Biological Functions In Mammals Research Articles

Lack of Bmal1 leads to changes in rhythmicity and impairs motivation towards natural stimuli.

Maintaining proper circadian rhythms is essential for coordinating biological functions in mammals. This study investigates the effects of daily arrhythmicity using Bmal1-knockout (KO) mice as a model, aiming to understand behavioural and motivational implications. By employing a new mathematical analysis based on entropy divergence, we identified disrupted intricate activity patterns in mice derived by the complete absence of BMAL1 and quantified the difference regarding the activity oscillation's complexity. Changes in locomotor activity coincided with disturbances in circadian gene expression patterns. Additionally, we found a dysregulated gene expression profile particularly in brain nuclei like the ventral striatum, impacting genes related to reward and motivation. Further investigation revealed that arrhythmic mice exhibited heightened motivation for food and water rewards, indicating a link between circadian disruptions and the reward system. This research sheds light on how circadian clock alterations impact the gene expression regulating the reward system and how this, in turn, can lead to altered seeking behaviour and motivation for natural rewards. In summary, the present study contributes to our understanding of how reward processing is under the regulation of circadian clock machinery.

Neurobiology of emotions in animal relationships: Facial expressions and their biological functions in mammals

This article aims to analyze the biological and communicative function of facial expressions and their relation to emotions in mammals. Facial expressions and their causes constitute an important yet largely unexplored field of scientific research. While the clinical usefulness of these expressions for recognizing pain in many species has been demonstrated, there is evidence that animals can also emit facial movements with other connotations. Reports show that facial expressions have a biological function by predicting and promoting social interaction in species that form complex social groups, but their meaning depends on the social context. For animals, the unconscious identification of facial expressions also implies an emotional value by modifying the compensatory physiological response, as occurs in species that have close relationships with humans. This corpus of evidence suggests that facial expressions have a kind of communicative function and may transmit emotions and, therefore, participate in affiliative or adverse relations as animals develop. Hence, exploring whether this nonverbal behavior may perform such a dual function is necessary.

Cellular and molecular functions of SETD2 in the central nervous system.

The covalent modification of histones is critical for many biological functions in mammals, including gene regulation and chromatin structure. Posttranslational histone modifications are added and removed by specialised 'writer' and 'eraser' enzymes, respectively. One such writer protein implicated in a wide range of cellular processes is SET domain-containing 2 (SETD2), a histone methyltransferase that catalyses the trimethylation of lysine 36 on histone H3 (H3K36me3). Recently, SETD2 has also been found to modify proteins other than histones, including actin and tubulin. The emerging roles of SETD2 in the development and function of the mammalian central nervous system (CNS) are of particular interest as several SETD2 variants have been implicated in neurodevelopmental disorders, such as autism spectrum disorder and the overgrowth disorder Luscan-Lumish syndrome. Here, we summarise the numerous roles of SETD2 in mammalian cellular functions and development, with a focus on the CNS. We also provide an overview of the consequences of SETD2 variants in human disease and discuss future directions for understanding essential cellular functions of SETD2.

Molecular characterization, transcriptional regulation of sea perch Moloney leukemia virus 10 and its antiviral function against VHSV.

Moloney leukemia virus 10 (MOV10) is a conserved RNA helicase and has multiple biological functions in mammals, but its role remains poorly understood in bony fish. Here, we cloned a MOV10 homolog from sea perch (Lateolabrax japonicus), which contained 23 exons and 22 introns, with an open reading frame of 3000 bp encoding 1000 amino acids. Tissue distribution analysis showed that MOV10 was high expressed in blood of sea perch. Promoter analysis revealed several putative multiple transcription factors binding sites, including upstream transcription factor 1, GATA-box, transcription initiation factor IIB, activator protein 1 and two interferon (IFN) stimulated response elements. Further analysis found that IFNc, IFNh, and IFNγ could not only activate IFN regulatory factor (IRF) 1 expression which in turn led to the induction of MOV10, but also prompted the expression of IRF10 to hinder excessive MOV10 expression. Moreover, IRF2 also suppressed MOV10 expression that was initiated by IRF1. Viral hemorrhagic septicemia virus (VHSV) infection upregulated MOV10 expression in vivo and in vitro, which in turn, enhanced IFNh expression and exhibited strong antiviral activity against VHSV proliferation. This study provides a basis to investigate the immune escape of VHSV by affecting the biological function of transcription factors in the signaling pathways associated with antiviral molecules.

