Carbonate chimneys at the highly productive point Dume methane seep: Fine-scale mineralogical, geochemical, and microbiological heterogeneity reflects dynamic and long-lived methane-metabolizing habitats.

Methane is a potent greenhouse gas that enters the marine system in large quantities at seafloor methane seeps. At a newly discovered seep site off the coast of Point Dume, CA, ~ meter-scale carbonate chimneys host microbial communities that exhibit the highest methane-oxidizing potential recorded to date. Here, we provide a detailed assessment of chimney geobiology through correlative mineralogical, geochemical, and microbiological studies of seven chimney samples in order to clarify the longevity and heterogeneity of these highly productive systems. U-Th dating indicated that a methane-driven carbonate precipitating system at Point Dume has existed for ~20 Kyr, while millimeter-scale variations in carbon and calcium isotopic values, elemental abundances, and carbonate polymorphs revealed changes in carbon source, precipitation rates, and diagenetic processes throughout the chimneys' lifespan. Microbial community analyses revealed diverse modern communities with prominent anaerobic methanotrophs, sulfate-reducing bacteria, and Anaerolineaceae; communities were more similar within a given chimney wall transect than in similar horizons of distinct structures. The chimneys represent long-lived repositories of methane-oxidizing communities and provide a window into how carbon can be transformed, sequestered, and altered over millennia at the Point Dume methane seep.

Ultrasonic displacement measurements from local absorption of ultrasound in thermochromic liquid crystal sensors.

Wavefield imaging can be used for measuring the wavefield produced by an ultrasound transducer for medical and industrial applications, or for the detection and monitoring of defects in non-destructive testing. Typical wavefield imaging methods include interferometry/vibrometry, and the use of microphones and hydrophones. These involve scanning, making them time consuming, and microphones have limited resolution. An alternative method presented here uses thermochromic liquid crystal sensors which react to heat generated due to absorption of ultrasonic waves. The result is a colour scale that varies with temperature, with the temperature change dependent on ultrasonic displacement. Measurements of the resonant modes of a flexural ultrasonic transducer were taken between 320 kHz and 6.77 MHz. Temperature maps were obtained from photographs of the TLC sensor using the true-colour image processing method. The obtained temperature change across the transducer face was compared with displacement measurements taken using interferometry, showing excellent agreement in the position of the mode features and good resolution at lower frequencies. Thermal measurements were also taken to directly observe the heating of the transducer cap, showing the effect of the thermal conductivity of the transducer along with confirming the increased heat generated by the ultrasound absorption when a backing layer is used. The sensors show promise for fast transducer characterisation, with further potential applications in structural health monitoring and defect detection.

A HIV-1 Gp41 Peptide-Liposome Vaccine Elicits Neutralizing Epitope-Targeted Antibody Responses in Healthy Individuals.

Background: HIV-1 vaccine development is a global health priority. Broadly neutralizing antibodies (bnAbs) which target the HIV-1 gp41 membrane-proximal external region (MPER) have some of the highest neutralization breadth. An MPER peptide-liposome vaccine has been found to expand bnAb precursors in monkeys. Methods: The HVTN133 phase 1 clinical trial (NCT03934541) studied the MPER-peptide liposome immunogen in 24 HIV-1 seronegative individuals. Participants were recruited between 15 July 2019 and 18 October 2019 and were randomized in a dose-escalation design to either 500 mcg or 2000 mcg of the MPER-peptide liposome or placebo. Four intramuscular injections were planned at months 0, 2, 6, and 12. Results: The trial was stopped prematurely due to an anaphylaxis reaction in one participant ultimately attributed to vaccine-associated polyethylene glycol. The immunogen induced robust immune responses, including MPER+ serum and blood CD4+ T-cell responses in 95% and 100% of vaccinees, respectively, and 35% (7/20) of vaccine recipients had blood IgG memory B cells with MPER-bnAb binding phenotype. Affinity purification of plasma MPER+ IgG demonstrated tier 2 HIV-1 neutralizing activity in two of five participants after 3 immunizations. Conclusions: MPER-peptide liposomes induced gp41 serum neutralizing epitope-targeted antibodies and memory B-cell responses in humans despite the early termination of the study. These results suggest that the MPER region is a promising target for a candidate HIV vaccine.

