Recent advances in synthetic strategies and SAR of thiazolidin-4-one containing molecules in cancer therapeutics.

Cancer is one of the life-threatening diseases accountable for millions of demises globally. The inadequate effectiveness of the existing chemotherapy and its harmful effects has resulted in the necessity of developing innovative anticancer agents. Thiazolidin-4-one scaffold is among the most important chemical skeletons that illustrate anticancer activity. Thiazolidin-4-one derivatives have been the subject of extensive research and current scientific literature reveals that these compounds have shown significant anticancer activities. This manuscript is an earnest attempt to review novel thiazolidin-4-one derivatives demonstrating considerable potential as anticancer agents along with a brief discussion of medicinal chemistry-related aspects of these compounds and structural activity relationship studies in order to develop possible multi-target enzyme inhibitors. Most recently, various synthetic strategies have been developed by researchers to get various thiazolidin-4-one derivatives. In this review, the authors highlight the various synthetic, green, and nanomaterial-based synthesis routes of thiazolidin-4-ones as well as their role in anticancer activity by inhibition of various enzymes and cell lines. The detailed description of the existing modern standards in the field presented in this article may be interesting and beneficial to the scientists for further exploration of these heterocyclic compounds as possible anticancer agents.

Cross-reactivity of hantavirus antibodies after immunization with PUUV antigens.

Nephropathia epidemica (NE), caused by Puumala (PUUV) orthohantavirus, is endemic in the Republic of Tatarstan (RT). There are limited options for NE prevention in RT. Currently, available vaccines are made using Haantan (HNTV) orthohantavirus antigens. In this study, the efficacy of microvesicles (MVs) loaded with PUUV antigens to induce the humoral immune response in small mammals was analyzed. Additionally, the cross-reactivity of serum from immunized small mammals and NE patients with HNTV, Dobrava, and Andes orthohantaviruses was investigated using nucleocapsid (N) protein peptide libraries. Finally, the selected peptides were analyzed for allergenicity, their ability to induce an autoimmune response, and their interaction with Class II HLA. Several N protein peptides were found to be cross-reactive with serum from MVs immunized small mammals. These cross-reactive epitopes were located in oligomerization perinuclear targeting and Daxx-interacting domains. Most cross-reactive peptides lack allergenic and autoimmune reactivity. Molecular docking revealed two cross-reacting peptides, N6 and N19, to have good binding with three Class II HLA alleles. These peptides could be candidates for developing vaccines and therapeutics for NE.

Novel quinolone substituted 1,3,4-oxadiazole derivatives: design, synthesis, antimicrobial and anti-inflammatory potential.

A novel series of quinolone-substituted 1,3,4-oxadiazole derivatives 4(a-l) have been designed and synthesized. The target compounds were investigated for their antibacterial activity against gram positive (Staphylococcus aureus, ATCC 25923, Enterococcus faecalis, ATCC 29212) and gram negative bacterium (Escherichia coli, ATCC 25922, Pseudomonas aeruginosa, ATCC 27853) for antifungal activity using (Candida albicans, ATCC 10231) and anti-inflammatory activity as COX-II inhibitors, respectively. The 1,3,4-oxadiazole functionality was introduced at C-6 position of pipemidic acid derivatives. IR, 1H NMR and Mass spectrometry techniques confirmed the structure of synthesized derivatives. The quinolone (pipemidic acid)-oxadiazole hybrid derivatives were effective against bacterial strains. When compared to ciprofloxacin (MIC 16 µg/mL), the compounds under consideration (4f, 4h, and 4k) showed significant antibacterial activity against all bacterial strains except Enterococcus faecalis, with MICs of 8 µg/mL. On the other hand, synthesized target compounds 4(a-l) did not respond well against Candida albicans fungal strain. The compound (4k) represents high % inhibition against COX-II. The compounds (4f, 4h and 4k) exhibited highest hydrogen bonding interaction with ARG57, ARG72, ARG78, LEU54 and MET16 target residues with a binding energy of - 8.4, - 8.6 and - 8.5 kcal/mol into the active pocket of DNA gyrase enzyme respectively even better in comparison to reference ligands. Based on the docking study, quinolone (pipemidic acid) oxadiazole hybrid structural ligands exhibited strong interaction at binding pockets of DNA gyrase enzyme.

Quinolone scaffolds as potential drug candidates against infectious microbes: a review.

