Small RNAs in the pathogenesis of preeclampsia.

Preeclampsia is a major contributor to maternal and fetal morbidity and mortality. The disorder can be classified into early- and late-onset subtypes, both of which evolve in two stages. The first stage comprises the development of pre-clinical, utero-placental malperfusion. Early and late utero-placental malperfusion have different causes and time courses. Early-onset preeclampsia (20 % of cases) is driven by dysfunctional placentation in the first half of pregnancy. In late-onset preeclampsia (80 % of cases), malperfusion is a consequence of placental compression within the confines of a limited uterine cavity. In both subtypes, the malperfused placenta releases stress signals into the maternal circulation. These stress signals trigger onset of the clinical syndrome (the second stage). Small RNA molecules, which are implicated in cellular stress responses in general, may be involved at different stages. Micro RNAs contribute to abnormal trophoblast invasion, immune dysregulation, angiogenic imbalance, and syncytiotrophoblast-derived extracellular vesicle signalling in preeclampsia. Transfer RNA fragments are placental signals known to be specifically involved in cell stress responses. Disorder-specific differences in small nucleolar RNAs and piwi-interacting RNAs have also been reported. Here, we summarise key small RNA advances in preeclampsia pathogenesis. We propose that existing small RNA classifications are unhelpful and that non-biased assessment of RNA expression, incorporation of non-annotated molecules and consideration of chemical modifications to RNAs may be important in elucidating preeclampsia pathogenesis.

A method to isolate syncytiotrophoblast-derived medium-large extracellular vesicle small RNA from maternal plasma.

Syncytiotrophoblast-derived extracellular vesicles (STB-EVs) have an important role in placental research: both as mediators of feto-maternal signalling and as liquid biopsies reflecting placental health. Recent evidence highlights the importance of STB-EV RNA. Isolation of STB-EV RNA from maternal blood is therefore an important challenge. We describe a novel technique where we first separate medium-large particles from plasma using centrifugation then use a highly specific bead-bound antibody to placental alkaline phosphatase to separate STB-EVs from other similar-sized particles. We demonstrate the yield and size profile of small RNA obtained from plasma STB-EVs. We present data confirming isolation of placenta-derived micro RNA from maternal plasma using this method. The technique has been successfully applied to validate novel RNA discoveries from placental perfusion models. We propose it could offer new insights through transcriptomic analyses, providing a syncytiotrophoblast-specific signal from maternal blood.

Protein Profiling of Placental Extracellular Vesicles in Gestational Diabetes Mellitus.

Throughout pregnancy, some degree of insulin resistance is necessary to divert glucose towards the developing foetus. In gestational diabetes mellitus (GDM), insulin resistance is exacerbated in combination with insulin deficiency, causing new-onset maternal hyperglycaemia. The rapid reversal of insulin resistance following delivery strongly implicates the placenta in GDM pathogenesis. In this case-control study, we investigated the proteomic cargo of human syncytiotrophoblast-derived extracellular vesicles (STBEVs), which facilitate maternal-fetal signalling during pregnancy, in a UK-based cohort comprising patients with a gestational age of 38-40 weeks. Medium/large (m/l) and small (s) STBEVs were isolated from GDM (n = 4) and normal (n = 5) placentae using ex vivo dual-lobe perfusion and subjected to mass spectrometry. Bioinformatics were used to identify differentially carried proteins and mechanistic pathways. In m/lSTBEVs, 56 proteins were differently expressed while in sSTBEVs, no proteins reached statistical difference. Differences were also observed in the proteomic cargo between m/lSTBEVs and sSTBEVs, indicating that the two subtypes of STBEVs may have divergent modes of action and downstream effects. In silico functional enrichment analysis of differentially expressed proteins in m/lSTBEVs from GDM and normal pregnancy found positive regulation of cytoskeleton organisation as the most significantly enriched biological process. This work presents the first comparison of two populations of STBEVs' protein cargos (m/l and sSTBEVs) from GDM and normal pregnancy isolated using placenta perfusion. Further investigation of differentially expressed proteins may contribute to an understanding of GDM pathogenesis and the development of novel diagnostic and therapeutic tools.

Differential 5'-tRNA Fragment Expression in Circulating Preeclampsia Syncytiotrophoblast Vesicles Drives Macrophage Inflammation.