Hydroclimatic changes on multiple timescales since 7800 y BP in the winter precipitation-dominated Central Asia.

Central Asia (CA) is one of the world's most significant arid regions, which is markedly impacted by global warming. A better understanding of the dynamical processes governing its Holocene climate variability is critical for a better understanding of possible future impacts of climate change in the region. To date, most of the existing CA paleoclimate records are from the summer precipitation-dominated eastern CA (ECA), with few records from the winter precipitation-dominated western CA (WCA). Here, we present a precisely dated (~6‰) and highly resolved (<4-y) record of hydroclimatic variations from the WCA covering the period between 7,774 and 656 y BP. Utilizing multiple proxies (δ18O, δ13C, and Sr/Ca) derived from a stalagmite from the Fergana Valley, Kyrgyzstan, we reveal a long-term drying trend in WCA, which is in contrast with the wetting trend in ECA. We propose that different responses of winter and summer westerly jets to seasonal solar insolation over the past 8,000 y may have resulted in an antiphased precipitation relationship between the WCA and ECA. Our data contain dominant quasiperiodicities of 1,400, 50 to 70, and 20 to 30 y, indicating close connections between the WCA climate and the North Atlantic. We further identified a series of droughts and pluvials on centennial-to-decadal timescales, which may have influenced regional societies and trans-Eurasian culture exchanges during historical and prehistorical times.

Acoustic field visualisation using local absorption of ultrasound and thermochromic liquid crystals.

Acoustic field and vibration visualisation is important in a wide range of applications. Laser vibrometry is often used for such visualisation, however, the equipment has a high cost and requires significant user expertise, and the method can be slow, as it requires scanning point by point. Here we suggest a different approach to visualisation of acoustic fields in the kHz - MHz range, using paint-on or removable film sensors, which produce a direct visual map of ultrasound displacement. The sensors are based on a film containing thermochromic liquid crystals (TLC), along with a backing/underlay layer which improves absorption of ultrasound. The absorption generates heat, which can be seen by a change in colour of the TLC film. A removable sensor is used to visualise the resonant modes of an air-coupled flexural transducer operated from 410 kHz to 7.23 MHz, and to visualise 40 kHz standing waves in a Perspex plate. The thermal basis of the visualisation is confirmed using thermal imaging. The speed and cost of visualisation makes the new sensor attractive for use in condition monitoring, for fast assessment of transducer quality, or for analysis of acoustic field distribution in power ultrasonic systems.

Dansgaard-Oeschger cycles of the penultimate and last glacial period recorded in stalagmites from Türkiye.

The last glacial period is characterized by abrupt climate oscillations, also known as Dansgaard-Oeschger (D-O) cycles. However, D-O cycles remain poorly documented in climate proxy records covering the penultimate glacial period. Here we present highly resolved and precisely dated speleothem time series from Sofular Cave in northern Türkiye to provide clear evidence for D-O cycles during Marine Isotope Stage (MIS) 6 as well as MIS 2-4. D-O cycles are most clearly expressed in the Sofular carbon isotope time series, which correlate inversely with regional sea surface temperature (SST) records from the Black Sea. The pacing of D-O cycles is almost twice as long during MIS 6 compared to MIS 2-4, and could be related to a weaker Atlantic Meridional Overturning Circulation (AMOC) and a different mean climate during MIS 6 compared to MIS 2-4, leading most likely to a higher threshold for the occurrence of D-O cycles.

Modern anthropogenic drought in Central Brazil unprecedented during last 700 years.

