p53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression.

Tumor suppression by TP53 involves cell-autonomous and non-cell-autonomous mechanisms. TP53 can suppress tumor growth by modulating immune system functions; however, the mechanistic basis for this activity is not well understood. We report that p53 promotes the degradation of the DNA exonuclease TREX1, resulting in cytosolic dsDNA accumulation. We demonstrate that p53 requires the ubiquitin ligase TRIM24 to induce TREX1 degradation. The cytosolic DNA accumulation resulting from TREX1 degradation activates the cytosolic DNA-sensing cGAS/STING pathway, resulting in induction of type I interferons. TREX1 overexpression sufficed to block p53 activation of the cGAS/STING pathway. p53-mediated induction of type I interferon (IFNB1) is suppressed by cGAS/STING knockout, and p53's tumor suppressor activities are compromised by the loss of signaling through the cGAS/STING pathway. Thus, our study reveals that p53 utilizes the cGAS/STING innate immune system pathway for both cell-intrinsic and cell-extrinsic tumor suppressor activities.

Correction: How much (ATP) does it cost to build a trypanosome? A theoretical study on the quantity of ATP needed to maintain and duplicate a bloodstream-form Trypanosoma brucei cell.

[This corrects the article DOI: 10.1371/journal.ppat.1011522.].

How much (ATP) does it cost to build a trypanosome? A theoretical study on the quantity of ATP needed to maintain and duplicate a bloodstream-form Trypanosoma brucei cell.

ATP hydrolysis is required for the synthesis, transport and polymerization of monomers for macromolecules as well as for the assembly of the latter into cellular structures. Other cellular processes not directly related to synthesis of biomass, such as maintenance of membrane potential and cellular shape, also require ATP. The unicellular flagellated parasite Trypanosoma brucei has a complex digenetic life cycle. The primary energy source for this parasite in its bloodstream form (BSF) is glucose, which is abundant in the host's bloodstream. Here, we made a detailed estimation of the energy budget during the BSF cell cycle. As glycolysis is the source of most produced ATP, we calculated that a single parasite produces 6.0 x 1011 molecules of ATP/cell cycle. Total biomass production (which involves biomass maintenance and duplication) accounts for ~63% of the total energy budget, while the total biomass duplication accounts for the remaining ~37% of the ATP consumption, with in both cases translation being the most expensive process. These values allowed us to estimate a theoretical YATP of 10.1 (g biomass)/mole ATP and a theoretical [Formula: see text] of 28.6 (g biomass)/mole ATP. Flagellar motility, variant surface glycoprotein recycling, transport and maintenance of transmembrane potential account for less than 30% of the consumed ATP. Finally, there is still ~5.5% available in the budget that is being used for other cellular processes of as yet unknown cost. These data put a new perspective on the assumptions about the relative energetic weight of the processes a BSF trypanosome undergoes during its cell cycle.

Placental mitochondrial impairment and its association with maternal metabolic dysfunction.

The placenta plays an essential role in pregnancy, leading to proper fetal development and growth. As an organ with multiple physiological functions for both mother and fetus, it is a highly energetic and metabolically demanding tissue. Mitochondrial physiology plays a crucial role in the metabolism of this organ and thus any alteration leading to mitochondrial dysfunction has a severe outcome in the development of the fetus. Pregnancy-related pathological states with a mitochondrial dysfunction outcome include preeclampsia and gestational diabetes mellitus. In this review, we address the role of mitochondrial morphology, metabolism and physiology of the placenta during pregnancy, highlighting the roles of the cytotrophoblast and syncytiotrophoblast. We also describe the relationship between preeclampsia, gestational diabetes, gestational diabesity and pre-pregnancy maternal obesity with mitochondrial dysfunction.

Long-term potentiation and its neurotrophin-dependent modulation in the superior cervical ganglion of the rat are influenced by KCNQ channel function.

