familial dilated cardiomyopathy

Dear Editor,Dilated cardiomyopathy(DCM)is a common form of inherited cardiomyopathy.In the past decades,single mutations in various genes encoding sarcomeric,cytoskeletal,and channel proteins etc.have been found to be associated with DCM(Hershberger et al.,2013;McNally and Mestroni,2017).However,the mechanisms how single mutations in sarcomeric or structural genes lead to the disease remain elusive.An interesting phenomenon often seen in familial cardiomyopathy is that different single mutations on the same gene can cause either DCM or hypertrophic cardiomyopathy(HCM)(Kathiresan and Srivastava,2012),which exhibit almost opposite disease phenotypes.DCM is characterized by thinned myocardium and septum,ventricular chamber dilation,and systolic dysfunction(Jefferies and Towbin,2010;McNally and Mestroni,2017),while HCM exhibits thickened myocardium and septum,reduced ventricular chamber,and diastolic dysfunction(Richard et al.,2003).At the cellular level,HCM cardiomyocytes exhibit concentric hypertrophy characterized by assembly of myofilaments in parallel and widening of the myocytes.In contrast,DCM cardiomyocytes show eccentric hypertrophy,with assembly of the myofilaments in series and myocyte elongation(Kehat and Molkentin,2010).