A better understanding of the relative roles of internal climate variability and external contributions, from both natural (solar, volcanic) and anthropogenic greenhouse gas forcing, is important to better project future hydrologic changes. Changes in the evaporative demand play a central role in this context, particularly in tropical areas characterized by high precipitation seasonality, such as the tropical savannah and semi-desertic biomes. Here we present a set of geochemical proxies in speleothems from a well-ventilated cave located in central-eastern Brazil which shows that the evaporative demand is no longer being met by precipitation, leading to a hydrological deficit. A marked change in the hydrologic balance in central-eastern Brazil, caused by a severe warming trend, can be identified, starting in the 1970s. Our findings show that the current aridity has no analog over the last 720 years. A detection and attribution study indicates that this trend is mostly driven by anthropogenic forcing and cannot be explained by natural factors alone. These results reinforce the premise of a severe long-term drought in the subtropics of eastern South America that will likely be further exacerbated in the future given its apparent connection to increased greenhouse gas emissions.

Microsecond dynamics control the HIV-1 envelope conformation.

The HIV-1 Envelope (Env) glycoprotein facilitates host cell fusion through a complex series of receptor-induced structural changes. Although significant progress has been made in understanding the structures of various Env conformations and transition intermediates that occur within the millisecond timescale, faster transitions in the microsecond timescale have not yet been observed. In this study, we employed time-resolved, temperature-jump small angle X-ray scattering to monitor structural rearrangements in an HIV-1 Env ectodomain construct with microsecond precision. We detected a transition correlated with Env opening that occurs in the hundreds of microseconds range and another more rapid transition that preceded this opening. Model fitting indicated that the early rapid transition involved an order-to-disorder transition in the trimer apex loop contacts, suggesting that conventional conformation-locking design strategies that target the allosteric machinery may be ineffective in preventing this movement. Utilizing this information, we engineered an envelope that locks the apex loop contacts to the adjacent protomer. This modification resulted in significant angle-of-approach shifts in the interaction of a neutralizing antibody. Our findings imply that blocking the intermediate state could be crucial for inducing antibodies with the appropriate bound state orientation through vaccination.

Highly Atherogenic Lipid Particles are Associated with Preeclampsia After Successful Fertility Treatment for Obese Women who have Unexplained Infertility.

Atherogenic dyslipidemia-before or during pregnancy-may contribute to preeclampsia and subsequent cardiovascular disease risk. We performed a nested case-control study to further understand dyslipidemia associated with preeclampsia. The cohort consisted of participants in the randomized clinical trial "Improving Reproductive Fitness Through Pretreatment with Lifestyle Modification in Obese Women with Unexplained Infertility" (FIT-PLESE). FIT-PLESE was designed to study the effect of a pre-fertility treatment 16-week randomized lifestyle intervention program (Nutrisystem diet + exercise + orlistat vs. training alone) on improvement in live birth rate among obese women with unexplained infertility. Of the 279 patients in FIT-PLESE, 80 delivered a viable infant. Maternal serum was analyzed across five visits: before and after lifestyle interventions and also at three pregnancy visits (16, 24, and 32 weeks gestation). Apolipoprotein lipids were measured in a blinded fashion using ion mobility. Cases were those who developed preeclampsia. Controls also had a live birth but did not develop preeclampsia. Generalized linear and mixed models with repeated measures were used to compare the mean lipoprotein lipid levels of the two groups across all visits. Complete data were available for 75 pregnancies, and preeclampsia developed in 14.5% of the pregnancies. Cholesterol/high-density lipoprotein (HDL) ratios (p < 0.003), triglycerides (p = 0.012), and triglyceride/HDL ratios, all adjusted for BMI, were worse in patients with preeclampsia (p < 0.001). Subclasses a, b, and c of highly atherogenic, very small, low-density lipoprotein (LDL) particles were higher during pregnancy for the preeclamptic women (p < 0.05). Very small LDL particle subclass d levels were significantly greater only at 24 weeks (p = 0.012). The role of highly atherogenic, very small LDL particle excess in the pathophysiology of preeclampsia awaits further investigation.

The role of adjuvant treatment for early-stage uterine clear cell carcinomas.