Ganglionic long-term potentiation (gLTP) in the rat superior cervical ganglion (SCG) is differentially modulated by neurotrophic factors (Nts): brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). KCNQ/M channels, key regulators of neuronal excitability, and firing pattern are modulated by Nts; therefore, they might contribute to gLTP expression and to the Nts-dependent modulation of gLTP. In the SCG of rats, we characterized the presence of the KCNQ2 isoform and the effects of opposite KCNQ/M channel modulators on gLTP in control condition and under Nts modulation. Immunohistochemical and reverse transcriptase polymerase chain reaction analyses showed the expression of the KCNQ2 isoform. We found that 1 µmol/L XE991, a channel inhibitor, significantly reduced gLTP (∼50%), whereas 5 µmol/L flupirtine, a channel activator, significantly increased gLTP (1.3- to 1.7-fold). Both modulators counterbalanced the effects of the Nts on gLTP. Data suggest that KCNQ/M channels are likely involved in gLTP expression and in the modulation exerted by BDNF and NGF.

Clinical Features and Neurodevelopmental Outcomes for Infants with Perinatal Vertical Transmission of Zika Virus, Colombia.

Transplacental transmission of Zika virus has been reported during all trimesters of pregnancy and might lead to central nervous system anomalies, including microcephaly. We report 3 cases of perinatal Zika infection identified during the epidemic in Colombia and provide detailed descriptions of clinical features, diagnosis, and neurodevelopmental outcome at 18 months of age (corrected).

Platelets immune response against Mycobacterium tuberculosis infection.

Tuberculosis (TB) is the first cause of death by a single infectious agent. Previous reports have highlighted the presence of platelets within Tb granulomas, albeit the immune-associated platelet response to Mycobacterium tuberculosis (Mtb) has not been deeply studied. Our results showed that platelets are recruited into the granuloma in the late stages of tuberculosis. Furthermore, electron-microscopy studies showed that platelets can internalize Mtb and produce host defense peptides (HDPs), such as RNase 7, HBD2 and hPF-4 that bind to the internalized Mtb. Mtb-infected platelets exhibited higher transcription and secretion of IL-1ß and TNF-α, whereas IL-10 and IL-6 protein levels decreased. These results suggest that platelets participate in the immune response against Mtb through HDPs and cytokines production.

Prediction of thromboembolic events and mortality by the CHADS2 and the CHA2DS2-VASc in COVID-19.

AIMS: Age, sex, and cardiovascular disease have been linked to thromboembolic complications and poorer outcomes in COVID-19. We hypothesize that CHADS2 and CHA2DS2-VASc scores may predict thromboembolic events and mortality in COVID-19. METHODS AND RESULTS: COVID-19 hospitalized patients with confirmed SARS-CoV-2 infection from 1 March to 20 April 2020 who completed at least 1-month follow-up or died were studied. CHADS2 and CHA2DS2-VASc scores were calculated. Given the worse prognosis of male patients in COVID-19, a modified CHA2DS2-VASc score (CHA2DS2-VASc-M) in which 1 point was given to male instead of female was also calculated. The associations of these scores with laboratory results, thromboembolic events, and death were analysed. A total of 3042 patients (mean age 62.3 ± 20.3 years, 54.9% male) were studied and 115 (3.8%) and 626 (20.6%) presented a definite thromboembolic event or died, respectively, during the study period [median follow 59 (50-66) days]. Higher score values were associated with more marked abnormalities of inflammatory and cardiac biomarkers. Mortality was significantly higher with increasing scores for CHADS2, CHA2DS2-VASc, and CHA2DS2-VASc-M (P < 0.001 for trend). The CHA2DS2-VASc-M showed the best predictive value for mortality [area under the receiver operating characteristic curve (AUC) 0.820, P < 0.001 for comparisons]. All scores had poor predictive value for thromboembolic events (AUC 0.497, 0.490, and 0.541, respectively). CONCLUSION: The CHADS2, CHA2DS2-VASc, and CHA2DS2-VASc-M scores are significantly associated with all-cause mortality but not with thromboembolism in COVID-19 patients. They are simple scoring systems in everyday use that may facilitate initial 'quick' prognostic stratification in COVID-19.

Mutant p53 cooperates with ETS2 to promote etoposide resistance.