BACKGROUND: The relationship between placental pathology and the maternal syndrome of preeclampsia is incompletely characterized. Mismatch between placental nutrient supply and fetal demands induces stress in the syncytiotrophoblast, the layer of placenta in direct contact with maternal blood. Such stress alters the content and increases the release of syncytiotrophoblast extracellular vesicles (STB-EVs) into the maternal circulation. We have previously shown 5'-tRNA fragments (5'-tRFs) constitute the majority of small RNA in STB-EVs in healthy pregnancy. 5'-tRFs are produced in response to stress. We hypothesized STB-EV 5'-tRF release might change in preeclampsia. METHODS: We perfused placentas from 8 women with early-onset preeclampsia and 6 controls, comparing small RNA expression in STB-EVs. We used membrane-affinity columns to isolate maternal plasma vesicles and investigate placental 5'-tRFs in vivo. We quantified 5'-tRFs from circulating STB-EVs using a placental alkaline phosphatase immunoassay. 5'-tRFs and scrambled RNA controls were added to monocyte, macrophage and endothelial cells in culture to investigate transcriptional responses. RESULTS: 5'-tRFs constitute the majority of small RNA in STB-EVs from both preeclampsia and normal pregnancies. More than 900 small RNA fragments are differentially expressed in preeclampsia STB-EVs. Preeclampsia-dysregulated 5'-tRFs are detectable in maternal plasma, where we identified a placentally derived load. 5'-tRF-Glu-CTC, the most abundant preeclampsia-upregulated 5'-tRF in perfusion STB-EVs, is also increased in preeclampsia STB-EVs from maternal plasma. 5'-tRF-Glu-CTC induced inflammation in macrophages but not monocytes. The conditioned media from 5'-tRF-Glu-CTC-activated macrophages reduced eNOS (endothelial NO synthase) expression in endothelial cells. CONCLUSIONS: Increased release of syncytiotrophoblast-derived vesicle-bound 5'-tRF-Glu-CTC contributes to preeclampsia pathophysiology.

Acute fasting reduces tolerance to progressive central hypovolemia in humans.

Potential health benefits of an acute fast include reductions in blood pressure and increases in vagal cardiac control. These purported health benefits could put fasted humans at risk for cardiovascular collapse when exposed to central hypovolemia. The purpose of this study was to test the hypothesis that an acute 24-h fast (vs. 3-h postprandial) would reduce tolerance to central hypovolemia induced via lower body negative pressure (LBNP). We measured blood ketones (ß-OHB) to confirm a successful fast (n = 18). We recorded the electrocardiogram (ECG), beat-to-beat arterial pressure, muscle sympathetic nerve activity (MSNA; n = 7), middle cerebral artery blood velocity (MCAv), and forearm blood flow. Following a 5-min baseline, LBNP was increased by 15 mmHg until -60 mmHg and then increased by 10 mmHg in a stepwise manner until onset of presyncope. Each LBNP stage lasted 5-min. Data are expressed as means ± SE ß-OHB increased (ß-OHB; 0.12 ± 0.04 fed vs. 0.47 ± 0.11, P < 0.01 mmol/L fast). Tolerance to central hypovolemia was decreased by ∼10% in the fasted condition measured via total duration of negative pressure (1,370 [Formula: see text] 89 fed vs. 1,229 ± 94 s fast, P = 0.04), and was negatively associated with fasting blood ketones (R = -0.542, P = 0.02). During LBNP, heart rate and MSNA increased similarly, but in the fasted condition forearm vascular resistance was significantly reduced. Our results suggest that acute fasting reduces tolerance to central hypovolemia by blunting increases in peripheral resistance, indicating that prolonged fasting may hinder an individual's ability to compensate to a loss of blood volume.NEW & NOTEWORTHY An acute 24 h fasting reduces tolerance to central hypovolemia, and tolerance is negatively associated with blood ketone levels. Compared with a fed condition (3-h postprandial), fasted participants exhibited blunted peripheral vasoconstriction and greater reductions in stroke volume during stepwise lower body negative pressure. These findings suggest that a prolonged fast may lead to quicker decompensation during central hypovolemia.

