Optogenetically controlled inflammasome activation demonstrates two phases of cell swelling during pyroptosis.

Inflammasomes are multiprotein platforms that control caspase-1 activation, which process the inactive precursor forms of the inflammatory cytokines IL-1ß and IL-18, leading to an inflammatory type of programmed cell death called pyroptosis. Studying inflammasome-driven processes, such as pyroptosis-induced cell swelling, under controlled conditions remains challenging because the signals that activate pyroptosis also stimulate other signaling pathways. We designed an optogenetic approach using a photo-oligomerizable inflammasome core adapter protein, apoptosis-associated speck-like containing a caspase recruitment domain (ASC), to temporally and quantitatively manipulate inflammasome activation. We demonstrated that inducing the light-sensitive oligomerization of ASC was sufficient to recapitulate the classical features of inflammasomes within minutes. This system showed that there were two phases of cell swelling during pyroptosis. This approach offers avenues for biophysical investigations into the intricate nature of cellular volume control and plasma membrane rupture during cell death.

Coral carbonate-bound isotopes reveal monsoonal influence on nitrogen sources in Southeastern China's Greater Bay Area from the mid-Holocene until the Anthropocene.

Most anthropogenic nitrogen (N) reaches coastal waters via rivers carrying increasing loads of sewage, fertilizer, and sediments. To understand anthropogenic N impacts, we need to understand historical N-dynamics before human influence. Stable isotope ratios of N preserved in carbonates are one way to create temporal N records. However, records that span periods of human occupation are scarce, limiting our ability to contextualize modern N dynamics. Here, we produce a fossil-bound N-record using coral subfossils, spanning 6700 years in China's Greater Bay Area (GBA). We found that during the mid-to-late Holocene, the GBA's coastal N was dominated by fluvial sources. The weakening of the Asia monsoon throughout the late-Holocene decreased river outflow, leading to a relative increase of marine nitrate. This source shift from riverine-to-ocean dominance was overprinted by anthropogenic N. During the late 1980s to early 1990s, human development and associated effluent inundated the coastal system, contributing to the decline of coral communities.

Weakened AMOC related to cooling and atmospheric circulation shifts in the last interglacial Eastern Mediterranean.

There is limited understanding of temperature and atmospheric circulation changes that accompany an Atlantic Meridional Overturning Circulation (AMOC) slowdown beyond the North Atlantic realm. A Peqi'in Cave (Israel) speleothem dated to the last interglacial period (LIG), 129-116 thousand years ago (ka), together with a large modern rainfall monitoring dataset, serve as the base for investigating past AMOC slowdown effects on the Eastern Mediterranean. Here, we reconstruct LIG temperatures and rainfall source using organic proxies (TEX86) and fluid inclusion water d-excess. The TEX86 data show a stepwise cooling from 19.8 ± 0.2° (ca. 128-126 ka) to 16.5 ± 0.6 °C (ca. 124-123 ka), while d-excess values decrease abruptly (ca. 126 ka). The d-excess shift suggests that rainfall was derived from more zonal Mediterranean air flow during the weakened AMOC interval. Decreasing rainfall d-excess trends over the last 25 years raise the question whether similar atmospheric circulation changes are also occurring today.

Hospital at Home as a Treatment Strategy for Worsening Heart Failure.

Hospital at home (HaH) is an innovative care model that may be particularly suited for heart failure (HF). Outpatient visits and inpatient care have been the 2 traditional settings for HF care, yet may not match the social and medical needs of patients at all times. Alternative models such as HaH may represent an effective and patient-centered option for select patients with worsening HF. To date, limited research in HF and other disease states has supported HaH as being safe and lower cost than traditional inpatient admission. Supporting HaH are new payment structures, such as Medicare's Acute Hospital Care at Home waiver program. In combination with outpatient visits, outpatient intravenous diuretic clinics, inpatient care, and cardiac intensive care, HaH could be a core component of a comprehensive care model with the potential to match resource utilization with the needs of patients across the spectrum of HF severity, and improve patient outcomes.

The Promise and Risks of mHealth in Heart Failure Care.

