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Background Spatially-resolved transcriptomics has now enabled the quantification of high-throughput and transcriptome-wide gene expression in intact tissue while also retaining the spatial coordinates. Incorporating the precise spatial mapping of gene activity advances our understanding of intact tissue-specific biological processes. In order to interpret these novel spatial data types, interactive visualization tools are necessary. Results We describe spatialLIBD , an R/Bioconductor package to interactively explore spatially-resolved transcriptomics data generated with the 10x Genomics Visium platform. The package contains functions to interactively access, visualize, and inspect the observed spatial gene expression data and data-driven clusters identified with supervised or unsupervised analyses, either on the user’s computer or through a web application. Conclusions spatialLIBD is available at https://bioconductor.org/packages/spatialLIBD . It is fully compatible with SpatialExperiment and the Bioconductor ecosystem. Its functionality facilitates analyzing and interactively exploring spatially-resolved data from the Visium platform.

Benefits associated with lowered serum DHT levels after 5α-reductase inhibitor (5AR-I) therapy in men have contributed to a misconception that circulating DHT levels are an important stimulus for androgenic action in target tissues (e.g., prostate). Yet evidence from clinical studies indicates that intracellular concentrations of androgens (particularly in androgen-sensitive tissues) are essentially independent of circulating levels. To assess the clinical significance of modest elevations in serum DHT and the DHT/testosterone (T) ratio observed in response to common T replacement therapy, a comprehensive review of the published literature was performed to identify relevant data. Although the primary focus of this review is about DHT in men, we also provide a brief overview of DHT in women. The available published data are limited by the lack of large, well-controlled studies of long duration that are sufficiently powered to expose subtle safety signals. Nonetheless, the preponderance of available clinical data indicates that modest elevations in circulating levels of DHT in response to androgen therapy should not be of concern in clinical practice. Elevated DHT has not been associated with increased risk of prostate disease (e.g., cancer or benign hyperplasia) nor does it appear to have any systemic effects on cardiovascular disease safety parameters (including increased risk of polycythemia) beyond those commonly observed with available T preparations. Well-controlled, long-term studies of transdermal DHT preparations have failed to identify safety signals unique to markedly elevated circulating DHT concentrations or signals materially different from T.Circulating levels of DHT in response to testosterone replacement therapy (TRT) do not correlate with those found in androgen sensitive tissue due to homeostatic control of intracellular DHT.

Unplanned pregnancies are an ongoing global burden, posing health and economic risks for women, children, and families. Advances in male contraception have been historically stymied by concerning failure rates, problematic side effects, and perceived market limitations. However, increased interest in reliable and reversible options for male contraception have resulted in resurgent efforts to introduce novel contraceptives for men. Hormonal male contraception relies on exogenous androgens and progestogens that suppress gonadotropin production, thereby suppressing testicular testosterone and sperm production. In many men, effective suppression of spermatogenesis can be achieved by androgen-progestin combination therapy. Small-scale contraceptive efficacy studies in couples have demonstrated effectiveness and reversibility with male hormonal methods, but side effects related to mood, sexual desire and cholesterol remain concerning. A number of novel androgens have reached clinical testing as potential contraceptive agents; many of these have both androgenic and progestogenic action in a single, modified steroid, thereby holding promise as single-agent contraceptives. Currently, these novel steroids hold promise as both a “male pill” and long-acting injections. Among non-hormonal methods, studies of reversible vaso-occlusive methods (polymers that block transport of sperm through the vas deferens) are ongoing, but reliable reversibility and long-term safety in men have not been established. Proteins involved in sperm maturation and motility are attractive targets, but to date both specificity and biologic redundancy have been challenges for drug development. In this review, we aim to summarize landmark studies on male contraception, highlight the most recent advances and future development in this important field of public health and medicine.