Comparative evolutionary and structural analyses of the TYRP1 gene reveal molecular mechanisms of biological functions in mammals

Molecular mechanisms underlying adaptation to the environments are still challengingin evolutionary biology. This study conducted a comparative analysis of tyrosine protein across different mammalian species to gain insight into the molecular mechanisms of adaptive evolution in response to oxidative stress. By examining tyrosine protein's structural and evolutionary patterns, the study identified specific amino acid residues that may have played a role in adaptive evolution in response to oxidative stress. We examined this protein's structural and evolutionary patterns and identified specific amino acid residues that may have played a role in adaptive evolution. Our results suggest that changes in the tyrosine protein may have contributed to the evolution of antioxidant defense mechanisms in mammals. We also reconstructed the evolutionary history of tyrosine protein in mammals and identified key events and lineages that may have contributed to the observed patterns of adaptation. These findings provide valuable insights into the molecular mechanisms that underlie adaptive evolution in response to environmental stressors and highlight the importance of the tyrosine protein in the evolution of antioxidant defense systems in mammals. The results suggest that changes in the tyrosine protein may have contributed to the evolution of antioxidant defense mechanisms in mammals. These findings provide a deeper understanding of the molecular mechanisms that underlie adaptive evolution in response to environmental stressors.

Cisplatin attenuates taste cell homeostasis and induces inflammatory activation in the circumvallate papilla.

Rationale: Gustation is important to several biological functions in mammals. However, chemotherapy drugs often harm taste perception in cancer patients, while the underlying mechanism is still unclear for most drugs and there is no effective way to restore taste function. This study investigated the effects of cisplatin on the taste cell homeostasis and gustatory function. Methods: We used both mice and taste organoid models to study the effect of cisplatin on taste buds. Gustometer assay, gustatory nerve recording, RNA-Sequencing, quantitative PCR, and immunohistochemistry was performed to analyze the cisplatin-induced alteration in taste behavior and function, transcriptome, apoptosis, cell proliferation and taste cell generation. Results: Cisplatin inhibited proliferation and promoted apoptosis in the circumvallate papilla, leading to significant impairment in taste function and receptor cell generation. The transcriptional profile of genes associated with cell cycle, metabolic process and inflammatory response was significantly altered after cisplatin treatment. Cisplatin inhibited growth, promoted apoptosis, and deferred taste receptor cell differentiation in taste organoids. LY411575, a γ-secretase inhibitor, reduced the number of apoptotic cells and increased the number of proliferative cells and taste receptor cells, potentially suggesting as a taste tissue protective agent against chemotherapy. LY411575 treatment could offset the increased number of Pax1+ or Pycr1+ cells induced by cisplatin in the circumvallate papilla and taste organoids. Conclusion: This study highlights the inhibitory effects of cisplatin on taste cell homeostasis and function, identifies critical genes and biological processes regulated by chemotherapy, and proposes potential therapeutic targets and strategy for taste dysfunction in cancer patients.

Targeting Abnormal PI3K/AKT/mTOR Signaling in Intracerebral Hemorrhage: A Systematic Review on Potential Drug Targets and Influences of Signaling Modulators on Other Neurological Disorders.