ExoCounter Assays Identify Women Who May Develop Early-Onset Preeclampsia From 12.5 µL First-Trimester Serum by Characterizing Placental Small Extracellular Vesicles.

BACKGROUND: Preeclampsia is a major cause of maternal and perinatal morbidity and mortality worldwide. Identifying women with high risk of developing preeclampsia in early pregnancy remains challenging. Extracellular vesicles released from the placenta offer an attractive biomarker but have been elusive to quantify. METHODS: Here, we tested ExoCounter, a novel device that immunophenotypes size-selected small extracellular vesicles <160 nm, for its ability to perform qualitative and quantitative placental small extracellular vesicles (psEV) analysis. To investigate disease-specific and gestational age-specific changes, we analyzed psEV counts in maternal plasma samples taken at each of the 3 trimesters from women who had (1) normal pregnancy (n=3); (2) women who developed early-onset preeclampsia (EOPE; n=3); and (3) women who developed late-onset preeclampsia (n=4) using 3 antibody pairs, CD10-placental alkaline phosphatase (PLAP), CD10-CD63, and CD63-PLAP. We further validated the findings in first-trimester serum samples among normal pregnancy (n=9), women who developed EOPE (n=7), and women who developed late-onset preeclampsia (n=8). RESULTS: We confirmed that CD63 was the major tetraspanin molecule coexpressed with PLAP-a known placental extracellular vesicles marker on psEV. Higher psEV counts for all 3 antibody pairs were detected in the plasma of women who developed EOPE than the other 2 groups in the first trimester, which persisted through the second and third trimesters. Significantly higher CD10-PLAP (P<0.01) and CD63-PLAP (P<0.01) psEV counts were validated in the serum of the first trimester of women who developed EOPE compared with normal pregnancy. CONCLUSIONS: Application of the ExoCounter assay developed here could identify patients at risk of developing EOPE in the first trimester, thereby providing a window of opportunity for early intervention.

A weakened AMOC may prolong greenhouse gas-induced Mediterranean drying even with significant and rapid climate change mitigation.

The Mediterranean region has been identified as a climate hot spot, with models projecting a robust warming and rainfall decline in response to increasing greenhouse gases. The projected rainfall decline would have impacts on agriculture and water resources. Can such changes be reversed with significant reductions in greenhouse gases? To explore this, we examine large ensembles of a high-resolution climate model with various future radiative forcing scenarios, including a scenario with substantial reductions in greenhouse gas concentrations beginning in the mid-21st century. In response to greenhouse gas reductions, the Mediterranean summer rainfall decline is reversed, but the winter rainfall decline continues. This continued winter rainfall decline results from a persistent atmospheric anticyclone over the western Mediterranean. Using additional numerical experiments, we show that the anticyclone and continued winter rainfall decline are attributable to greenhouse gas-induced weakening of the Atlantic Meridional Overturning Circulation (AMOC) that continues throughout the 21st century. The persistently weak AMOC, in concert with greenhouse gas reductions, leads to rapid cooling and sea ice growth in the subpolar North Atlantic. This cooling leads to a strong cyclonic atmospheric circulation anomaly over the North Atlantic subpolar gyre and, via atmospheric teleconnections, to the anticyclonic circulation anomaly over the Mediterranean. The failure to reverse the winter rainfall decline, despite substantial climate change mitigation, is an example of a "surprise" in the climate system. In this case, a persistent AMOC change unexpectedly impedes the reversibility of Mediterranean climate change. Such surprises could complicate pathways toward full climate recovery.

Relationship Between Environmental Air Quality and Congenital Heart Defects.