Prevalence of microbial infections and new rising pathogens are signified as causative agent for variety of serious and lethal health crisis in past years. Despite medical advances, bacterial and fungal infections continue to be a rising problem in the health care system. As more bacteria develop resistance to antibiotics used in therapy, and as more invasive microbial species develop resistance to conventional antimicrobial drugs. Relevant published publications from the last two decades, up to 2024, were systematically retrieved from the MEDLINE/PubMed, SCOPUS, EMBASE, and WOS databases using keywords such as quinolones, anti-infective, antibacterial, antimicrobial resistance and patents on quinolone derivatives. With an approach of considerable interest towards novel heterocyclic derivatives as novel anti-infective agents, researchers have explored these as essential tools in vistas of drug design and development. Among heterocycles, quinolones have been regarded extremely essential for the development of novel derivatives, even able to tackle the associated resistance issues. The quinolone scaffold with its bicyclic structure and specific functional groups such as the carbonyl and acidic groups, is indeed considered a valuable functionalities for further lead generation and optimization in drug discovery. Besides, the substitution at N-1, C-3 and C-7 positions also subjected to be having a significant role in anti-infective potential. In this article, we intend to highlight recent quinolone derivatives based on the SAR approach and anti-infective potential such as antibacterial, antifungal, antimalarial, antitubercular, antitrypanosomal and antiviral activities. Moreover, some recent patents granted on quinolone-containing derivatives as anti-infective agents have also been highlighted in tabular form. Due consideration of this, future research in this scaffold is expected to be useful for aspiring scientists to get pharmacologically significant leads.

Comparative evaluation of milk proteins and oil-seed-cake-derived proteins extracted by chemical and biological methods for obesity management.

BACKGROUND: In light of the exponential rise in global population, there is a critical requirement to reduce food waste on a global scale. According to studies, agricultural wastes such as oil-seed cakes offer great nutritional value. Acid precipitation (A) and alkaline extraction methods (traditional methods) were used to extract protein from oil-seed cakes; however, both procedures are linked to decreased protein quality and quantity, which prompted the development of a novel strategy known as the biological/microbial/probiotic (B) method. Therefore, the present study aimed to highlight the optimal way of protein extraction from oil-seed cakes and the effect of extraction methods on protein efficacy against obesity. The outcomes were also compared with milk proteins. RESULTS: In vitro study provided evidence that proteins from both sources (plant and milk) suppressed adipogenesis and stimulated adipolysis in 3T3L-1 cells. For the in vivo study, mice were fed with different protein extracts: soya protein preparation (SPP), ground protein preparation (GPP), whey protein (WP) and casein protein (CP) containing 40% of their calories as fat. Body weight decreased significantly in all the rats except CP-fed rats. Body mass index, atherogenic index, plasma triglyceride and very-low-density lipoprotein cholesterol level decreased significantly in all the groups in comparison to the model group (high-fat-diet group), but the decrease was more pronounced in plant proteins than milk proteins. In hepatocytes, the expression of fasting-induced adipose factor, carnitine palmitoyltransferase I and peroxisome proliferator-activated receptor α genes was increased significantly in SPP-fed groups. Adiponectin gene expression was upregulated significantly in visceral fat tissue in groups fed SPP-B, GPP-A and CP, whereas leptin gene was downregulated significantly in all groups except SPP-A. CONCLUSION: This study demonstrates that SPP-B showed the most effective anti-obesity property, followed by WP. Additionally, we found that the biological precipitation approach produced better outcomes for plant proteins isolated from oil-seed cakes than the acid precipitation method. © 2023 Society of Chemical Industry.

Fate, source apportionment and fractionation of potentially toxic elements in agricultural soil around a densely populated, semiarid urban center of India: baseline study and ecological risk assessment.

This study is on the outskirts of the rapidly growing city of Jaipur, located in the semiarid region of India and gateway to the 'Great Indian Thar' desert, and focused on potentially toxic elements (PTE) pollution in the farmlands around the city. Concentrations of PTE, along with associated soil parameters such as pH, available nitrogen, organic carbon, phosphorus, and potassium, were estimated in agricultural soil samples near an industrial region on the outskirts of the capital city of the largest state of India. The PTE concentrations in the soil were in the following order: Mn > Pb > Ni > Cr > Cu > Cd. Soil pollution indices, such as the geochemical accumulation index (Igeo), contamination factor (CF), and ecological risk index (ERI), indicated that the soil was moderately to highly polluted. The result of BCR extraction techniques showed Cd is found mainly in the exchangeable and residual fractions, Pb, Mn were found in the reducible as well as residual fractions, while other PTE were mostly bound to residual fraction. All other PTEs are primarily found in the residual fraction, tightly linked with the silicate lattice of soil minerals. Multivariate analysis and the Pearson correlation matrix indicate a common source apportionment for Pb and Cd. Cd, and Pb concentrations in agricultural soil indicate ecological harm that warrants immediate attention and policy-level intervention.