The TCF4 gene is the subject of numerous and varied investigations of it’s role in the genesis of neuropsychiatric disease. The gene has been identified as the cause of Pitt–Hopkins syndrome (PTHS) and it has been implicated in various other neuropsychiatric diseases, including schizophrenia, depression, and autism. However, the precise molecular mechanisms of the gene’s involvement in neurogenesis, particularly, corticogenesis, are not well understood. Here, we present data showing that TCF4 is expressed in a region-specific manner in the radial glia and stem cells of transient embryonic zones at early gestational ages in both humans and mice. TCF4 haploinsufficiency mice exhibit a delay in neuronal migration, and a significant increase in the number of upper-layer cortical neurons, as well as abnormal dendrite and synapse formation. Our research also reveals that TCF3 up-regulates Tcf4 by binding to the specific “E-box” and its flank sequence in intron 2 of the Tcf4 gene. Additionally, our transcriptome study substantiates that Tcf4 transcriptional function is essential for locomotion, cognition, and learning. By activating expression of TCF4 in the regulation of neuronal proliferation and migration to the overlaying neocortex and subsequent differentiation leading to laminar formation TCF4 fulfills its normal function, but if not, abnormalities such as those reported here result. These findings provide new insight into the specific roles of Tcf4 molecular pathway in neocortical development and their relevance in the pathogenesis of neuropsychiatric diseases.

We define and identify a new class of control genes for next-generation sequencing called total RNA expression genes (TREGs), which correlate with total RNA abundance in cell types of different sizes and transcriptional activity. We provide a data-driven method to identify TREGs from single-cell RNA sequencing data, allowing the estimation of total amount of RNA when restricted to quantifying a limited number of genes. We demonstrate our method in postmortem human brain using multiplex single-molecule fluorescent in situ hybridization and compare candidate TREGs against classic housekeeping genes. We identify AKT3 as a top TREG across five brain regions.

Autism spectrum disorder (ASD) is genetically heterogeneous with convergent symptomatology, suggesting common dysregulated pathways. In this study, we analyzed brain transcriptional changes in five mouse models of Pitt–Hopkins syndrome (PTHS), a syndromic form of ASD caused by mutations in the TCF4 gene, but not the TCF7L2 gene. Analyses of differentially expressed genes (DEGs) highlighted oligodendrocyte (OL) dysregulation, which we confirmed in two additional mouse models of syndromic ASD (Ptenm3m4/m3m4 and Mecp2tm1.1Bird). The PTHS mouse models showed cell-autonomous reductions in OL numbers and myelination, functionally confirming OL transcriptional signatures. We also integrated PTHS mouse model DEGs with human idiopathic ASD postmortem brain RNA-sequencing data and found significant enrichment of overlapping DEGs and common myelination-associated pathways. Notably, DEGs from syndromic ASD mouse models and reduced deconvoluted OL numbers distinguished human idiopathic ASD cases from controls across three postmortem brain data sets. These results implicate disruptions in OL biology as a cellular mechanism in ASD pathology.The authors identify an impaired myelination signature from the brains of mouse models of Pitt–Hopkins syndrome and show that it is shared in the postmortem brains of people with autism.

Progression of prostate cancer following castration is associated with increased androgen receptor (AR) expression and signaling despite AR blockade. Recent studies suggest that these activities are due to the generation of constitutively active AR splice variants, but the mechanisms by which these splice variants could mediate such effects are not fully understood. Here we have identified what we believe to be a novel human AR splice variant in which exons 5, 6, and 7 are deleted (ARv567es) and demonstrated that this variant can contribute to cancer progression in human prostate cancer xenograft models in mice following castration. We determined that, in human prostate cancer cell lines, ARv567es functioned as a constitutively active receptor, increased expression of full-length AR (ARfl), and enhanced the transcriptional activity of AR. In human xenografts, human prostate cancer cells transfected with ARv567es cDNA formed tumors that were resistant to castration. Furthermore, the ratio of ARv567es to ARfl expression within the xenografts positively correlated with resistance to castration. Importantly, we also detected ARv567es frequently in human prostate cancer metastases. In summary, these data indicate that constitutively active AR splice variants can contribute to the development of castration-resistant prostate cancers and may serve as biomarkers for patients who are likely to suffer from early recurrence and are candidates for therapies directly targeting the AR rather than ligand.