BACKGROUND: Congenital heart defects (CHDs) affect 40,000 U.S. infants annually. One fourth of these infants have a critical CHD, requiring intervention within the first year of life for survival. Over 80% of CHDs have an unknown etiology. Fine particulate matter ≤2.5 (PM2.5) and ozone (O3) may be air pollutants associated with CHD. OBJECTIVES: The purpose of this study was to explore relationships between first-trimester maternal exposure to air pollutants PM2.5 and O3 and a critical CHD diagnosis. METHODS: A retrospective cohort study with nested case controls was conducted using data from January 1, 2014, to December 31, 2016, and consisted of 199 infants with a diagnosed critical CHD and 550 controls. Air pollution data were obtained from the U.S. Environmental Protection Agency air monitors. Geographic information system software was used to geocode monitoring stations and infant residential locations. Data analysis included frequencies, chi-square, independent t-test analysis, and binary logistic regression for two time periods: the entire first trimester (Weeks 1-12) and the critical exposure window (Weeks 3-8 gestation). RESULTS: Critical CHD odds were not significantly increased by exposure during the first trimester. However, weekly analyses revealed CHD odds were higher in Weeks 5 and 8 as PM2.5 increased and decreased in Week 11 with increased O3 exposure. DISCUSSION: Our study shows no evidence to support the overall association between air pollutants PM2.5 and O3 and a critical CHD diagnosis. However, analyses by week suggested vulnerability in certain weeks of gestation and warrant additional surveillance and study.

Influence of an acute fast on ambulatory blood pressure and autonomic cardiovascular control.

Evidence suggests that intermittent fasting improves cardiovascular health by reducing arterial blood pressure, but contributing mechanisms are unclear. The purpose of this study was to determine the influence of an acute fast on hemodynamics, muscle sympathetic nerve activity (MSNA), and autonomic control at rest and during an arterial pressure challenge. Twenty-five young normotensive volunteers were tested twice, in the fed and fasted (24 h) states (randomized). Twenty-four hour ambulatory blood pressure was measured before an autonomic function test, which consisted of a 10-min period of controlled breathing (CB) at 0.25 Hz followed by 3, 15-s Valsalva maneuvers (VMs). We recorded the ECG, beat-to-beat arterial pressure, and MSNA throughout the autonomic test. Vagal-cardiac modulation via heart rate variability (HRV) was assessed in both time and frequency domains, cardiovagal baroreflex sensitivity (cvBRS) was assessed with linear regression, and stroke volume was estimated from pulse contour. All fed versus fasted comparisons presented are different at P < 0.05. Fasting reduced ambulatory mean arterial pressure (81 ± 1 vs. 78 ± 1 mmHg) and heart rate (69 ± 2 vs. 65 ± 2 beats/min). CB revealed enhanced HRV through increased R-R intervals (992 ± 30 vs. 1,059 ± 37 ms) and normalized high frequency (HFnu) R-R interval spectral power (55 ± 3 vs. 62 ± 3%). Estimated stroke volume was higher after fasting (by 13%) as was cvBRS (20 ± 2 vs. 26 ± 5 ms/mmHg) and cvBRS during phase IV of the VM (9 ± 1 vs. 12 ± 1 ms/mmHg). MSNA (n = 12) did not change (16 ± 11 vs. 15 ± 8 bursts/min; P = 0.18). Our results show that acute fasting is consistent with improved cardiovascular health: such improvements are driven by reduced ambulatory arterial pressure and enhanced vagal-cardiac modulation.

In sickness and in health: The functional role of extracellular vesicles in physiology and pathology in vivo: Part I: Health and Normal Physiology: Part I: Health and Normal Physiology.

Previously thought to be nothing more than cellular debris, extracellular vesicles (EVs) are now known to mediate physiological and pathological functions throughout the body. We now understand more about their capacity to transfer nucleic acids and proteins between distant organs, the interaction of their surface proteins with target cells, and the role of vesicle-bound lipids in health and disease. To date, most observations have been made in reductionist cell culture systems, or as snapshots from patient cohorts. The heterogenous population of vesicles produced in vivo likely act in concert to mediate both beneficial and detrimental effects. EVs play crucial roles in both the pathogenesis of diseases, from cancer to neurodegenerative disease, as well as in the maintenance of system and organ homeostasis. This two-part review draws on the expertise of researchers working in the field of EV biology and aims to cover the functional role of EVs in physiology and pathology. Part I will outline the role of EVs in normal physiology.

In sickness and in health: The functional role of extracellular vesicles in physiology and pathology in vivo: Part II: Pathology: Part II: Pathology.