BACKGROUND: Uterine clear cell carcinoma is a rare and aggressive subtype of endometrial carcinoma. Prospective clinical trials have not been feasible for this rare tumor, and data regarding the optimal adjuvant treatment regimen for early-stage uterine clear cell carcinomas is limited. Our study's objective was to determine if adjuvant chemotherapy or radiation therapy improves patients' outcomes in stage I and II uterine clear cell carcinoma. METHODS: Patients with stage I and II uterine clear cell carcinoma were identified at a single institution. All cases were reviewed by a gynecologic pathologist. Both pure and mixed non-serous uterine clear cell carcinomas were included. Primary outcomes were recurrence free survival and overall survival. RESULTS: A total of 71 patients were identified including 39 (55%) pure and 32 (45%) mixed clear cell carcinoma. Most patients were FIGO stage IA (77.5%). Most patients (n = 58, 82%) received adjuvant therapy, including 43 (61%) receiving chemotherapy, 50 (70%) receiving radiation therapy, and 35 (49%) receiving both. Recurrence free survival was not significantly different among patients receiving no or <6 cycles of chemotherapy versus patients receiving 6 cycles of chemotherapy (p = 0.39). However, median OS was significantly different among patients receiving no or <6 cycles of chemotherapy versus 6 cycles of chemotherapy (p = 0.004). On univariable analysis, 6 cycles of chemotherapy was significantly associated with improved OS (HR 0.1, 95% CI 0.01-0.07). Presence of LVSI, mutated p53, number of pelvic and para-aortic lymph nodes assessed, adjuvant chemotherapy (any number of cycles), and >2 medical co-morbidities were not significant predictors of OS on univariable analysis. On multivariable analysis, 6 cycles of adjuvant chemotherapy remained a significant predictor of improved OS (HR 0.1, 95% CI 0.01-0.8). CONCLUSIONS: In this study, administration of 6 cycles of chemotherapy appears to significantly improve OS. This finding suggests consideration of 6 cycles of adjuvant chemotherapy in patients with early-stage uterine clear cell carcinoma, however clinical trials are needed to confirm these findings.

Does gabapentin provide benefit for patients with knee OA? A benefit-harm and cost-effectiveness analysis.

OBJECTIVE: Gabapentin can treat neuropathic pain syndromes and has increasingly been prescribed to treat nociplastic pain. Some patients with knee osteoarthritis (OA) suffer from both nociceptive and nociplastic pain. We examined the cost-effectiveness of adding gabapentin to knee OA care. METHOD: We used the Osteoarthritis Policy Model, a validated Monte Carlo simulation of knee OA, to examine the value of gabapentin in treating knee OA by comparing three strategies: 1) usual care, gabapentin sparing (UC-GS); 2) targeted gabapentin (TG), which provides gabapentin plus usual care for those who screen positive for nociplastic pain on the modified PainDETECT questionnaire (mPD-Q) and usual care only for those who screen negative; and 3) universal gabapentin plus usual care (UG). Outcomes included cumulative quality-adjusted life years (QALYs), lifetime direct medical costs, and incremental cost-effectiveness ratios (ICERs), discounted at 3% annually. We derived model inputs from published literature and national databases and varied key input parameters in sensitivity analyses. RESULTS: UC-GS dominated both gabapentin-containing strategies, as it led to lower costs and more QALYs. TG resulted in a cost increase of $689 and a cumulative QALY reduction of 0.012 QALYs. UG resulted in a further $1,868 cost increase and 0.036 QALY decrease. The results were robust to plausible changes in input parameters. The lowest TG strategy ICER of $53,000/QALY was reported when mPD-Q specificity was increased to 100% and AE rate was reduced to 0%. CONCLUSION: Incorporating gabapentin into care for patients with knee OA does not appear to offer good value.

A 350,000-year history of groundwater recharge in the southern Great Basin, USA.

Estimating groundwater recharge under various climate conditions is important for predicting future freshwater availability. This is especially true for the water-limited region of the southern Great Basin, USA. To investigate the response of groundwater recharge to different climate states, we calculate the paleo recharge to a groundwater basin in southern Nevada over the last 350,000 years. Our approach combines a groundwater model with paleo-water-table data from Devils Hole cave. The minimum water-table during peak interglacial conditions was more than 1.6 m below modern levels, representing a recharge decline of less than 17% from present-day conditions. During peak glacial conditions, the water-table elevation was at least 9.5 m above modern levels, representing a recharge increase of more than 233-244% compared to present-day conditions. The elevation of the Devils Hole water-table is 3-4 times more sensitive to groundwater recharge during dry interglacial periods, compared to wet glacial periods. This study can serve as a benchmark for understanding long-term effects of past and future climate change on groundwater resources.