PI3K/AKT/mTOR (phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin) signaling pathway is an important signal transduction pathway mediated by enzyme-linked receptors with many biological functions in mammals. This pathway modulates the epigenetic modification of DNA and target gene histones and plays a significant role in regulating biological activity, disease progression, oncogenesis, and cancer progression. PI3K/AKT/mTOR signaling pathway involves and mediates many cellular processes such as nutrient uptake, proliferation, anabolic reactions, and cell survival. Several studies have shown that PI3K/AKT/mTOR has been a promising therapeutic approach to intracerebral hemorrhage (ICH). ICH is characterized by the progressive development of hematoma, which leads to the structural destabilization of the neurons and glial cells, leading to neuronal deformation, further contributing to mitochondrial dysfunction, membrane depolarization, oligaemia, and neurotransmitter imbalance. Partial suppression of cell metabolism and necrosis can occur, depending on the degree of mitochondrial dysfunction. Therefore in the following review, we discuss whether or not the activation of the PI3K/AKT/mTOR signaling pathway could minimize neuronal dysfunction following ICH. We further elaborate the review by discussing the updated pathophysiology of brain hemorrhage and the role of molecular targets in other neurodegenerative diseases. This review provides current approachable disease treatment in various disease states, single and dual PI3K/AKT/mTOR signaling pathway modulators.

NOD1 splenic activation confers ferroptosis protection and reduces macrophage recruitment under pro-atherogenic conditions

The bioavailability and regulation of iron is essential for central biological functions in mammals. The role of this element in ferroptosis and the dysregulation of its metabolism contribute to diseases, ranging from anemia to infections, alterations in the immune system, inflammation and atherosclerosis. In this sense, monocytes and macrophages modulate iron metabolism and splenic function, while at the same time they can worsen the atherosclerotic process in pathological conditions. Since the nucleotide-binding oligomerization domain 1 (NOD1) has been linked to numerous disorders, including inflammatory and cardiovascular diseases, we investigated its role in iron homeostasis. The iron content was measured in various tissues of Apoe-/- and Apoe-/-Nod1-/- mice fed a high-fat diet (HFD) for 4 weeks, under normal or reduced splenic function after ligation of the splenic artery. In the absence of NOD1 the iron levels decreased in spleen, heart and liver regardless the splenic function. This iron decrease was accompanied by an increase in the recruitment of F4/80+-macrophages in the spleen through a CXCR2-dependent signaling, as deduced by the reduced recruitment after administration of a CXCR2 inhibitor. CXCR2 mediates monocyte/macrophage chemotaxis to areas of inflammation and accumulation of leukocytes in the atherosclerotic plaque. Moreover, in the absence of NOD1, inhibition of CXCR2 enhanced atheroma progression. NOD1 activation increased the levels of GPX4 and other iron and ferroptosis regulatory proteins in macrophages. Our findings highlight the preeminent role of NOD1 in iron homeostasis and ferroptosis. These results suggest promising avenues of investigation for the diagnosis and treatment of iron-related diseases directed by NOD1.

Neuroprotective Effect of Chrysophanol as a PI3K/AKT/mTOR Signaling Inhibitor in an Experimental Model of Autologous Blood-induced Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) refers to predominant, sporadic, and non-traumatic bleeding in the brain parenchyma. The PI3K/AKT/mTOR signaling pathway is an important signal transduction pathway regulated by enzyme-linked receptors and has many biological functions in mammals. It plays a key role in neuronal metabolism, gene expression regulation, and tissue homeostasis in the healthy and diseased brain. In the present study, the role of the PI3K/AKT/mTOR pathway inhibitor chrysophanol (CPH) (10 mg/kg and 20 mg/kg, orally) in the improvement of ICH-associated neurological defects in rats was investigated. Autologous blood (20 µL/5 min/unilateral/intracerebroventricular) mimics ICH-like defects involving cellular and molecular dysfunction and neurotransmitter imbalance. The current study also included various behavioral assessments to examine cognition, memory, and motor and neuromuscular coordination. The protein expression levels of PI3K, AKT, and mTOR as well as myelin basic protein and apoptotic markers, such as Bax, Bcl-2, and caspase-3, were examined using ELISA kits. Furthermore, the levels of various neuroinflammatory cytokines and oxidative stress markers were assessed. Additionally, the neurological severity score, brain water content, gross brain pathology, and hematoma size were used to indicate neurological function and brain edema. CPH was found to be neuroprotective by restoring neurobehavioral alterations and significantly reducing the elevated PI3K, AKT, and mTOR protein levels, and modulating the apoptotic markers such as Bax, Bcl-2, and caspase-3 in rat brain homogenate. CPH substantially reduced the inflammatory cytokines like interleukin (IL)-1β, IL-6, and tumor necrosis factor-α. CPH administration restored the neurotransmitters GABA, glutamate, acetylcholine, dopamine, and various oxidative stress markers. Our results show that CPH may be a promising therapeutic approach for overcoming neuronal damage caused by the overexpression of the PI3K/AKT/mTOR signaling pathway in ICH-induced neurological dysfunctions in rats.