It is clear from Part I of this series that extracellular vesicles (EVs) play a critical role in maintaining the homeostasis of most, if not all, normal physiological systems. However, the majority of our knowledge about EV signalling has come from studying them in disease. Indeed, EVs have consistently been associated with propagating disease pathophysiology. The analysis of EVs in biofluids, obtained in the clinic, has been an essential of the work to improve our understanding of their role in disease. However, to interfere with EV signalling for therapeutic gain, a more fundamental understanding of the mechanisms by which they contribute to pathogenic processes is required. Only by discovering how the EV populations in different biofluids change-size, number, and physicochemical composition-in clinical samples, may we then begin to unravel their functional roles in translational models in vitro and in vivo, which can then feedback to the clinic. In Part II of this review series, the functional role of EVs in pathology and disease will be discussed, with a focus on in vivo evidence and their potential to be used as both biomarkers and points of therapeutic intervention.

Beyond the Baroreflex: A New Measure of Autonomic Regulation Based on the Time-Frequency Assessment of Variability, Phase Coherence and Couplings.

For decades the role of autonomic regulation and the baroreflex in the generation of the respiratory sinus arrhythmia (RSA) - modulation of heart rate by the frequency of breathing - has been under dispute. We hypothesized that by using autonomic blockers we can reveal which oscillations and their interactions are suppressed, elucidating their involvement in RSA as well as in cardiovascular regulation more generally. R-R intervals, end tidal CO2, finger arterial pressure, and muscle sympathetic nerve activity (MSNA) were measured simultaneously in 7 subjects during saline, atropine and propranolol infusion. The measurements were repeated during spontaneous and fixed-frequency breathing, and apnea. The power spectra, phase coherence and couplings were calculated to characterise the variability and interactions within the cardiovascular system. Atropine reduced R-R interval variability (p < 0.05) in all three breathing conditions, reduced MSNA power during apnea and removed much of the significant coherence and couplings. Propranolol had smaller effect on the power of oscillations and did not change the number of significant interactions. Most notably, atropine reduced R-R interval power in the 0.145-0.6 Hz interval during apnea, which supports the hypothesis that the RSA is modulated by a mechanism other than the baroreflex. Atropine also reduced or made negative the phase shift between the systolic and diastolic pressure, indicating the cessation of baroreflex-dependent blood pressure variability. This result suggests that coherent respiratory oscillations in the blood pressure can be used for the non-invasive assessment of autonomic regulation.

Controlled breathing and autonomic rhythms: Influence of auditory versus visual cues.

We compared standard metrics of autonomic control in 20 humans (10 female) during spontaneous and controlled breathing. Subjects controlled breathing at 0.25 Hz following a metronome (auditory) or scrolling waveforms (visual). Respiratory rates and heart rates were lower during spontaneous breathing compared with auditory and visual. One heart rate variability metric was higher during visual compared with spontaneous breathing, but baroreflex sensitivity and muscle sympathetic nerve activity were not affected by breathing cues. A majority of subjects (86%) perceived that breathing to auditory cues was more difficult compared with visual cues, but this elevated perceived stress did not manifest physiologically.

Multilaboratory Collaborative Study of a Nontarget Data Acquisition for Target Analysis (nDATA) Workflow Using Liquid Chromatography-High-Resolution Accurate Mass Spectrometry for Pesticide Screening in Fruits and Vegetables.