Mobile health (mHealth) is an emerging approach to health care. It involves wearable, connected technologies that facilitate patient-symptom or physiological monitoring, support clinical feedback to patients and physicians, and promote patients' education and self-care. Evolving algorithms may involve artificial intelligence and can assist in data aggregation and health care teams' interpretations. Ultimately, the goal is not merely to collect data; rather, it is to increase actionability. mHealth technology holds particular promise for patients with heart failure, especially those with frequently changing clinical status. mHealth, ideally, can identify care opportunities, anticipate clinical courses and augment providers' capacity to implement, titrate and monitor interventions safely, including evidence-based therapies. Although there have been marked advancements in the past decade, uncertainties remain for mHealth, including questions regarding optimal indications and acceptable payment models. In regard to mHealth capability, a better understanding is needed of the incremental benefit of mHealth data over usual care, the accuracy of specific mHealth data points in making clinical care decisions, and the efficiency and precision of algorithms used to dictate actions. Importantly, emerging regulations in the wake of COVID-19, and now the end of the federal public health emergency, offer both opportunity and risks to the broader adoption of mHealth-enabled services. In this review, we explore the current state of mHealth in heart failure, with particular attention to the opportunities and challenges this technology creates for patients, health care providers and other stakeholders.

Estimating the burden of influenza-attributable severe acute respiratory infections on the hospital system in Metropolitan France, 2012-2018.

BACKGROUND: To date, estimating the burden of seasonal influenza on the hospital system in France has been restricted to influenza diagnoses in patients (estimated hospitalization rate of 35/100,000 on average from 2012 to 2018). However, many hospitalizations for diagnosed respiratory infections (e.g. pneumonia, acute bronchitis) occur without concurrent screening for virological influenza, especially in the elderly. Specifically, we aimed to estimate the burden of influenza on the French hospital system by examining the proportion of severe acute respiratory infections (SARI) attributable to influenza. METHODS: Using French national hospital discharge data from 1/7/2012 to 30/6/2018, we extracted SARI hospitalizations with ICD-10 codes J09-J11 (influenza codes) in main or associated diagnoses, and J12-J20 (pneumonia and bronchitis codes) in main diagnoses. We estimated influenza-attributable SARI hospitalizations during influenza epidemics, as the number of influenza-coded hospitalizations plus the influenza-attributable number of pneumonia- and acute bronchitis-coded hospitalizations using periodic regression and generalized linear models. Additional analyses stratified by age group, diagnostic category (pneumonia and bronchitis), and region of hospitalization were performed using the periodic regression model only. RESULTS: The average estimated hospitalization rate of influenza-attributable SARI during the five annual influenza epidemics covered (2013-2014 to 2017-2018) was 60/100,000 with the periodic regression model, and 64/100,000 with the generalized linear model. Over the six epidemics (2012-2013 to 2017-2018), of the 533,456 SARI hospitalizations identified, an estimated 227,154 were influenza-attributable (43%). Fifty-six percent of cases were diagnosed with influenza, 33% pneumonia, and 11% bronchitis. Diagnoses varied between age groups: 11% of patients under 15 years old had pneumonia versus 41% of patients aged 65 and older. CONCLUSION: Compared to influenza surveillance in France to date, analyzing excess SARI hospitalizations provided a much larger estimate of the burden of influenza on the hospital system. This approach was more representative and allowed the burden to be assessed according to age group and region. The emergence of SARS-Cov-2 has led to a change in the dynamics of winter respiratory epidemics. The co-circulation of the three current major respiratory viruses (influenza, SARS-Cov-2, and RSV) and the evolution of diagnostic confirmation practices must now be taken into account when analyzing SARI.

Value-Based Care for Chest Physicians.

Value-based care aims to improve the health outcomes of patients, eliminate waste and unwarranted clinical variation, and reduce the total cost of care. Professional medical societies have put forward guidelines to raise awareness on unproven practice patterns (Choosing Wisely Campaign), and payers have sought to replace the traditional fee-for-service payment models with value-based contracts that share financial gains or losses based on achieving high-quality outcomes and lowering the cost of care. Regardless of whether their practices are engaged in value-based arrangements, chest physicians should seek understanding of these principles, participate in designing and implementing practical and impactful high-value initiatives in their practices, and have a national voice on the path forward.

Predicting genotoxicity of viral vectors for stem cell gene therapy using gene expression-based machine learning.

