Fab-dimerized glycan-reactive antibodies are a structural category of natural antibodies.

Natural antibodies (Abs) can target host glycans on the surface of pathogens. We studied the evolution of glycan-reactive B cells of rhesus macaques and humans using glycosylated HIV-1 envelope (Env) as a model antigen. 2G12 is a broadly neutralizing Ab (bnAb) that targets a conserved glycan patch on Env of geographically diverse HIV-1 strains using a unique heavy-chain (VH) domain-swapped architecture that results in fragment antigen-binding (Fab) dimerization. Here, we describe HIV-1 Env Fab-dimerized glycan (FDG)-reactive bnAbs without VH-swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques. FDG Abs also recognized cell-surface glycans on diverse pathogens, including yeast and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike. FDG precursors were expanded by glycan-bearing immunogens in macaques and were abundant in HIV-1-naive humans. Moreover, FDG precursors were predominately mutated IgM+IgD+CD27+, thus suggesting that they originated from a pool of antigen-experienced IgM+ or marginal zone B cells.

RAB11FIP5 Expression and Altered Natural Killer Cell Function Are Associated with Induction of HIV Broadly Neutralizing Antibody Responses.

HIV-1 broadly neutralizing antibodies (bnAbs) are difficult to induce with vaccines but are generated in ∼50% of HIV-1-infected individuals. Understanding the molecular mechanisms of host control of bnAb induction is critical to vaccine design. Here, we performed a transcriptome analysis of blood mononuclear cells from 47 HIV-1-infected individuals who made bnAbs and 46 HIV-1-infected individuals who did not and identified in bnAb individuals upregulation of RAB11FIP5, encoding a Rab effector protein associated with recycling endosomes. Natural killer (NK) cells had the highest differential expression of RAB11FIP5, which was associated with greater dysregulation of NK cell subsets in bnAb subjects. NK cells from bnAb individuals had a more adaptive/dysfunctional phenotype and exhibited impaired degranulation and cytokine production that correlated with RAB11FIP5 transcript levels. Moreover, RAB11FIP5 overexpression modulated the function of NK cells. These data suggest that NK cells and Rab11 recycling endosomal transport are involved in regulation of HIV-1 bnAb development.

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.

Coupling of Indo-Pacific climate variability over the last millennium.

The Indian Ocean Dipole (IOD) affects climate and rainfall across the world, and most severely in nations surrounding the Indian Ocean1-4. The frequency and intensity of positive IOD events increased during the twentieth century5 and may continue to intensify in a warming world6. However, confidence in predictions of future IOD change is limited by known biases in IOD models7 and the lack of information on natural IOD variability before anthropogenic climate change. Here we use precisely dated and highly resolved coral records from the eastern equatorial Indian Ocean, where the signature of IOD variability is strong and unambiguous, to produce a semi-continuous reconstruction of IOD variability that covers five centuries of the last millennium. Our reconstruction demonstrates that extreme positive IOD events were rare before 1960. However, the most extreme event on record (1997) is not unprecedented, because at least one event that was approximately 27 to 42 per cent larger occurred naturally during the seventeenth century. We further show that a persistent, tight coupling existed between the variability of the IOD and the El Niño/Southern Oscillation during the last millennium. Indo-Pacific coupling was characterized by weak interannual variability before approximately 1590, which probably altered teleconnection patterns, and by anomalously strong variability during the seventeenth century, which was associated with societal upheaval in tropical Asia. A tendency towards clustering of positive IOD events is evident in our reconstruction, which-together with the identification of extreme IOD variability and persistent tropical Indo-Pacific climate coupling-may have implications for improving seasonal and decadal predictions and managing the climate risks of future IOD variability.

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.

Ancient DNA and multimethod dating confirm the late arrival of anatomically modern humans in southern China.

The expansion of anatomically modern humans (AMHs) from Africa around 65,000 to 45,000 y ago (ca. 65 to 45 ka) led to the establishment of present-day non-African populations. Some paleoanthropologists have argued that fossil discoveries from Huanglong, Zhiren, Luna, and Fuyan caves in southern China indicate one or more prior dispersals, perhaps as early as ca. 120 ka. We investigated the age of the human remains from three of these localities and two additional early AMH sites (Yangjiapo and Sanyou caves, Hubei) by combining ancient DNA (aDNA) analysis with a multimethod geological dating strategy. Although U-Th dating of capping flowstones suggested they lie within the range ca. 168 to 70 ka, analyses of aDNA and direct AMS 14C dating on human teeth from Fuyan and Yangjiapo caves showed they derive from the Holocene. OSL dating of sediments and AMS 14C analysis of mammal teeth and charcoal also demonstrated major discrepancies from the flowstone ages; the difference between them being an order of magnitude or more at most of these localities. Our work highlights the surprisingly complex depositional history recorded at these subtropical caves which involved one or more episodes of erosion and redeposition or intrusion as recently as the late Holocene. In light of our findings, the first appearance datum for AMHs in southern China should probably lie within the timeframe set by molecular data of ca. 50 to 45 ka.