Neuroprotective Effect of Chrysophanol as a PI3K/AKT/mTOR Signaling Inhibitor in an Experimental Model of Autologous Blood-induced Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) refers to predominant, sporadic, and non-traumatic bleeding in the brain parenchyma. The PI3K/AKT/mTOR signaling pathway is an important signal transduction pathway regulated by enzyme-linked receptors and has many biological functions in mammals. It plays a key role in neuronal metabolism, gene expression regulation, and tissue homeostasis in the healthy and diseased brain. In the present study, the role of the PI3K/AKT/mTOR pathway inhibitor chrysophanol (CPH) (10 mg/kg and 20 mg/kg, orally) in the improvement of ICH-associated neurological defects in rats was investigated. Autologous blood (20 µL/5 min/unilateral/intracerebroventricular) mimics ICH-like defects involving cellular and molecular dysfunction and neurotransmitter imbalance. The current study also included various behavioral assessments to examine cognition, memory, and motor and neuromuscular coordination. The protein expression levels of PI3K, AKT, and mTOR as well as myelin basic protein and apoptotic markers, such as Bax, Bcl-2, and caspase-3, were examined using ELISA kits. Furthermore, the levels of various neuroinflammatory cytokines and oxidative stress markers were assessed. Additionally, the neurological severity score, brain water content, gross brain pathology, and hematoma size were used to indicate neurological function and brain edema. CPH was found to be neuroprotective by restoring neurobehavioral alterations and significantly reducing the elevated PI3K, AKT, and mTOR protein levels, and modulating the apoptotic markers such as Bax, Bcl-2, and caspase-3 in rat brain homogenate. CPH substantially reduced the inflammatory cytokines like interleukin (IL)-1β, IL-6, and tumor necrosis factor-α. CPH administration restored the neurotransmitters GABA, glutamate, acetylcholine, dopamine, and various oxidative stress markers. Our results show that CPH may be a promising therapeutic approach for overcoming neuronal damage caused by the overexpression of the PI3K/AKT/mTOR signaling pathway in ICH-induced neurological dysfunctions in rats.

The Effect of Blue Light Source in a Lighting Installations on Human Circadian Rhythms