Hematopoietic stem cell gene therapy is emerging as a promising therapeutic strategy for many diseases of the blood and immune system. However, several individuals who underwent gene therapy in different trials developed hematological malignancies caused by insertional mutagenesis. Preclinical assessment of vector safety remains challenging because there are few reliable assays to screen for potential insertional mutagenesis effects in vitro. Here we demonstrate that genotoxic vectors induce a unique gene expression signature linked to stemness and oncogenesis in transduced murine hematopoietic stem and progenitor cells. Based on this finding, we developed the surrogate assay for genotoxicity assessment (SAGA). SAGA classifies integrating retroviral vectors using machine learning to detect this gene expression signature during the course of in vitro immortalization. On a set of benchmark vectors with known genotoxic potential, SAGA achieved an accuracy of 90.9%. SAGA is more robust and sensitive and faster than previous assays and reliably predicts a mutagenic risk for vectors that led to leukemic severe adverse events in clinical trials. Our work provides a fast and robust tool for preclinical risk assessment of gene therapy vectors, potentially paving the way for safer gene therapy trials.

Fibrinogen Levels and Bleeding Risk in Patients Undergoing Ultrasound-Assisted Catheter-Directed Thrombolysis for Submassive Pulmonary Embolism.

OBJECTIVES: We sought to test the hypothesis that patients undergoing ultrasound-assisted catheter-directed thrombolysis (USAT) with standard alteplase and heparin dosing would not develop significant depletion of systemic fibrinogen, which may account for the lower risk of bleeding seen in contemporary trials. We also sought to compare the relative outcomes of individuals with submassive pulmonary embolism (PE) undergoing USAT and anticoagulation alone. METHODS: Utilizing a single-center prospective registry, we identified 102 consecutive adult patients with submassive PE who were considered for USAT based on a standardized treatment algorithm between November 2016 and May 2019. Patients not receiving USAT therapy were treated with anticoagulation alone. RESULTS: Baseline characteristics were generally similar between groups (n = 51 in each group). Major bleeding rates were not significantly different between groups (2.0% vs 5.9% in USAT vs control, respectively; P=.62). Notably, no USAT patient experienced clinically significant hypofibrinogenemia (mean trough fibrinogen, 369.8 ± 127.1 mg/dL; minimum, 187 mg/dL). The mean trough fibrinogen of patients experiencing any bleeding event (major or minor) was 306.6 mg/dL (SE, 23.9 mg/dL) vs 380.3 mg/dL (SE, 20.4 mg/dL) in those without a bleeding event (P=.02). CONCLUSIONS: In this cohort analysis of patients undergoing USAT, there was no evidence for clinically significant depletion of fibrinogen or intracranial hemorrhage. Although our data suggest an association between lower fibrinogen levels and bleeding events, our results are not clear enough to suggest a clinically useful fibrinogen cut-off value. Further study is needed to determine the utility of routine fibrinogen monitoring in this population.

Isotope ratio infrared spectroscopy analysis of water samples without memory effects.

RATIONALE: Since their introduction more than a decade ago, isotope ratio infrared spectroscopy (IRIS) systems have rapidly become the standard for oxygen (δ18 O) and hydrogen (δ2 H) isotope analysis of water samples. An important disadvantage of IRIS systems is the well-documented sample-to-sample memory effect, which requires each sample to be analyzed multiple times before the desired accuracy is reached, lengthening analysis times and driving up the costs of analyses. METHODS: We present an adapted set-up and calculation protocol for fully automated analysis of water samples using a Picarro L2140-i cavity ring-down spectroscopy instrument. The adaptation removes memory effects by use of a continuously moisturized nitrogen carrier gas. Water samples of 0.5 µL are measured on top of the water vapor background, after which isotope ratios are calculated by subtraction of the background from the sample peaks. RESULTS: With this new technique, single injections of water samples have internal precisions (1σ) below 0.05‰ for δ18 O values and 0.1‰ for δ2 H values, regardless of the isotope ratio of the previous sample. Precision is worse, however, when the isotope difference between the sample and background water is too large (i.e., exceeding approximately 9‰ for δ18 O values and 70‰ for δ2 H values). Isotope ratios show negligible drift across the four weeks within which the experiments were performed. The single-injection 1σ precision for 17 O excess (Δ'17 O) determined with this method is 60 per meg. CONCLUSIONS: Our experiments demonstrate that by removing sample-to-sample memory effects with a moisturized carrier gas, the time for measurement of δ18 O and δ2 H values using an IRIS system can be reduced markedly without compromising the analytical precision and accuracy. Thorough replication is needed to achieve sufficiently low uncertainties for Δ'17 O.