Nontarget data acquisition for target analysis (nDATA) workflows using liquid chromatography-high-resolution accurate mass (LC-HRAM) spectrometry, spectral screening software, and a compound database have generated interest because of their potential for screening of pesticides in foods. However, these procedures and particularly the instrument processing software need to be thoroughly evaluated before implementation in routine analysis. In this work, 25 laboratories participated in a collaborative study to evaluate an nDATA workflow on high moisture produce (apple, banana, broccoli, carrot, grape, lettuce, orange, potato, strawberry, and tomato). Samples were extracted in each laboratory by quick, easy, cheap, effective, rugged, and safe (QuEChERS), and data were acquired by ultrahigh-performance liquid chromatography (UHPLC) coupled to a high-resolution quadrupole Orbitrap (QOrbitrap) or quadrupole time-of-flight (QTOF) mass spectrometer operating in full-scan mass spectrometry (MS) data-independent tandem mass spectrometry (LC-FS MS/DIA MS/MS) acquisition mode. The nDATA workflow was evaluated using a restricted compound database with 51 pesticides and vendor processing software. Pesticide identifications were determined by retention time (tR, ±0.5 min relative to the reference retention times used in the compound database) and mass errors (δM) of the precursor (RTP, δM ≤ ±5 ppm) and product ions (RTPI, δM ≤ ±10 ppm). The elution profiles of all 51 pesticides were within ±0.5 min among 24 of the participating laboratories. Successful screening was determined by false positive and false negative rates of <5% in unfortified (pesticide-free) and fortified (10 and 100 µg/kg) produce matrices. Pesticide responses were dependent on the pesticide, matrix, and instrument. The false negative rates were 0.7 and 0.1% at 10 and 100 µg/kg, respectively, and the false positive rate was 1.1% from results of the participating LC-HRAM platforms. Further evaluation was achieved by providing produce samples spiked with pesticides at concentrations blinded to the laboratories. Twenty-two of the 25 laboratories were successful in identifying all fortified pesticides (0-7 pesticides ranging from 5 to 50 µg/kg) for each produce sample (99.7% detection rate). These studies provide convincing evidence that the nDATA comprehensive approach broadens the screening capabilities of pesticide analyses and provide a platform with the potential to be easily extended to a larger number of other chemical residues and contaminants in foods.

Acute effects of electronic cigarettes on arterial pressure and peripheral sympathetic activity in young nonsmokers.

Electronic cigarettes (e-cigarettes) are marketed as an alternative to smoking for those who want to decrease the health risks of tobacco. Tobacco cigarettes increase heart rate (HR) and arterial pressure, while reducing muscle sympathetic nerve activity (MSNA) through sympathetic baroreflex inhibition. The acute effects of e-cigarettes on arterial pressure and MSNA have not been reported: our purpose was to clarify this issue. Using a randomized crossover design, participants inhaled on a JUUL e-cigarette containing nicotine (59 mg/mL) and a similar placebo e-cigarette (0 mg/mL). Experiments were separated by ∼1 mo. We recorded baseline ECG, finger arterial pressure (n = 15), and MSNA (n = 10). Subjects rested for 10 min (BASE) and then inhaled once every 30 s on an e-cigarette that contained nicotine or placebo (VAPE) for 10 min followed by a 10-min recovery (REC). Data were expressed as Δ means ± SE from BASE. Heart rate increased in the nicotine condition during VAPE and returned to BASE values in REC (5.0 ± 1.3 beats/min nicotine vs. 0.1 ± 0.8 beats/min placebo, during VAPE; P < 0.01). Mean arterial pressure increased in the nicotine condition during VAPE and remained elevated during REC (6.5 ± 1.6 mmHg nicotine vs. 2.6 ± 1 mmHg placebo, during VAPE and 4.6.0 ± 1.7 mmHg nicotine vs. 1.4 ± 1.4 mmHg placebo, during REC; P < 0.05). MSNA decreased from BASE to VAPE and did not restore during REC (-7.1 ± 1.6 bursts/min nicotine vs. 2.6 ± 2 bursts/min placebo, during VAPE and -5.8 ± 1.7 bursts/min nicotine vs. 0.5 ± 1.4 bursts/min placebo, during REC; P < 0.05). Our results show that acute e-cigarette usage increases mean arterial pressure leading to a baroreflex-mediated inhibition of MSNA.NEW & NOTEWORTHY The JUUL e-cigarette is the most popular e-cigarette in the market. In the present study, inhaling on a JUUL e-cigarette increased mean arterial pressure and heart rate, and decreased muscle sympathetic nerve activity (MSNA). In contrast, inhaling on a placebo e-cigarette without nicotine elicited no sympathomimetic effects. Although previous tobacco cigarette studies have demonstrated increased mean arterial pressure and MSNA inhibition, ours is the first study to report similar responses while inhaling on an e-cigarette. Listen to this article's corresponding podcast at @ https://ajpheart.podbean.com/e/aerosolized-nicotine-and-cardiovascular-control/.

Increasing risk of another Cape Town "Day Zero" drought in the 21st century.