Hydroclimate variability in the Caribbean during North Atlantic Heinrich cooling events (H8 and H9).

We present a speleothem record from western Cuba, spanning the period 98.7-84.9 ka BP. Our record shows two distinctive periods of high δ18O corresponding to dry and/or cold periods during 85-87.6 and 90.2-93.1 ka BP, synchronous with Heinrich events 8 and 9 (H8 and H9). Hence, we provide the first proxy evidence of the local Caribbean climate response to H8 and H9. Interestingly, H8 is more pronounced compared to H9, which may be a local response to lower temperatures in the North Atlantic resulting in a weak AMOC and reduced deep water formation, therefore a stronger south shift of the ITCZ. Our data complement existing speleothem records from western Cuba which, collectively, provide a nearly continuous paleoclimate time-series spanning the last 100 ka BP, indicating a consistent response to millennial-scale events as dry and/or cooler conditions. The comparison with regional paleoclimate records reveals an anti-phased relationship with South America, caused by the southern movements of the ITCZ during millennial-scale events which lead to dry conditions in the Caribbean and a stronger South American Monsoon System.

Antiphase response of the Indonesian-Australian monsoon to millennial-scale events of the last glacial period.

Antiphase behaviour of monsoon systems in alternate hemispheres is well established at yearly and orbital scales in response to alternating sensible heating of continental landmasses. At intermediate timescales without a sensible heating mechanism both in-phase and antiphase behaviours of northern and southern hemisphere monsoon systems are recorded at different places and timescales. At present, there is no continuous, high resolution, precisely dated record of millennial-scale variability of the Indonesian-Australian monsoon during the last glacial period with which to test theories of paleomonsoon behaviour. Here, we present an extension of the Liang Luar, Flores, speleothem δ18O record of past changes in southern hemisphere summer monsoon intensity back to 55.7 kyr BP. Negative δ18O excursions (stronger monsoon) occur during Heinrich events whereas positive excursions (weaker monsoon) occur during Dansgaard-Oeschger interstadials-a first order antiphase relationship with northern hemisphere summer monsoon records. An association of negative δ18O excursions with speleothem growth phases in Liang Luar suggests that these stronger monsoons are related to higher rainfall amounts. However, the response to millennial-scale variability is inconsistent, including a particularly weak response to Heinrich event 3. We suggest that additional drivers such as underlying orbital-scale variability and drip hydrology influence the δ18O response.

Identification of a Quaternary rock avalanche deposit (Central Apennines, Italy): Significance for recognition of fossil catastrophic mass-wasting.

Whereas deposits of extremely-rapid, 'catastrophic' mass wastings >105 m3 in volume (for example, the Marocche di Dro rock avalanche in the Southern Alps and the Flims rockslide in the Western Alps) are easily recognized by their sheer mass and blocky surface, the identification of fossil catastrophic mass wastings partly removed by erosion must be based on deposit characteristics. Herein, a 'fossil' (pre-last glacial) rock avalanche, previously interpreted as either a till or debris flow, is described. The deposit, informally called 'Rubble Breccia', is located in the intramontane Campo Imperatore halfgraben that is bounded by a master fault with up to ca 900 m topographic throw. Based on documentation from field to thin section, and by comparative analysis with post-glacial rock avalanches, tills and debris flows, the Rubble Breccia is reinterpreted as a rock avalanche. The Rubble Breccia consists of an extremely-poorly sorted, disordered mixture of angular clasts from sand to block size. Many clasts show fitted subclast boundaries in crackle, jigsaw and mosaic fabrics, as diagnostic of catastrophic mass wasting deposits. Intercalated layers of angular to well-rounded clasts of coarse sand to fine pebble size, and deformed into open to recumbent folds, may represent shear belts folded during terminal avalanche propagation. The clast spectrum of the Rubble Breccia - mainly shallow-water bioclastic limestones, Saccocoma wackestones and other deep-water limestones and dolostones - is derived from the front range along the northern margin of the basin. Calcite cement found within the Rubble Breccia was dated with the U/Th disequilibrium method to 124.25 ± 2.76 ka bp, providing an ante-quam age constraint to the rock avalanche event. Because catastrophic mass wasting is a common erosional process, fossil deposits thereof should be more widespread than have been identified to date, although this may be a consequence of misidentification. The criteria outlined here provide a template to identify fossil catastrophic mass wasting deposits of any age.