First ICON-FUV Nighttime NmF2 and hmF2 Comparison to Ground and Space-Based Measurements.

The Far Ultra Violet (FUV) ultraviolet imager onboard the NASA-ICON mission is dedicated to the observation and study of the ionosphere dynamics at mid and low latitudes. We compare O+ density profiles provided by the ICON FUV instrument during nighttime with electron density profiles measured by the COSMIC-2 constellation (C2) and ground-based ionosondes. Co-located simultaneous observations are compared, covering the period from November 2019 to July 2020, which produces several thousands of coincidences. Manual scaling of ionogram sequences ensures the reliability of the ionosonde profiles, while C2 data are carefully selected using an automatic quality control algorithm. Photoelectron contribution coming from the magnetically conjugated hemisphere is clearly visible in FUV data around solstices and has been filtered out from our analysis. We find that the FUV observations are consistent with the C2 and ionosonde measurements, with an average positive bias lower than 1 × 1011 e/m3. When restricting the analysis to cases having an NmF2 value larger than 5 × 1011 e/m3, FUV provides the peak electron density with a mean difference with C2 of 10%. The peak altitude, also determined from FUV observations, is found to be 15 km above that obtained from C2, and 38 km above the ionosonde value on average.

A multimillennial climatic context for the megafaunal extinctions in Madagascar and Mascarene Islands.

Madagascar and the Mascarene Islands of Mauritius and Rodrigues underwent catastrophic ecological and landscape transformations, which virtually eliminated their entire endemic vertebrate megafauna during the past millennium. These ecosystem changes have been alternately attributed to either human activities, climate change, or both, but parsing their relative importance, particularly in the case of Madagascar, has proven difficult. Here, we present a multimillennial (approximately the past 8000 years) reconstruction of the southwest Indian Ocean hydroclimate variability using speleothems from the island of Rodrigues, located ∼1600 km east of Madagascar. The record shows a recurring pattern of hydroclimate variability characterized by submillennial-scale drying trends, which were punctuated by decadal-to-multidecadal megadroughts, including during the late Holocene. Our data imply that the megafauna of the Mascarenes and Madagascar were resilient, enduring repeated past episodes of severe climate stress, but collapsed when a major increase in human activity occurred in the context of a prominent drying trend.

High-precision stable isotope analysis of <5 µg CaCO3 samples by continuous-flow mass spectrometry.

RATIONALE: Oxygen (δ18 O) and carbon (δ13 C) isotope analysis of foraminifera and other CaCO3 samples has been a key technique for paleoceanographical and paleoclimatological research for more than 60 years. There is ongoing demand for the analysis of ever smaller CaCO3 samples, driven, for example, by the desire to analyse single specimen planktic foraminifera, or small samples of tooth enamel. METHODS: We present a continuous-flow mass spectrometric technique that uses cryo-focusing of sample CO2 to analyse CaCO3 samples in a weight range between 10 and 3 µg. These are considerably lower sample weights than achievable on most currently available standard instrumentation. The technique is automated, so that sample throughput lies at >60 samples per day. The method involves an on-line vial-flushing routine designed to remove machine drift due to blank CO2 build-up in the sample vials. RESULTS: In a series of experiments the effect of blank CO2 build-up is quantified, and outgassing from the chlorobutyl septa identified as the source. An improved flushing routine together with the use of a cryo-focusing step in the analysis is demonstrated to provide the analytical stability and sensitivity to analyse CaCO3 samples in a weight range between 10 and 3 µg at ≤0.1‰ precision (1σ) for both δ18 O and δ13 C values. The technique yields similarly precise results for the analysis of the structural carbonate fraction of small tooth enamel samples. CONCLUSIONS: This study demonstrates that high-precision oxygen and carbon isotope analysis is possible on CaCO3 samples smaller than 5 µg by use of a continuous-flow isotope technique. Of key importance are (1) the application of a cold trap that drastically reduces sample gas loss, and (2) a modified flushing regime that eliminates increasing background CO2 build-up in sample vials during longer automated sample runs.

Ocean warming is the key filter for successful colonization of the migrant octocoral Melithaea erythraea (Ehrenberg, 1834) in the Eastern Mediterranean Sea.