Mutant p53 (mtp53) promotes chemotherapy resistance through multiple mechanisms, including disabling proapoptotic proteins and regulating gene expression. Comparison of genome wide analysis of mtp53 binding revealed that the ETS-binding site motif (EBS) is prevalent within predicted mtp53-binding sites. We demonstrate that mtp53 regulates gene expression through EBS in promoters and that ETS2 mediates the interaction with this motif. Importantly, we identified TDP2, a 5'-tyrosyl DNA phosphodiesterase involved in the repair of DNA damage caused by etoposide, as a transcriptional target of mtp53. We demonstrate that suppression of TDP2 sensitizes mtp53-expressing cells to etoposide and that mtp53 and TDP2 are frequently overexpressed in human lung cancer; thus, our analysis identifies a potentially "druggable" component of mtp53's gain-of-function activity.

Zika virus infection: A correlation between prenatal ultrasonographic and postmortem neuropathologic changes.

This study presents a correlation between prenatal ultrasonographic images and neuropathologic findings of postmortem tissue samples from five confirmed cases of perinatal Zika virus (ZIKV) infection belonging to the cohort of the ZEN Initiative in Bucaramanga, Colombia. Deaths occurred between June 2016 and March 2017. Mothers consulted with ZIKV infection clinical manifestations or fetal central nervous system (CNS) abnormalities or both. A detailed ultrasound scan and neurosonographic protocol was performed by maternal fetal specialists. Perinatal autopsies were performed following the Colombian National Health Institute's ZIKV protocol. The autopsies were from two fetal deaths, and three early neonatal deaths. Gestational age was between 262/7 and 382/7 weeks. Two cases were classified as mild microcephaly. Few findings by ultrasound and pathology were found in case 1 because it was a late infection; the other cases presented findings corresponding to congenital Zika syndrome: craniofacial malformations, cerebellar hypoplasia, anomalies of the corpus callosum and ventriculomegaly, all confirmed in autopsy specimens. By ultrasonography, hyperechogenicities were seen in several brain structures, which correspond to cortical and periventricular calcifications, subependymal glial reactivity and perivascular rings. The ultrasound and pathological findings show a wide spectrum of CNS anomalies that confirm the neurotropic effect of the ZIKV, recognizing the neuroimaging findings of this disease (unilateral ventriculomegaly, alterations in the corpus callosum and cerebellum, and calcifications) are highly suggestive of ZIKV infection.

Ganglionic Long-Term Potentiation in Prehypertensive and Hypertensive Stages of Spontaneously Hypertensive Rats Depends on GABA Modulation.

The sympathetic nervous system (SNS) regulates body functions in normal and pathological conditions and is characterized by the presence of a neuroplastic phenomenon, termed ganglionic long-term potentiation (gLTP). In hypertension, either in spontaneously hypertensive rats (SHR) or in humans, sympathetic hyperfunction, such as elevated SNS outflow and changes in synaptic plasticity have been described. Because enhanced SNS outflow is detected in the hypertensive stage and, more importantly, in the prehypertensive phase of SHR, here we explored whether synaptic plasticity, particularly gLTP, was modified in the superior cervical ganglia (SCG) of prehypertensive SHR. Furthermore, considering that GABA modulates sympathetic synaptic transmission and gLTP in Wistar rats, we studied whether GABA might modulate gLTP expression in SHR. We characterized gLTP in the SCG of young prehypertensive 6-week-old (wo) and adult hypertensive (12 wo) SHR and in the SCG of Wistar Kyoto (WKy) normotensive control rats of the same ages. We found that gLTP was expressed in 6 wo SHR, but not in 12 wo rats. By contrast, in WKy, gLTP was expressed in 12 wo, but not in 6 wo rats. We also found that gLTP depends on GABA modulation, as blockade of GABA-A subtype receptors with its antagonist bicuculline unmasked gLTP expression in adult SHR and young WKy. We propose that (1) activity-dependent changes in synaptic efficacy are altered not only during hypertension but also before its onset and (2) GABA may play a modulatory role in the changes in synaptic plasticity in SHR, because the blockade of GABA-A receptors unmasked the expression of gLTP. These early changes in neuroplasticity and GABA modulation of gLTP could be part of the sympathetic hyperfunction observed in hypertension.

Mitochondrial form, function and signalling in aging.