Unintended pregnancy is a global public health problem. Despite a variety of female contraceptive options, male contraceptive options are limited to the condom and vasectomy. Condoms have high failure rates and surgical vasectomy is not reliably reversible. There is a global need and desire for novel male contraceptive methods. Hormonal methods have progressed the furthest in clinical development and androgen plus progestin formulations hold promise as a marketable, reversible male contraceptive over the next decade. Investigators have tested androgen plus progestin approaches using oral, transdermal, subdermal, and injectable drug formulations and demonstrated the short-term safety and reversibility of hormonal male contraception. The most commonly reported side effects associated with hormonal male contraception include weight gain, acne, slight suppression of serum high-density cholesterol, mood changes, and changes in libido. Efficacy trials of hormonal male contraceptives have demonstrated contraceptive efficacy rates greater than that of condoms. Although there has been less progression in the development of nonhormonal male contraceptives, potentially reversible vaso-occlusive methods are currently in clinical trials in some countries. Various studies have confirmed both men and women's desire for novel male contraceptives. Barriers to development include an absence of investment from pharmaceutical companies, concerns regarding side effects and spermatogenic rebound with hormonal methods, and lack of clear reversibility and proven effectiveness of nonhormonal methods. The ultimate availability of male contraceptives could have an important impact on decreasing global unintended pregnancy rates (currently 40% of all pregnancies) and will be a step towards reproductive justice and greater equity in family planning.

Norepinephrine (NE) neurons in the locus coeruleus (LC) make long-range projections throughout the central nervous system, playing critical roles in arousal and mood, as well as various components of cognition including attention, learning, and memory. The LC-NE system is also implicated in multiple neurological and neuropsychiatric disorders. Importantly, LC-NE neurons are highly sensitive to degeneration in both Alzheimer’s and Parkinson’s disease. Despite the clinical importance of the brain region and the prominent role of LC-NE neurons in a variety of brain and behavioral functions, a detailed molecular characterization of the LC is lacking. Here, we used a combination of spatially-resolved transcriptomics and single-nucleus RNA-sequencing to characterize the molecular landscape of the LC region and the transcriptomic profile of LC-NE neurons in the human brain. We provide a freely accessible resource of these data in web-accessible and downloadable formats.

Background Multispectral fluorescence imaging coupled with linear unmixing is a form of image data collection and analysis that allows for measuring multiple molecular signals in a single biological sample. Multiple fluorescent dyes, each measuring a unique molecule, are simultaneously measured and subsequently “unmixed” to provide a read-out for each molecular signal. This strategy allows for measuring highly multiplexed signals in a single data capture session, such as multiple proteins or RNAs in tissue slices or cultured cells, but can often result in mixed signals and bleed-through problems across dyes. Existing spectral unmixing algorithms are not optimized for challenging biological specimens such as post-mortem human brain tissue, and often require manual intervention to extract spectral signatures. We therefore developed an intuitive, automated, and flexible package called SUFI : spectral unmixing of fluorescent images . Results This package unmixes multispectral fluorescence images by automating the extraction of spectral signatures using vertex component analysis, and then performs one of three unmixing algorithms derived from remote sensing. We evaluate these remote sensing algorithms’ performances on four unique biological datasets and compare the results to unmixing results obtained using ZEN Black software (Zeiss). We lastly integrate our unmixing pipeline into the computational tool dotdotdot, which is used to quantify individual RNA transcripts at single cell resolution in intact tissues and perform differential expression analysis , and thereby provide an end-to-end solution for multispectral fluorescence image analysis and quantification. Conclusions In summary, we provide a robust, automated pipeline to assist biologists with improved spectral unmixing of multispectral fluorescence images.