Three consecutive dry winters (2015-2017) in southwestern South Africa (SSA) resulted in the Cape Town "Day Zero" drought in early 2018. The contribution of anthropogenic global warming to this prolonged rainfall deficit has previously been evaluated through observations and climate models. However, model adequacy and insufficient horizontal resolution make it difficult to precisely quantify the changing likelihood of extreme droughts, given the small regional scale. Here, we use a high-resolution large ensemble to estimate the contribution of anthropogenic climate change to the probability of occurrence of multiyear SSA rainfall deficits in past and future decades. We find that anthropogenic climate change increased the likelihood of the 2015-2017 rainfall deficit by a factor of five to six. The probability of such an event will increase from 0.7 to 25% by the year 2100 under an intermediate-emission scenario (Shared Socioeconomic Pathway 2-4.5 [SSP2-4.5]) and to 80% under a high-emission scenario (SSP5-8.5). These results highlight the strong sensitivity of the drought risk in SSA to future anthropogenic emissions.

Detected climatic change in global distribution of tropical cyclones.

Owing to the limited length of observed tropical cyclone data and the effects of multidecadal internal variability, it has been a challenge to detect trends in tropical cyclone activity on a global scale. However, there is a distinct spatial pattern of the trends in tropical cyclone frequency of occurrence on a global scale since 1980, with substantial decreases in the southern Indian Ocean and western North Pacific and increases in the North Atlantic and central Pacific. Here, using a suite of high-resolution dynamical model experiments, we show that the observed spatial pattern of trends is very unlikely to be explained entirely by underlying multidecadal internal variability; rather, external forcing such as greenhouse gases, aerosols, and volcanic eruptions likely played an important role. This study demonstrates that a climatic change in terms of the global spatial distribution of tropical cyclones has already emerged in observations and may in part be attributable to the increase in greenhouse gas emissions.

In vivo evidence of significant placental growth factor release by normal pregnancy placentas.

Placental growth factor (PlGF) is an angiogenic factor identified in the maternal circulation, and a key biomarker for the diagnosis and management of placental disorders. Furthermore, enhancing the PlGF pathway is regarded as a promising therapy for preeclampsia. The source of PlGF is still controversial with some believing it to be placental in origin while others refute this. To explore the source of PlGF, we undertook a prospective study enrolling normal pregnant women undergoing elective caesarean section. The level of PlGF was estimated in 17 paired serum samples from the uterine vein (ipsilateral or contralateral to the placental insertion) during caesarean section and from a peripheral vein on the same day and second day post-partum. PlGF levels were higher in the uterine than in the peripheral vein with a median difference of 52.2 (IQR 20.1-85.8) pg/mL p = 0.0006. The difference when the sampled uterine vein was ipsilateral to the placenta was 54.8 (IQR 37.1-88.4) pg/mL (n = 11) and 23.7 (IQR -11; 70.5) pg/mL (n = 6) when the sample was contralateral. Moreover, PlGF levels fell by 83% on day 1-2 post-partum. Our findings strongly support the primary source of PlGF to be placental. These findings will be of value in designing target therapies such as PlGF overexpression, to cure placental disorders during pregnancy.

Maternal circulating syncytiotrophoblast-derived extracellular vesicles contain biologically active 5'-tRNA halves.

The placenta releases syncytiotrophoblast-derived extracellular vesicles (STB-EV) into the maternal circulation throughout gestation. STB-EV dependent signalling is believed to contribute to the widespread maternal adaptive physiological changes seen in pregnancy. Transfer RNA (tRNA) halves have been identified in vesicles released from other human and murine organ systems, which alter gene expression in target cells. Here, we characterise tRNA-half expression in STB-EV and demonstrate biological activity of a highly abundant tRNA-half. Short RNA from ex-vivo, dual-lobe placental perfusion STB-EV was sequenced, showing that most (>95%) comprised tRNA species. Whole placental tissue contained <50% tRNA species, suggesting selective packaging and export of tRNA into STB-EV. Most tRNA within STB-EV were 5'-tRNA halves cleaved at 30-32 nucleotides. The pattern of tRNA expression differed depending on the size/origin of the STB-EV; this was confirmed by qPCR. Protein synthesis was suppressed in human fibroblasts when they were cultured with a 5'-tRNA half identified from STB-EV sequencing. This study is the first to evaluate tRNA species in STB-EV. The presence of biologically active 5'-tRNA halves, specific to a vesicular origin, suggests a novel mechanism for maternal-fetal signalling in normal pregnancy.