Aging is often accompanied by a decline in mitochondrial mass and function in different tissues. Additionally, cell resistance to stress is frequently found to be prevented by higher mitochondrial respiratory capacity. These correlations strongly suggest mitochondria are key players in aging and senescence, acting by regulating energy homeostasis, redox balance and signalling pathways central in these processes. However, mitochondria display a wide array of functions and signalling properties, and the roles of these different characteristics are still widely unexplored. Furthermore, differences in mitochondrial properties and responses between tissues and cell types, and how these affect whole body metabolism are also still poorly understood. This review uncovers aspects of mitochondrial biology that have an impact upon aging in model organisms and selected mammalian cells and tissues.

Control of Nucleotide Metabolism Enables Mutant p53's Oncogenic Gain-of-Function Activity.

Since its discovery as an oncoprotein in 1979, investigation into p53's many identities has completed a full circle and today it is inarguably the most extensively studied tumor suppressor (wild-type p53 form or WTp53) and oncogene (mutant p53 form or mtp53) in cancer research. After the p53 protein was declared "Molecule of the Year" by Science in 1993, the p53 field exploded and a plethora of excellent reviews is now available on every aspect of p53 genetics and functional repertoire in a cell. Nevertheless, new functions of p53 continue to emerge. Here, we discuss a novel mechanism that contributes to mtp53's Gain of Functions GOF (gain-of-function) activities and involves the upregulation of both nucleotide de novo synthesis and nucleoside salvage pathways.

The Saccharomyces cerevisiae mitochondrial unselective channel behaves as a physiological uncoupling system regulated by Ca2+, Mg2+, phosphate and ATP.

It is proposed that the Saccharomyces cerevisiae the Mitochondrial Unselective Channel ((Sc)MUC) is tightly regulated constituting a physiological uncoupling system that prevents overproduction of reactive oxygen species (ROS). Mg(2+), Ca(2+) or phosphate (Pi) close (Sc)MUC, while ATP or a high rate of oxygen consumption open it. We assessed (Sc)MUC activity by measuring in isolated mitochondria the respiratory control, transmembrane potential (ΔΨ), swelling and production of ROS. At increasing [Pi], less [Ca(2+)] and/or [Mg(2+)] were needed to close (Sc)MUC or increase ATP synthesis. The Ca(2+)-mediated closure of (Sc)MUC was prevented by high [ATP] while the Mg(2+) or Pi effect was not. When Ca(2+) and Mg(2+) were alternatively added or chelated, (Sc)MUC opened and closed reversibly. Different effects of Ca(2+) vs Mg(2+) effects were probably due to mitochondrial Mg(2+) uptake. Our results suggest that (Sc)MUC activity is dynamically controlled by both the ATP/Pi ratio and divalent cation fluctuations. It is proposed that the reversible opening/closing of (Sc)MUC leads to physiological uncoupling and a consequent decrease in ROS production.

Effects of housing condition and early corticosterone treatment on learned features of song in adult male zebra finches.

Early developmental stress can have long-term physiological and behavioral effects on an animal. Developmental stress and early corticosterone (Cort) exposure affect song quality in many songbirds. Early housing condition can act as a stressor and affect the growth of nestlings and adult song, and improvements in housing condition can reverse adverse effects of early stress exposure in rodents. However, little is known about this effect in songbirds. Therefore, we took a novel approach to investigate if housing condition can modify the effects of early Cort exposure on adult song in male zebra finches. We manipulated early housing conditions to include breeding in large communal flight cages (FC; standard housing condition; with mixed-sex and mix-aged birds) versus individual breeding cages (IBC, one male-female pair with small, IBC-S, or large clutches, IBC-L) in post-hatch Cort treated male birds. We found that Cort treated birds from IBC-S have higher overall song learning scores (between tutor and pupil) than from FC but there is no difference between these groups in the No-Cort treated birds. When examining the effects of Cort within each housing condition, overall song learning scores decreased in Cort treated birds from flight cages but increased in birds from IBC-S compared to controls. Likewise, the total number of syllables and syllable types increased significantly in Cort treated birds from IBC-S, but decreased in FC-reared birds though this effect was not statistically significant. These findings suggest that the effects of early Cort treatment on learned features of song depend on housing condition.

Serine Depletion Promotes Antitumor Immunity by Activating Mitochondrial DNA-Mediated cGAS-STING Signaling.