This article describes effect of the blue light on a human health. This effect is emmiting by electrical devices and has a negative impact on person, even if it does not fall into your eyes. This work consists on comparison study of blue radiation spectrum and impact on human organism. It helps to define permissible level of energy dependence on light radiation. The conception of biological impact connected with melanopsin, which one has rods and cones. For humans, nonvisual biological effects, which can be parameterized by the circadian action factor (CAF), are important for their health and work performance. When we spend a lot of time in front of screens of devices, we are receiving radiation of blue light. The article analyses questions associated with biological exposure to radiation from some light emitting diode and lamp light sources with various radiation spectrum (correlated colour temperature Tcc). The biological exposure concept is connected with melanopsyn containing receptors on the eye retina, signals from which arrive to epiphysis and control concentration of the hormone melatonin in the blood. Circadian rhythms are seen at every level of biology, from single cells to complex behaviors. The timing of every biological function in mammals is governed by the master clock in the suprachiasmatic nuclei (SCN), which has an intrinsic period of slightly longer than 24 hours. The light/dark pattern incident on the retina synchronizes the SCN to the 24-hour local time, coordinating and enabling diverse biological functions to occur at the correct time of day and night for optimum species survival. A wide range of modern maladies, from sleep disorders to cancer, has been linked to light-induced circadian disruption. Light has, however, been defined only in terms of the human visual system, not the circadian system. Light source and systems development should consider the needs of both the visual and non-visual systems. Certain signals are fulfil function of controlling the concentration chromatophorotropic hormone within blood. As a basis for calculation were included photochemical and electrical processes in amphiblestrodes, physiological human parameters, as well as coefficient of circadian efficiency, coefficient of growth-inhibitory activity of melatonin and biological equivalent. The optical information is essential for physiological systems of humans, because it not only provides the visual information but also affects their physical, physiological, and psychological behaviors, in which researchers call the latter “non-visual biological effects of light”. In the evolution of lives on earth, the sun and its spectrum, and the alternation of day and night play an important role in the adaptation of human to the natural environment. As receptors of light, human eyes are deeply influenced by standard light, to which the structure and function of human eyes are developed more accustomed during the long-term daily work.

Dosing-time dependent testicular toxicity of everolimus in mice

The circadian timing system controls many biological functions in mammals including drug metabolism and detoxification, cell cycle events, and thus may affect pharmacokinetics, target organ toxicity and efficacy of medicines. Selective mTOR (mammalian target of rapamycin) inhibitor everolimus is an immunosuppressant and anticancer drug that is effective against several cancers. The aim of this study was to investigate dosing-time dependent testicular toxicity of subacute everolimus administration in mice. C57BL/6 J male mice were synchronized with Light-Dark (12h:12 h) cycle, with Light-onset at Zeitgeber Time (ZT)-0. Everolimus (5 mg/kg/day) was administered orally to mice at ZT1rest-span or ZT13activity-span for 4 weeks. Body weight loss, clinical signs, changes in testicular weights, testis histology, spermatogenesis and proliferative activity of germinal epithelium of seminiferous tubules were examined. Steady-state everolimus concentrations in testes were determined with validated HPLC method. Everolimus toxicity was less severe following dosing at ZT13 compared to ZT1, as shown with least body weight loss (p<0.001), least reductions in testes weights (p<0.001) and least histopathological findings. Everolimus-induced histological changes on testes included vacuolisation and atrophy of germinal epithelium, and loss of germinal cell attachment. The severity of everolimus-induced histological toxicity on testes was significantly more evident in mice treated at ZT1 than ZT13 (p<0.001). Spermatogenic cell population significantly decreased when everolimus administered at ZT1 compared to ZT13 (p<0.001). Proliferative activity of germinal epithelium was significantly decreased due to treatment at ZT1 compared to ZT13 (p<0.001). Everolimus concentrations in testes indicated a pronounced circadian variation, which was greater in mice treated at ZT1 compared to ZT13 (p<0.05). Our study revealed dosing-time dependent testicular toxicity of everolimus in mice, which was greater in severity when everolimus administered at early rest-span (daytime-ZT1) than early activity-span (nighttime-ZT13). These findings support the concept of everolimus chronotherapy for minimizing reproductive toxicity and increasing the tolerability of everolimus, as a clinical advantage.

N-Acetylcysteine as Adjuvant Therapy for COVID-19 - A Perspective on the Current State of the Evidence.