Recent advances in microbial toxin-related strategies to combat cancer.

It is a major concern to treat cancer successfully, due to the distinctive pathophysiology of cancer cells and the gradual manifestation of resistance. Specific action, adverse effects and development of resistance has prompted the urgent requirement of exploring alternative anti-tumour treatment therapies. The naturally derived microbial toxins as a therapy against cancer cells are a promisingly new dimension. Various important microbial toxins such as Diphtheria toxin, Vibrio cholera toxin, Aflatoxin, Patulin, Cryptophycin-55, Chlorella are derived from several bacterial, fungal and algal species. These agents act on different biotargets such as inhibition of protein synthesis, reduction in cell growth, regulation of cell cycle and many cellular processes. Bacterial toxins produce actions primarily by targeting protein moieties and some immunomodulation and few acts through DNA. Fungal toxins appear to have more DNA damaging activity and affect the cell cycle. Algal toxins produce alteration in mitochondrial phosphorylation. In conclusion, microbial toxins and their metabolites appear to have a great potential to provide a promising option for the treatment and management to combat cancer.

Pharmacological modulation of HIF-1 in the treatment of neuropsychiatric disorders.

Hypoxia-inducible factor 1 has been identified as an important therapeutic target in psychiatric illnesses. Hypoxia is a condition in which tissues do not receive enough oxygen, resulting in less oxidative energy production. HIF-1, the master regulator of molecular response to hypoxia, is destabilized when oxygen levels fall. HIF-1, when activated, increases the gene transcription factors that promote adaptive response and longevity in hypoxia. HIF-regulated genes encode proteins involved in cell survival, energy metabolism, angiogenesis, erythropoiesis, and vasomotor control. Multiple genetic and environmental variables contribute to the pathophysiology of psychiatric disease. This review focuses on the most recent findings indicating the role of oxygen deprivation in CNS damage, with strong attention on HIF-mediated pathways. Several pieces of evidence suggested that, in the case of hypoxia, induction and maintenance of HIF-1 target genes may help reduce nerve damage. Major new insights into the molecular mechanisms that control HIF's sensitivity to oxygen are used to make drugs that can change the way HIF works as a therapeutic target for some CNS diseases.

Women's awareness of perinatal mental health conditions and the acceptability of being asked about mental health in two regions in India: a qualitative study.

BACKGROUND: Mental health conditions are common during pregnancy and the first year after childbirth. Early detection allows timely support and treatment to be offered, but identifying perinatal mental health conditions may be challenging due to stigma and under-recognition of symptoms. Asking about symptoms of mental health conditions during routine antenatal and postnatal appointments can help to identify women at risk. This study explores women's awareness of perinatal mental health conditions, their views on the acceptability of being asked about mental health and any preference for specific assessment tools in two regions in India. METHODS: Focus group discussions (FGDs) were conducted with pregnant, post-partum and non-perinatal women in Kangra, Himachal Pradesh (northern India) and Bengaluru, Karnataka (southern India). Settings included a hospital antenatal clinic and obstetric ward, Anganwadi Centres and Primary Health Centres. FGDs were facilitated, audio-recorded and transcribed. Narratives were coded for emerging themes and analysed using thematic analysis. RESULTS: Seven FGDs including 36 participants were conducted. Emerging themes were: manifestations of and contributors to mental health conditions; challenges in talking about mental health; and the acceptability of being asked about mental health. Difficult familial relationships, prioritising the needs of others and pressure to have a male infant were cited as key stressors. Being asked about mental health was generally reported to be acceptable, though some women felt uncomfortable with questions about suicidality. No preference for any specific assessment tool was reported. CONCLUSIONS: Women face many stressors during the perinatal period including difficult familial relationships and societal pressure to bear a male infant. Being asked about mental health was generally considered to be acceptable, but questions relating to suicidality may be challenging in a community setting, requiring sensitivity by the interviewer. Future studies should assess the acceptability of mental health assessments in 'real world' antenatal and postnatal clinics and explore ways of overcoming the associated challenges in resource-constrained settings.

Computational Design of Plant-Based Antistress Agents Targeting Nociceptin Receptor.