Serine is critical for supporting cancer metabolism, and depriving malignant cells of this nonessential amino acid exerts antineoplastic effects, in large part, through disrupting metabolic pathways. Given the intricate relationship between cancer metabolism and the immune system, the metabolic defects imposed by serine deprivation might impact tumor-targeting immunity. In this study, we demonstrated that restricting endogenous and exogenous sources of serine in colorectal cancer cells results in mitochondrial dysfunction, leading to mitochondrial DNA (mtDNA) accumulation in the cytosol and consequent cGAS-STING1-driven type I IFN secretion. Depleting mtDNA or blocking its release attenuated cGAS-STING1 activation during serine deprivation. In vivo studies revealed that serine deprivation limits tumor growth, accompanied by enhanced type I IFN signaling and intratumoral infiltration of immune effector cells. Notably, the tumor-suppressive and immune-enhancing effects of serine restriction were impaired by T-cell depletion and IFN receptor blockade. Moreover, disrupting cGAS-STING1 signaling in colorectal cancer cells limited the immunostimulatory and tumor-suppressive effects of serine deprivation. Lastly, serine depletion increased the sensitivity of tumors to an immune checkpoint inhibitor targeting PD-1. Taken together, these findings reveal a role for serine as a suppressor of antitumor immunity, suggesting that serine deprivation may be employed to enhance tumor immunogenicity and improve responsiveness to immune checkpoint inhibitors. Significance: Depriving cancer cells of serine provokes mitochondrial perturbations that induce cytosolic mitochondrial DNA accumulation and subsequent activation of cGAS-STING signaling, stimulating tumor-targeting immune responses that can be enhanced with PD-1 targeted therapy. See related commentary by Borges and Garg, p. 2569.

Binary mixtures of Vanderbilt University allosteric agonist thermolysis components act as volatile spatial repellents for malaria vector mosquitoes.

BACKGROUND: The development of economically viable and environmentally neutral tools to control insects that consume or damage over 20% of global agriculture or vector human and animal disease represents one of the most important challenges of the 21st century. The suite of chemical-based strategies currently employed to control insect populations rely primarily on insecticides, which are subject to rapid resistance and often have harmful off-target environmental and health-related impacts, and, to a lesser degree, repellents, which typically rely on masking attractive odors. The discovery and characterization of Vanderbilt University allosteric agonists (VUAAs), a family of small-molecule agonists that target the highly conserved, insect-specific odorant receptor coreceptor (Orco), raise the potential for the development of a novel repellent paradigm for vector/pest management. VUAAs have the potential to target nearly all insect olfactory sensory neurons, leading to highly aversive behavioral responses, but importantly have limited volatility, thereby reducing their utility as spatial repellents. RESULTS: We have characterized VUAA thermolysis components and identified a suite of volatiles (VUAA-based active ingredients, VUAIs) that act specifically in novel binary combinations as robust and long-lasting spatial repellents against Anopheline mosquitoes. In mobility-based behavioral experiments, VUAIs act synergistically as effective spatial repellents and outperform parent VUAA compounds against host-seeking Anopheline mosquitoes. CONCLUSIONS: VUAIs are volatile alternatives to Vanderbilt University allosteric agonists (VUAAs) that have the potential for use as spatial repellents in disease vector and agricultural pest control. The repellency observed is odorant receptor coreceptor (Orco)-dependent, supporting the hypothesis that VUAIs and VUAAs similarly target an allosteric Orco recognition site. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Probing Quantum Efficiency: Exploring System Hardness in Electronic Ground State Energy Estimation.

We consider the question of how correlated the system hardness is between classical algorithms of electronic structure theory in ground state estimation and quantum algorithms. To define the system hardness for classical algorithms, we employ empirical criterion based on the deviation of electronic energies produced by coupled cluster and configuration interaction methods from the exact ones along multiple bonds dissociation in a set of molecular systems. For quantum algorithms, we have selected the Variational Quantum Eigensolver (VQE) and Quantum Phase Estimation (QPE) methods. As characteristics of the system hardness for quantum methods, we analyzed circuit depths for the state preparation, the number of quantum measurements needed for the energy expectation value, and various cost characteristics for the Hamiltonian encodings via Trotter approximation and linear combination of unitaries (LCU). Our results show that the quantum resource requirements are mostly unaffected by classical hardness, with the only exception being the state preparation part, which contributes to both VQE and QPE algorithm costs. However, there are clear indications that constructing the initial state with a significant overlap with the true ground state is easier than obtaining the state with an energy expectation value within chemical precision. These results support optimism regarding the identification of a molecular system where a quantum algorithm excels over its classical counterpart, as quantum methods can maintain efficiency in classically challenging systems.