The looming severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a long-lasting pandemic of coronavirus disease 2019 (COVID-19) around the globe with substantial morbidity and mortality. N-acetylcysteine, being a nutraceutical precursor of an important antioxidant glutathione, can perform several biological functions in mammals and microbes. It has consequently garnered a growing interest as a potential adjunctive therapy for coronavirus disease. Here, we review evidence concerning the effects of N-acetylcysteine in respiratory viral infections based on currently available in vitro, in vivo, and human clinical investigations. The repurposing of a known drug such as N-acetylcysteine may significantly hasten the deployment of a novel approach for COVID-19. Since the drug candidate has already been translated into the clinic for several decades, its established pharmacological properties and safety and side-effect profiles expedite preclinical and clinical assessment for the treatment of COVID-19. In vitro data have depicted that N-acetylcysteine increases antioxidant capacity, interferes with virus replication, and suppresses expression of pro-inflammatory cytokines in cells infected with influenza viruses or respiratory syncytial virus. Furthermore, findings from in vivo studies have displayed that, by virtue of immune modulation and anti-inflammatory mechanism, N-acetylcysteine reduces the mortality rate in influenza-infected mice animal models. The promising in vitro and in vivo results have prompted the initiation of human subject research for the treatment of COVID-19, including severe pneumonia and acute respiratory distress syndrome. Albeit some evidence of benefits has been observed in clinical outcomes of patients, precision nanoparticle design of N-acetylcysteine may allow for greater therapeutic efficacy.

The effects of P-glycoprotein inhibitor zosuquidar on the sex and time-dependent pharmacokinetics of parenterally administered talinolol in mice

P-glycoprotein (P-gp) is an efflux protein that forms a tissue barrier and plays a role in the pharmacokinetics of drugs, limiting the influx of them and other xenobiotics into the cells, as expressed in various tissues such as liver, brain, intestinal mucosa and kidneys. Circadian clock controls many biological functions in mammals including xenobiotic metabolism and detoxification. Circadian rhythms of biological functions may affect the pharmacokinetics, and thus efficacy and/or toxicity of drugs. Aim of this study is to determine how the intraperitoneally administered pharmacokinetics of talinolol, as the probe substrate of P-gp, will change depending on the circadian time and sex in the presence of P-gp inhibitor zosuquidar. 20 mg/kg talinolol with or without 30 mg/kg zosuquidar was administred intraperitoneally to male and female mice at day period (ZT3) and night period (ZT15). Plasma and tissue concentrations of talinolol were determined by using validated HPLC/UV method. The protein levels of P-gp in the liver and small intestine in male and female mice were determined by PCR and Western blot techniques. P-gp protein levels in liver and ileum tissues were not different in female mice but higher in ZT15 as compared to ZT3 in male mice (p<0.05). There was no statistically significant difference in talinolol concentration depending on time and sex in the plasma and liver. There was significant time-dependent difference between ZT3 and ZT15 groups in ileum AUC0–5 h of talinolol (p<0.01). Talinolol plasma and liver AUC0–5 h were increased by zosuquidar administration regardless of dosing-time and sex (p<0.05). Our study findings are considerable in terms of revealing changes in pharmacokinetic profiles of P-gp substrates due to the time of administration in combination with P-gp inhibitors/modulators in managing polypharmacy.

Structures of mammalian GLD-2 proteins reveal molecular basis of their functional diversity in mRNA and microRNA processing.

The stability and processing of cellular RNA transcripts are efficiently controlled via non-templated addition of single or multiple nucleotides, which is catalyzed by various nucleotidyltransferases including poly(A) polymerases (PAPs). Germline development defective 2 (GLD-2) is among the first reported cytoplasmic non-canonical PAPs that promotes the translation of germline-specific mRNAs by extending their short poly(A) tails in metazoan, such as Caenorhabditis elegans and Xenopus. On the other hand, the function of mammalian GLD-2 seems more diverse, which includes monoadenylation of certain microRNAs. To understand the structural basis that underlies the difference between mammalian and non-mammalian GLD-2 proteins, we determine crystal structures of two rodent GLD-2s. Different from C. elegans GLD-2, mammalian GLD-2 is an intrinsically robust PAP with an extensively positively charged surface. Rodent and C. elegans GLD-2s have a topological difference in the β-sheet region of the central domain. Whereas C. elegans GLD-2 prefers adenosine-rich RNA substrates, mammalian GLD-2 can work on RNA oligos with various sequences. Coincident with its activity on microRNAs, mammalian GLD-2 structurally resembles the mRNA and miRNA processor terminal uridylyltransferase 7 (TUT7). Our study reveals how GLD-2 structurally evolves to a more versatile nucleotidyltransferase, and provides important clues in understanding its biological function in mammals.