Stress is the body's reaction to the challenges it faces, and it produces a multitude of chemical molecules known as stressors as a result of these reactions. It's also a misalignment of the sympathetic and parasympathetic nervous systems causing changes in a variety of physiological reactions and perhaps leading to stress disorders. The reduction in neurotransmitter & neurohormonal hormones is mainly governed by the nociceptin receptor as G-protein coupled receptor and increased the level of reactive oxygen species. Various synthetic medicines that target nociceptin receptors were utilized to reduce the effects of stress but they come up with a variety of side effects. Because of the widespread utilization and renewed interest in medicinal herbal plants considered to be alternative antistress therapy. Our present work is an approach to decipher the molecular nature of novel herbal leads by targeting nociceptin receptor, under which herbal compounds were screened and validated through in-silico methods. Among screened leads, withanolide-B showed stable association in the active site of the nociceptin receptor as an antistress agent with no side effects. Furthermore, the selected lead was also evaluated for stability by molecular dynamic stimulation as well as for pharmacokinetics and toxicity profile. It has been concluded stable conformation of withanolide-B without presence of any major toxic effects. As a result, the in silico molecular docking technique is a highly successful method for selecting a prospective herbal lead molecule with respect to a specific target, and future research can pave the way for further exploration in the drug development field.

Chemical Diversity and Medicinal Potential of Vitex negundo L.: From Traditional Knowledge to Modern Clinical Trials.

BACKGROUND: In Vedic context, Nirgundi (V. negundo) has been utilized for its anti-inflammatory, analgesic, and wound-healing properties. It has been employed to alleviate pain, treat skin conditions, and address various ailments. The plant's leaves, roots, and seeds have all found applications in traditional remedies. The knowledge of Nirgundi's medicinal benefits has been passed down through generations, and it continues to be a part of Ayurvedic and traditional medicine practices in India.

A new method for determining ribosomal DNA copy number shows differences between Saccharomyces cerevisiae populations.

Ribosomal DNA genes (rDNA) encode the major ribosomal RNAs and in eukaryotes typically form tandem repeat arrays. Species have characteristic rDNA copy numbers, but there is substantial intra-species variation in copy number that results from frequent rDNA recombination. Copy number differences can have phenotypic consequences, however difficulties in quantifying copy number mean we lack a comprehensive understanding of how copy number evolves and the consequences. Here we present a genomic sequence read approach to estimate rDNA copy number based on modal coverage to help overcome limitations with existing mean coverage-based approaches. We validated our method using Saccharomyces cerevisiae strains with known rDNA copy numbers. Application of our pipeline to a global sample of S. cerevisiae isolates showed that different populations have different rDNA copy numbers. Our results demonstrate the utility of the modal coverage method, and highlight the high level of rDNA copy number variation within and between populations.

Phytoplankton growth and community shift over a short-term high-CO2 simulation experiment from the southwestern shelf of India, Eastern Arabian Sea (summer monsoon).

The southwestern shelf water of India (eastern Arabian Sea) experiences high seasonality. This area is one of the understudied regions in terms of phytoplankton response to the projected ocean acidification, particularly, during the summer monsoon when phytoplankton abundance is high. Here we present the results of a short-term simulated ocean acidification experiment (ambient CO2 424 µatm; high CO2, 843, 1138 µatm) on the natural phytoplankton assemblages conducted onboard (R. V. Sindhu Sadhana) during the summer monsoon (Aug 2017). Among the dissolved inorganic nutrients, dissolved silicate (DSi) and nitrate + nitrite levels were quite low (< 2 µM). Phytoplankton biomass did not show any net enhancement after the incubation in any treatment. Both marker pigment analysis and microscopy revealed the dominance of diatoms in the phytoplankton community, and a significant restructuring was noticed over the experimental period. Divinyl chlorophylla (DVChla) containing picocyanobacteria and 19'-hexanoyloxyfucoxanthin (19'HF) containing prymnesiophytes did not show any noticeable change in response to CO2 enrichment. A CO2-induced positive growth response was noticed in some diatoms (Guinardia flaccida, Cylindrotheca closterium, and Pseudo-nitzschia sp.) and dinoflagellates (Protoperidinium sp. and Peridinium sp.) indicating their efficiency to quickly acclimatize at elevated CO2 levels. This is important to note that the positive growth response of toxigenic pennate diatoms like Pseudo-nitzschia as well as a few dinoflagellates at elevated CO2 levels can be expected in the future-ocean scenario. The proliferation of such non-palatable phytoplankton may impact grazing, the food chain, and carbon cycling in this region.