Coupled atmosphere-ice-ocean dynamics during Heinrich Stadial 2.

Our understanding of climate dynamics during millennial-scale events is incomplete, partially due to the lack of their precise phase analyses under various boundary conditions. Here we present nine speleothem oxygen-isotope records from mid-to-low-latitude monsoon regimes with sub-centennial age precision and multi-annual resolution, spanning the Heinrich Stadial 2 (HS2) - a millennial-scale event that occurred at the Last Glacial Maximum. Our data suggests that the Greenland and Antarctic ice-core chronologies require +320- and +400-year adjustments, respectively, supported by extant volcanic evidence and radiocarbon ages. Our chronological framework shows a synchronous HS2 onset globally. Our records precisely characterize a centennial-scale abrupt "tropical atmospheric seesaw" superimposed on the conventional "bipolar seesaw" at the beginning of HS2, implying a unique response/feedback from low-latitude hydroclimate. Together with our observation of an early South American monsoon shift at the HS2 termination, we suggest a more active role of low-latitude hydroclimate dynamics underlying millennial events than previously thought.

Single-cell analysis of immune cell transcriptome during HIV-1 infection and therapy.

BACKGROUND: Cellular immune responses are phenotypically and functionally perturbed during HIV-1 infection, with the majority of function restored upon antiretroviral therapy (ART). Despite ART, residual inflammation remains that can lead to HIV-related co-morbidities and mortality, indicating that ART does not fully restore normal immune cell function. Thus, understanding the dynamics of the immune cell landscape during HIV-1 infection and ART is critical to defining cellular dysfunction that occurs during HIV-1 infection and imprints during therapy. RESULTS: Here, we have applied single-cell transcriptome sequencing of peripheral blood immune cells from chronic untreated HIV-1 individuals, HIV-1-infected individuals receiving ART and HIV-1 negative individuals. We also applied single-cell transcriptome sequencing to a primary cell model of early HIV-1 infection using CD4+ T cells from healthy donors. We described changes in the transcriptome at high resolution that occurred during HIV-1 infection, and perturbations that remained during ART. We also determined transcriptional differences among T cells expressing HIV-1 transcripts that identified key regulators of HIV-1 infection that may serve as targets for future therapies to block HIV-1 infection. CONCLUSIONS: This work identified key molecular pathways that are altered in immune cells during chronic HIV-1 infection that could remain despite therapy. We also identified key genes that are upregulated during early HIV-1 infection that provide insights on the mechanism of HIV-1 infection and could be targets for future therapy.

Protracted Indian monsoon droughts of the past millennium and their societal impacts.

Protracted droughts lasting years to decades constitute severe threats to human welfare across the Indian subcontinent. Such events are, however, rare during the instrumental period (ca. since 1871 CE). In contrast, the historic documentary evidence indicates the repeated occurrences of protracted droughts in the region during the preinstrumental period implying that either the instrumental observations underestimate the full spectrum of monsoon variability or the historic accounts overestimate the severity and duration of the past droughts. Here we present a temporally precise speleothem-based oxygen isotope reconstruction of the Indian summer monsoon precipitation variability from Mawmluh cave located in northeast India. Our data reveal that protracted droughts, embedded within multidecadal intervals of reduced monsoon rainfall, frequently occurred over the past millennium. These extreme events are in striking temporal synchrony with the historically documented droughts, famines, mass mortality events, and geopolitical changes in the Indian subcontinent. Our findings necessitate reconsideration of the region's current water resources, sustainability, and mitigation policies that discount the possibility of protracted droughts in the future.