Biosensors for D-Amino Acids: Detection Methods and Applications.

D-enantiomers of amino acids (D-AAs) are only present in low amounts in nature, frequently at trace levels, and for this reason, their biological function was undervalued for a long time. In the past 25 years, the improvements in analytical methods, such as gas chromatography, HPLC, and capillary electrophoresis, allowed to detect D-AAs in foodstuffs and biological samples and to attribute them specific biological functions in mammals. These methods are time-consuming, expensive, and not suitable for online application; however, life science investigations and industrial applications require rapid and selective determination of D-AAs, as only biosensors can offer. In the present review, we provide a status update concerning biosensors for detecting and quantifying D-AAs and their applications for safety and quality of foods, human health, and neurological research. The review reports the main challenges in the field, such as selectivity, in order to distinguish the different D-AAs present in a solution, the simultaneous assay of both L- and D-AAs, the production of implantable devices, and surface-scanning biosensors. These innovative tools will push future research aimed at investigating the neurological role of D-AAs, a vibrant field that is growing at an accelerating pace.

The Drosophila melanogaster Ortholog of RFWD3 Functions Independently of RAD51 During DNA Repair.

Repair of damaged DNA is required for the viability of all organisms. Studies in Drosophila melanogaster, driven by the power of genetic screens, pioneered the discovery and characterization of many genes and pathways involved in DNA repair in animals. However, fewer than half of the alleles identified in these screens have been mapped to a specific gene, leaving a potential for new discoveries in this field. Here we show that the previously uncharacterized mutagen sensitive gene mus302 codes for the Drosophila melanogaster ortholog of the E3 ubiquitin ligase RING finger and WD domain protein 3 (RFWD3). In human cells, RFWD3 promotes ubiquitylation of RPA and RAD51 to facilitate repair of collapsed replication forks and double-strand breaks through homologous recombination. Despite the high similarity in sequence to the human ortholog, our evidence fails to support a role for Mus302 in the repair of these types of damage. Last, we observe that the N-terminal third of RFWD3 is only found in mammals, but not in other vertebrates or invertebrates. We propose that the new N-terminal sequence accounts for the acquisition of a new biological function in mammals that explains the functional differences between the human and the fly orthologs, and that Drosophila Mus302 may retain the ancestral function of the protein.

Knockdown of METTL14 inhibits the growth and invasion of cervical cancer

Background: Increasing evidence has revealed that N6-methyladenosine (m6A) modification is implicated in multiple biological functions in mammals. Methyltransferase-like 14 (METTL14), an important component of m6A modification, has been reported to play important roles in the pathogenesis of acute myeloid leukaemia and hepatocellular carcinoma metastasis. However, its role in cervical cancer remains unclear. Methods: Expression of METTL14 was knocked down by shRNA-METTL14 interference in HPV-positive and HPV-negative cervical cancer cell lines SiHa and C33a. CCK8, colony formation, wound-healing, and Transwell assays were performed to evaluate the effects of METTL14 knockdown on the proliferation, migration and invasion abilities of SiHa and C33a cells. Flow cytometry analysis was utilized to detect cell cycle distribution, and the expression of related proteins was examined by western blot analysis. Results: Bioinformatics analysis demonstrated that up-regulation of METTL14 acted as an adverse prognostic factor for overall survival in cervical cancer patients. We demonstrated that down-regulation of METTL14 inhibited the proliferation, migration and invasion abilities of SiHa and C33a cells. Moreover, silencing METTL14 induced cell cycle arrest in cervical cancer cells. METTL14 knockdown suppressed the PI3K/Akt/mTOR signaling pathway by decreasing the phosphorylation of Akt and mTOR, and the expression of downstream apoptosis-related proteins was also impacted. Conclusions: In conclusion, these data suggest an important oncogenic role of METTL14 in the growth and invasion of both HPV-positive and HPV-negative cervical cancer cells.