Seroprevalence and immunological characterization of Trypanosoma evansi infection in livestock of four agro-climatic zones of Himachal Pradesh, India.

Trypanosoma evansi, a hemoflagellate protozoan parasite, causes wasting disease called surra in wide range of animals. Although the organism has been reported from various parts of India, data generated from organized epidemiological study is still in infancy in majority states of India. In the present study, livestock of Himachal Pradesh, India, was targeted for epidemiological investigation of T. evansi infections. A total of 440 equines and 444 cattle serum samples were collected from four agro-climatic zones. Furthermore, serum samples of 280 buffaloes from three different agro-climatic zones of Himachal Pradesh were also collected and evaluated for the presence of T. evansi infection by indirect ELISA. Data generated showed higher prevalence in buffalo (23.57%) followed by cattle (22.52%) and equines (1.82%). Disease was found to be more prevalent (P < 0.01) in cattle of lower altitude as compared to those of higher altitudes. No significant variation was seen in prevalence of disease on the basis of age and sex of the animals. Serum biochemical analysis revealed increased levels of BUN in T. evansi-infected equines. Levels of liver function enzymes such as ALT/GGT and AST were found to be significantly elevated (P < 0.01) in seropositive animals whereas glucose levels were significantly lower in surra-seropositive animals as compared to seronegative animals. Immunoblot analysis of whole cell lysate (WCL) antigen of T. evansi using surra-seropositive samples of equines showed immunodominant bands in the range of 100-25 kDa. Bovine-seropositive samples recognized polypeptide bands in the range of 85-32 kDa, including protein clusters of 52-55 and 48-46 kDa. Polypeptide cluster of 62-66 kDa was found common in seropositive samples of bovines and equines from all agro-climatic zones. T. evansi was found to be highly prevalent in livestock of Himachal Pradesh, and thus, there is dire need for designing of proper control strategies against surra.

Diseases and pathogens of marine invertebrate corals in Indian reefs.

Diseases in marine invertebrate corals have been reported worldwide and have been associated with infection by various microbial pathogens that cause massive mortality. Several bacterial species, especially Vibrio species but also members of the cyanobacteria, fungi, viruses, and protists, are described as important pathogens associated with coral disease and mortality. The present work provides an updated overview of main diseases and implicated microbial species affecting corals in Indian reefs. Further study on pathogen diversity, classification, spread and environmental factors on pathogen-host interactions may contribute a better understanding of the coral diseases.

Liquid Crystal based Detection of Pb(II) Ions Using Spinach RNA as Recognition Probe.

We report a new method for label-free, sensitive, and facile detection of lead(II) ions (Pb2+) based on an aptamer-target binding event, which is recognized by orientations of liquid crystals (LCs) at aqueous interfaces. The LC film suspended in the aqueous phase demonstrated a homeotropic orientation in contact with a cationic surfactant cetyltrimethylammonium bromide (CTAB) due to self-assembly of CTAB molecules at the aqueous-LC interface. The ordering of LC subsequently changed to planar in the presence of the spinach RNA aptamer (SRNA) due to interactions between CTAB and SRNA. In the presence of the Pb2+ ion, the ordering of LC changed to homeotropic caused by reorganization of CTAB at the LC-aqueous interface. This is due to formation of more stable quadruplex structures of SRNA with Pb2+ ions in comparison to the CTAB-SRNA complex. The sensor exhibited a detection limit of 3 nM, which is well below the permissible limit of Pb2+ in drinking water. Our experiments establish that addition of Pb2+ leads to (i) the formation of Pb2+-SRNA complexes and (ii) a decrease in density of SRNA on the LC interface, but additional studies are required to determine which of these processes underlie the response of the LCs to the Pb2+. We have also demonstrated the potential application of the LC sensor for detection of Pb2+ in tap water. Unlike current laboratory-based heavy-metal-ion assays, this method is comparatively simple in terms of instrumentation, operation, and optical readout.

Heterogeneity of Stem Cells in the Ovary.