Performance of the First-Trimester Cervical Consistency Index to Predict Preterm Birth.

Background/Objectives: Preterm birth (PTB) remains a significant global health challenge. Previous attempts to predict preterm birth in the first trimester using cervical length have been contradictory. The cervical consistency index (CCI) was introduced to quantify early cervical changes and has shown promise across various clinical scenarios in the mid-trimester, though testing in the first trimester is lacking. This study aims to assess the cervical consistency index performance in predicting preterm birth during the first trimester of pregnancy. Methods: In this prospective cohort study, focused exclusively on research, women with singleton pregnancies, both with and without a history of spontaneous preterm birth (sPTB), were included. The primary outcome was sPTB before 37 weeks, with a secondary outcome of sPTB before 34 weeks. CCI measurements were taken between 11+0 to 13+6 weeks of gestation. Receiver operating characteristic (ROC) curves were generated, and sensitivity and specificity were calculated for the optimal cut-off and for the 5th, 10th, and 15th percentile. Intraobserver and interobserver agreements were assessed using the intraclass correlation coefficient (ICC). Results: Among the 667 patients analyzed, the rates of sPTB before 37 and 34 weeks were 9.2% (61/667) and 1.8% (12/667), respectively. The detection rates (DRs) for CCI predicting PTB before 37 and 34 weeks were 19.7% (12/61) and 33.3% (4/12). Negative predictive values were 91.8% (546/595) and 98.7% (588/596), while the areas under the curve (AUC) for sPTB before 37 and 34 weeks were 0.62 (95% CI: 0.54-0.69) and 0.80 (95% CI: 0.71-0.89), respectively. Of the 61 patients with preterm birth, 13 (21.3%) had a preterm birth history; in this group, the CCI percentile 10th identified 39% (5/13). Intraobserver ICC was 0.862 (95% CI: 0.769-0.920), and interobserver ICC was 0.833 (95% CI: 0.722-0.902). Conclusions: This study suggests that utilizing CCI in the first trimester of pregnancy could serve as a valuable tool for predicting preterm birth before 34 weeks of gestation, demonstrating robust intraobserver and interobserver reliability.

The medial preoptic area is necessary for sexual odor preference, but not sexual solicitation, in female Syrian hamsters.

Precopulatory behaviors that are preferentially directed towards opposite-sex conspecifics are critical for successful reproduction, particularly in species wherein the sexes live in isolation, such as Syrian hamsters (Mesocricetus auratus). In females, these behaviors include sexual odor preference and vaginal scent marking. The neural regulation of precopulatory behaviors is thought to involve a network of forebrain areas that includes the medial amygdala (MA), the bed nucleus of the stria terminalis (BNST), and the medial preoptic area (MPOA). Although MA and BNST are necessary for sexual odor preference and preferential vaginal marking to male odors, respectively, the role of MPOA in odor-guided female precopulatory behaviors is not well understood. To address this issue, female Syrian hamsters with bilateral, excitotoxic lesions of MPOA (MPOA-X) or sham lesions (SHAM) were tested for sexual odor investigation, scent marking, and lordosis. MPOA-X females did not investigate male odors more than female odors in an odor preference test, indicating that MPOA may be necessary for normal sexual odor preference in female hamsters. This loss of preference cannot be attributed to a sensory deficit, since MPOA-X females successfully discriminated male odors from female odors during an odor discrimination test. Surprisingly, no deficits in vaginal scent marking were observed in MPOA-X females, although these females did exhibit decreased overall levels of flank marking compared to SHAM females. Finally, all MPOA-X females exhibited lordosis appropriately. These results suggest that MPOA plays a critical role in the neural regulation of certain aspects of odor-guided precopulatory behaviors in female Syrian hamsters.