Climate, which sets broad limits for migrating species, is considered a key filter to species migration between contrasting marine environments. The Southeast Mediterranean Sea (SEMS) is one of the regions where ocean temperatures are rising the fastest under recent climate change. Also, it is the most vulnerable marine region to species introductions. Here, we explore the factors which enabled the colonization of the endemic Red Sea octocoral Melithaea erythraea (Ehrenberg, 1834) along the SEMS coast, using sclerite oxygen and carbon stable isotope composition (δ 18OSC and δ 13CSC), morphology, and crystallography. The unique conditions presented by the SEMS include a greater temperature range (∼15 °C) and ultra-oligotrophy, and these are reflected by the lower δ 13CSCvalues. This is indicative of a larger metabolic carbon intake during calcification, as well as an increase in crystal size, a decrease of octocoral wart density and thickness of the migrating octocoral sclerites compared to the Red Sea samples. This suggests increased stress conditions, affecting sclerite deposition of the SEMS migrating octocoral. The δ 18Osc range of the migrating M. erythraea indicates a preference for warm water sclerite deposition, similar to the native depositional temperature range of 21-28 °C. These findings are associated with the observed increase of minimum temperatures in winter for this region, at a rate of 0.35 ± 0.27 °C decade-1 over the last 30 years, and thus the region is becoming more hospitable to the Indo-Pacific M. erythraea. This study shows a clear case study of "tropicalization" of the Mediterranean Sea due to recent warming.

Lentiviral gene therapy rescues p47phox chronic granulomatous disease and the ability to fight Salmonella infection in mice.

Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency disorder characterised by recurrent and often life-threatening infections and hyperinflammation. It is caused by defects of the phagocytic NADPH oxidase, a multicomponent enzyme system responsible for effective pathogen killing. A phase I/II clinical trial of lentiviral gene therapy is underway for the most common form of CGD, X-linked, caused by mutations in the gp91phox subunit of the NADPH oxidase. We propose to use a similar strategy to tackle p47phox-deficient CGD, caused by mutations in NCF1, which encodes the p47phox cytosolic component of the enzymatic complex. We generated a pCCLCHIM-p47phox lentiviral vector, containing the chimeric Cathepsin G/FES myeloid promoter and a codon-optimised version of the human NCF1 cDNA. Here we show that transduction with the pCCLCHIM-p47phox vector efficiently restores p47phox expression and biochemical NADPH oxidase function in p47phox-deficient human and murine cells. We also tested the ability of our gene therapy approach to control infection by challenging p47phox-null mice with Salmonella Typhimurium, a leading cause of sepsis in CGD patients, and found that mice reconstituted with lentivirus-transduced hematopoietic stem cells had a reduced bacterial load compared with untreated mice. Overall, our results potentially support the clinical development of a gene therapy approach using the pCCLCHIM-p47phox vector.

A comparison of isotope ratio mass spectrometry and cavity ring-down spectroscopy techniques for isotope analysis of fluid inclusion water.

RATIONALE: Online oxygen (δ18 O) and hydrogen (δ2 H) isotope analysis of fluid inclusion water entrapped in minerals is widely applied in paleo-fluid studies. In the state of the art of fluid inclusion isotope research, however, there is a scarcity of reported inter-technique comparisons to account for possible analytical offsets. Along with improving analytical precisions and sample size limitations, interlaboratory comparisons can lead to a more robust application of fluid inclusion isotope records. METHODS: Mineral samples-including speleothem, travertine, and vein material-were analyzed on two newly setup systems for fluid inclusion isotope analysis to provide an inter-platform comparison. One setup uses a crusher unit connected online to a continuous-flow pyrolysis furnace and an isotope ratio mass spectrometry (IRMS) instrument. In the other setup, a crusher unit is lined up with a cavity ring-down spectroscopy (CRDS) system, and water samples are analyzed on a continuous standard water background to achieve precisions on water injections better than 0.1‰ for δ18 O values and 0.4‰ for δ2 H values for amounts down to 0.2 µL. RESULTS: Fluid inclusion isotope analyses on the IRMS setup have an average 1σ reproducibility of 0.4‰ and 2.0‰ for δ18 O and δ2 H values, respectively. The CRDS setup has a better 1σ reproducibility (0.3‰ for δ18 O values and 1.1‰ for δ2 H values) and also a more rapid sample throughput (<30 min per sample). Fluid inclusion isotope analyses are reproducible at these uncertainties for water amounts down to 0.1 µL on both setups. Fluid inclusion isotope data show no systematic offsets between the setups. CONCLUSIONS: The close match in fluid inclusion isotope results between the two setups demonstrates the high accuracy of the presented continuous-flow techniques for fluid inclusion isotope analysis. Ideally, experiments such as the one presented in this study will lead to further interlaboratory comparison efforts and the selection of suitable reference materials for fluid inclusion isotopes studies.