Every organ in the body is thought to harbor two populations of stem cells, including the quiescent and the actively dividing, that leads to heterogeneity among them. It is generally believed that the ovary harbors a fixed number of follicles at birth that differentiate during fetal development from the primordial germ cells. The numbers of follicles decrease by age, leading to menopause. However, in 2004, it was suggested that ovary may harbor stem cells that are possibly involved in the formation of new follicles throughout reproductive life. Research over little more than a decade shows that ovarian stem cells include a quiescent population of very small embryonic-like stem cells (VSELs) and slightly bigger, actively dividing ovarian stem cells (OSCs). This heterogeneity among ovarian stem cells is similar to the presence of VSELs along with spermatogonial stem cells (SSCs) in the testis or hematopoietic stem cells (HSCs) in the hematopoietic system. VSELs express embryonic markers, including nuclear OCT-4, and are lodged in the ovary surface epithelium (OSE). Ovarian VSELs undergo asymmetric cell division to self-renew and give rise to OSCs that in turn undergo symmetric cell divisions and clonal expansion (germ cell nest) followed by meiosis to form an oocyte that gets assembled as a primordial follicle. Both VSELs and OSCs also express receptors for follicle-stimulating hormone (FSHR) and are directly activated by FSH to undergo neo-oogenesis and primordial follicle assembly. Whether stimulation of ovaries by FSH in Infertility Clinics activates the stem cells leading to the formation of multiple follicles needs further investigation. Epithelial cells lining the surface of ovary provide a niche to the stem cells under normal circumstances and undergo epithelial-mesenchymal transition (EMT) to form granulosa cells for primordial follicle assembly. Compromised function of the epithelial cells with age possibly leads to inability of stem cells to form follicles, leading to menopause. More than 90% of ovarian cancers arise in the OSE, possibly due to excessive self-renewal of VSELs. Altered biology of the OSE cells results in the formation of myofibroblasts by EMT and may provide a cancerous niche that supports excessive expansion of the stem cells lodged in the OSE, leading to ovarian cancer. Ovarian cancer cells express markers like OCT-4 and FSHR, which are also expressed by the VSELs lodged in the OSE, whereas the epithelial cells are distinctly negative for the same. Lot more research is required in the field to gain further understanding of ovarian stem cell biology.

Stem Cells in the Mammalian Gonads.

Besides spermatogonial stem cells (SSCs) and ovarian stem cells (OSCs), a novel population of pluripotent stem cells termed very small embryonic-like stem cells (VSELs) has been reported in both adult mouse and human testes and ovaries. VSELs and SSCs/OSCs are developmentally linked to each other. VSELs are relatively quiescent, small-sized stem cells that undergo asymmetrical cell divisions (ACDs) whereby they self-renew and give rise to the slightly bigger SSCs/OSCs which in turn undergo symmetrical cell divisions (SCDs) and clonal expansion to form germ cell chains/nests before further differentiation into gametes. Comparison of VSELs and SSCs/OSCs for their potential to differentiate into sperm/oocytes is irrelevant since VSELs only undergo ACD to give rise to SSCs/OSCs that further differentiate into gametes. Being relatively quiescent, VSELs survive oncotherapy and can be manipulated to regenerate nonfunctional gonads of cancer survivors, and thus there is possibly no need to bank testicular/ovarian tissue prior to oncotherapy. Being developmentally linked to the primordial germ cells (PGCs) which are the natural precursors to the gametes, VSELs differentiate into haploid sperm/oocyte-like structures in vitro when cultured on appropriate feeder support, in the absence of a cocktail of growth factors. VSELs express receptors for pituitary and sex hormones (FSHR, ER) and thus get directly stimulated/affected by their circulating levels. Excessive self-renewal of VSELs in the gonads may initiate testicular and ovarian cancers. To conclude, VSELs can be targeted to regenerate the gonads of patients with gonadal insufficiency including cancer survivors and are excellent candidates to differentiate into gametes in vitro.

PAS Dimerization at the Nexus of the Mammalian Circadian Clock.

Circadian rhythms are genetically encoded molecular clocks for internal biological timekeeping. Organisms from single-cell bacteria to humans use these clocks to adapt to the external environment and synchronize their physiology and behavior to solar light/dark cycles. Although the proteins that constitute the molecular 'cogs' and give rise to circadian rhythms are now known, we still lack a detailed understanding of how these proteins interact to generate and sustain the ∼24-hour circadian clock. Structural studies have helped to expand the architecture of clock proteins and have revealed the abundance of the only well-defined structured regions in the mammalian clock called Per-ARNT-Sim (PAS) domains. PAS domains are modular, evolutionarily conserved sensory and signaling domains that typically mediate protein-protein interactions. In the mammalian circadian clock, PAS domains modulate homo and heterodimerization of several core clock proteins that assemble into transcription factors or repressors. This review will focus on the functional importance of the PAS domains in the circadian clock from a biophysical and biochemical standpoint and describe their roles in clock protein interactions and circadian timekeeping.