Hypophysis Size Evolution in Chiroptera

The hypophysis influences biological functions in mammals at various levels, and its volumetric variation in Chiroptera is recently well known. We explored the relation of the hypophysis size as a whole (Hyp) and its separate components, adenohypophysis (Adh) and neurohypophysis (Neh), from 96 species of bats (Yinpterochiroptera and Yangochiroptera), with social (roosting association), reproductive (testes mass, mating system, female promiscuity), body size (body mass) and foraging (diet) variables (when available for the sampled species), through ANCOVA and linear regressions analyses. We also explored the phylogenetic legacy of the volumetric changes of Hyp, Adh and Neh over a well-resolved phylogenetic tree, through Phylogenetically independent contrasts analysis, phylogenetic signal, and character optimizations. Hyp, Adh, Neh volumes and testes mass showed significant relation with body mass. When body mass effect was excluded, Hyp, Adh and Neh showed no significant relation with testes mass nor significant differences within roosting association, mating system and female promiscuity variables. However, Hyp, Adh and Neh volumes showed a pattern with diet, probably related to the regulatory role of the hypophysis at the endogenous protein metabolism in Mammals. The significant phylogenetic effect at linear regressions of Hyp, Adh and Neh volumes against body mass suggests the hypophysis volume and the body mass has coevolved, which was also supported by the significant phylogenetic signal and the optimizations considering body mass. Optimizations excluding body mass also showed significant phylogenetic signal, demonstrating that the volumetric changes bear phylogenetic information beyond body size. Our results suggest that the hypophysis size variations in bats are rather explained by phylogenetic legacy, as phylogenetic inertia linked to the ecology of the ancestors of the different clades, than current ecological aspects related to the natural history of the extant species.

Knockdown of METTL14 inhibits the growth and invasion of cervical cancer.

BackgroundIncreasing evidence has revealed that N6-methyladenosine (m6A) modification is implicated in multiple biological functions in mammals. Methyltransferase-like 14 (METTL14), an important component of m6A modification, has been reported to play important roles in the pathogenesis of acute myeloid leukaemia and hepatocellular carcinoma metastasis. However, its role in cervical cancer remains unclear.MethodsExpression of METTL14 was knocked down by shRNA-METTL14 interference in HPV-positive and HPV-negative cervical cancer cell lines SiHa and C33a. CCK8, colony formation, wound-healing, and Transwell assays were performed to evaluate the effects of METTL14 knockdown on the proliferation, migration and invasion abilities of SiHa and C33a cells. Flow cytometry analysis was utilized to detect cell cycle distribution, and the expression of related proteins was examined by western blot analysis.ResultsBioinformatics analysis demonstrated that up-regulation of METTL14 acted as an adverse prognostic factor for overall survival in cervical cancer patients. We demonstrated that down-regulation of METTL14 inhibited the proliferation, migration and invasion abilities of SiHa and C33a cells. Moreover, silencing METTL14 induced cell cycle arrest in cervical cancer cells. METTL14 knockdown suppressed the PI3K/Akt/mTOR signaling pathway by decreasing the phosphorylation of Akt and mTOR, and the expression of downstream apoptosis-related proteins was also impacted.ConclusionsIn conclusion, these data suggest an important oncogenic role of METTL14 in the growth and invasion of both HPV-positive and HPV-negative cervical cancer cells.