Megacity development and the demise of coastal coral communities: Evidence from coral skeleton δ15 N records in the Pearl River estuary.

Historical coral skeleton (CS) δ18 O and δ15 N records were produced from samples recovered from sedimentary deposits, held in natural history museum collections, and cored into modern coral heads. These records were used to assess the influence of global warming and regional eutrophication, respectively, on the decline of coastal coral communities following the development of the Pearl River Delta (PRD) megacity, China. We find that, until 2007, ocean warming was not a major threat to coral communities in the Pearl River estuary; instead, nitrogen (N) inputs dominated impacts. The high but stable CS-δ15 N values (9‰-12‰ vs. air) observed from the mid-Holocene until 1980 indicate that soil and stream denitrification reduced and modulated the hydrologic inputs of N, blunting the rise in coastal N sources during the early phase of the Pearl River estuary urbanization. However, an unprecedented CS-δ15 N peak was observed from 1987 to 1993 (>13‰ vs. air), concomitant to an increase of NH4+ concentration, consistent with the rapid Pearl River estuary urbanization as the main cause for this eutrophication event. We suggest that widespread discharge of domestic sewage entered directly into the estuary, preventing removal by natural denitrification hotspots. We argue that this event caused the dramatic decline of the Pearl River estuary coral communities reported from 1980 to 2000. Subsequently, the coral record shows that the implementation of improved wastewater management policies succeeded in bringing down both CS-δ15 N and NH4+ concentrations in the early 2000s. This study points to the potential importance of eutrophication over ocean warming in coral decline along urbanized coastlines and in particular in the vicinity of megacities.

Relevance of the eastern African coastal forest for early hominin biogeography.

The influence of climate change on hominin evolution is much debated. Two issues hamper our understanding of this process: the limited hominin fossil record, and incomplete knowledge about hominin spatial occupation of Africa. Here, we analyze the presently known hominin fossil distribution pattern and explore the potential geographic distribution of hominins between ∼4.5 and ∼2.5 Ma. We focus on assessing the relevance of the Coastal Forest of Eastern Africa (CFEA) along the Indian Ocean as a core area for early hominin evolution. Based on biogeographic-phylogeographic data we propose the coastal refuge hypothesis: the CFEA provided a refugium for early hominins in periods of variable climate and strong seasonality during eccentricity maxima. From this refuge, evolved species could disperse inland (e.g. to rift basins) via vegetated humid corridors, whenever onset of stable climate periods with low seasonality during eccentricity minima allowed expansion out of the coastal enclave. We develop a conceptual model in time and space, comparing predictions with climatic and hominin fossil records. The results imply that: 1) between ∼4.5 and 3 Ma, ongoing (mostly anagenetic) hominin evolution occurred in the CFEA, punctuated by inland dispersal events at ∼4.4, 4.2, 3.8, 3.5, and 3.2 Ma; 2) before ∼3 Ma, the Afar Basin was a (sub)core area often connected to and relatively similar to the CFEA, while other inland areas were more or less marginal for early hominin habitation; 3) after ∼3 Ma, Northern Hemisphere Glaciation exerted strong influence by causing latitudinal contraction of the CFEA, leading to habitat fragmentation, isolation of hominin populations and possible cladogenetic evolution. A major challenge for the coastal refuge model is the fact that at present, no (hominin) fossils are known from the CFEA. We consider how this can be explained, and possibly overcome with targeted search efforts. Furthermore we discuss how the model can be tested, e.g. with molecular phylogeography approaches, and used to predict new hominin fossil locations. With this study, we hope to contribute a fresh perspective to the climate-evolution debate, emphasizing the role of climatic stability, length of dry season and vegetation cover to facilitate connectivity between hominin core and marginal habitats.