Advancements in personalized stem cell models for aging-related neurodegenerative disorders

Neurodegenerative diseases(NDDs)are a class of disorders characterized by the gradual loss or malfunction of specific cell populations in the nervous system,which can be triggered by genetic or environmental factors.As a result,patients often experience a decline in mobility,sensation,memory,and cognition,which can ultimately lead to a fatal outcome.The global incidence of NDDs,including Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,amyotrophic lateral sclerosis(ALS),and multiple sclerosis,is increasing.

The chemical reprogramming of unipotent adult germ cells towards authentic pluripotency and de novo establishment of imprinting

Although somatic cells can be reprogrammed to pluripotent stem cells(PsCs)with pure chemicals,authentic pluripotency of chemically induced pluripotent stem celis(CipsCs)has never been achieved through tetraploid complementation assay.Spontaneous reprogramming of spermatogonial stem cells(ssCs)was another non-transgenic way to obtain PsCs,but this process lacks mechanistic explanation.Here,we reconstructed the trajectory of mouse SsC reprogramming and developed a five-chemical combination,boosting the reprogramming effciency by nearly 80-to 100-folds.More importantly,chemical induced germline-derived PsCs(5C-gPSCs),but not gpsCs and chemical induced pluripotent stem cells,had authentic pluripotency,as determined by tetraploid complementation.Mechanistically,ssCs traversed through an inverted pathway of in vivo germ ceil development,exhibiting the expression signatures and DNA methylation dynamics from spermatogonia to primordial germ cells and further to epiblasts.Besides,ssC-specific imprinting control regions switched from biallelic methylated states to monoallelic methylated states by imprinting demethylation and then re-methylation on one of the two alleles in 5c-gPsCs,which was apparently distinct with the imprinting reprogramming in vivo as DNA methylation simultaneously occurred on both alleles.Our work sheds ight on the unique regulatory network underpinning SsC reprogramming,providing insights to understand generic mechanisms for cell-fate decision and epigenetic-relateddisorders in regenerative medicine.

glbase:a framework for combining,analyzing and displaying heterogeneous genomic and high-throughput sequencing data

Genomic datasets and the tools to analyze them have proliferated at an astonishing rate.However,such tools are often poorly integrated with each other:each program typically produces its own custom output in a variety of non-standard file formats.Here we present glbase,a framework that uses a flexible set of descriptors that can quickly parse non-binary data files.glbase includes many functions to intersect two lists of data,including operations on genomic interval data and support for the efficient random access to huge genomic data files.Many glbase functions can produce graphical outputs,including scatter plots,heatmaps,boxplots and other common analytical displays of high-throughput data such as RNA-seq,ChIP-seq and microarray expression data.glbase is designed to rapidly bring biological data into a Python-based analytical environment to facilitate analysis and data processing.In summary,glbase is a flexible and multifunctional toolkit that allows the combination and analysis of high-throughput data(especially next-generation sequencing and genome-wide data),and which has been instrumental in the analysis of complex data sets.glbase is freely available at http://bitbucket.org/oaxiom/glbase/.

OCT4:A penetrant pluripotency inducer

Native OCT4 protein has the intrinsic ability of crossing cellular membranes to enter cells.This finding could revive efforts to induce pluripotency with proteins replacing nucleic acid-based approaches,and raises the intriguing question as to whether OCT4 can act non-cell-autonomously.

Exploring the utility of organo-polyoxometalate hybrids to inhibit SOX transcription factors

Background:SOX transcription factors constitute an attractive target class for intervention with small molecules as they play a prominent role in the field of regenerative biomedicine and cancer biology.However,rationally engineering specific inhibitors that interfere with transcription factor DNA interfaces continues to be a monumental challenge in the field of transcription factor chemical biology.Polyoxometalates(POMs)are inorganic compounds that were previously shown to target the high-mobility group(HMG)of SOX proteins at nanomolar concentrations.In continuation of this work,we carried out an assessment of the selectivity of a panel of newly synthesized organo-polyoxometalate hybrids in targeting different transcription factor families to enable the usage of polyoxometalates as specific SOX transcription factor drugs.Results:The residual DNA-binding activities of 15 different transcription factors were measured after treatment with a panel of diverse polyoxometalates.Polyoxometalates belonging to the Dawson structural class were found to be more potent inhibitors than the Keggin class.Further,organically modified Dawson polyoxometalates were found to be the most potent in inhibiting transcription factor DNA binding activity.The size of the polyoxometalates and its derivitization were found to be the key determinants of their potency.Conclusion:Polyoxometalates are highly potent,nanomolar range inhibitors of the DNA binding activity of the Sox-HMG family.However,binding assays involving a limited subset of structurally diverse polyoxometalates revealed a low selectivity profile against different transcription factor families.Further progress in achieving selectivity and deciphering structure-activity relationship of POMs require the identification of POM binding sites on transcription factors using elaborate approaches like X-ray crystallography and multidimensional NMR.In summary,our report reaffirms that transcription factors are challenging molecular architectures and that future polyoxometalate chemistry must consider further modification strategies,to address the substantial challenges involved in achieving target selectivity.