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.

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.

Hydroclimate changes across the Amazon lowlands over the past 45,000 years.

Reconstructing the history of tropical hydroclimates has been difficult, particularly for the Amazon basin-one of Earth's major centres of deep atmospheric convection. For example, whether the Amazon basin was substantially drier or remained wet during glacial times has been controversial, largely because most study sites have been located on the periphery of the basin, and because interpretations can be complicated by sediment preservation, uncertainties in chronology, and topographical setting. Here we show that rainfall in the basin responds closely to changes in glacial boundary conditions in terms of temperature and atmospheric concentrations of carbon dioxide. Our results are based on a decadally resolved, uranium/thorium-dated, oxygen isotopic record for much of the past 45,000 years, obtained using speleothems from Paraíso Cave in eastern Amazonia; we interpret the record as being broadly related to precipitation. Relative to modern levels, precipitation in the region was about 58% during the Last Glacial Maximum (around 21,000 years ago) and 142% during the mid-Holocene epoch (about 6,000 years ago). We find that, as compared with cave records from the western edge of the lowlands, the Amazon was widely drier during the last glacial period, with much less recycling of water and probably reduced plant transpiration, although the rainforest persisted throughout this time.

Timing and structure of the Younger Dryas event and its underlying climate dynamics.

The Younger Dryas (YD), arguably the most widely studied millennial-scale extreme climate event, was characterized by diverse hydroclimate shifts globally and severe cooling at high northern latitudes that abruptly punctuated the warming trend from the last glacial to the present interglacial. To date, a precise understanding of its trigger, propagation, and termination remains elusive. Here, we present speleothem oxygen-isotope data that, in concert with other proxy records, allow us to quantify the timing of the YD onset and termination at an unprecedented subcentennial temporal precision across the North Atlantic, Asian Monsoon-Westerlies, and South American Monsoon regions. Our analysis suggests that the onsets of YD in the North Atlantic (12,870 ± 30 B.P.) and the Asian Monsoon-Westerlies region are essentially synchronous within a few decades and lead the onset in Antarctica, implying a north-to-south climate signal propagation via both atmospheric (decadal-time scale) and oceanic (centennial-time scale) processes, similar to the Dansgaard-Oeschger events during the last glacial period. In contrast, the YD termination may have started first in Antarctica at ∼11,900 B.P., or perhaps even earlier in the western tropical Pacific, followed by the North Atlantic between ∼11,700 ± 40 and 11,610 ± 40 B.P. These observations suggest that the initial YD termination might have originated in the Southern Hemisphere and/or the tropical Pacific, indicating a Southern Hemisphere/tropics to North Atlantic-Asian Monsoon-Westerlies directionality of climatic recovery.

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.

The neuroinflammatory component of negative affect in patients with chronic pain.

Negative affect (NA) is a significant cause of disability for chronic pain patients. While little is known about the mechanism underlying pain-comorbid NA, previous studies have implicated neuroinflammation in the pathophysiology of both depression and chronic pain. Here, we tested the hypothesis that NA in pain patients is linked to elevations in the brain levels of the glial marker 18 kDa translocator protein (TSPO), and changes in functional connectivity. 25 cLBP patients (42.4 ± 13 years old; 13F, 12M) with chronic low back pain (cLBP) and 27 healthy control subjects (48.9 ± 13 years old; 14F, 13M) received an integrated (i.e., simultaneous) positron emission tomography (PET)/magnetic resonance imaging (MRI) brain scan with the second-generation TSPO ligand [11C]PBR28. The relationship between [11C]PBR28 signal and NA was assessed first with regression analyses against Beck Depression Inventory (BDI) scores in patients, and then by comparing cLBP patients with little-to-no, or mild-to-moderate depression against healthy controls. Further, the relationship between PET signal, BDI and frontolimbic functional connectivity was evaluated in patients with mediation models. PET signal was positively associated with BDI scores in patients, and significantly elevated in patients with mild-to-moderate (but not low) depression compared with controls, in anterior middle and pregenual anterior cingulate cortices (aMCC, pgACC). In the pgACC, PET signal was also associated with this region's functional connectivity to the dorsolateral PFC (pgACC-dlPFC), and mediated of the association between pgACC-dlPFC connectivity and BDI. These observations support a role for glial activation in pain-comorbid NA, identifying in neuroinflammation a potential therapeutic target for this condition.

The Asian monsoon over the past 640,000 years and ice age terminations.

Oxygen isotope records from Chinese caves characterize changes in both the Asian monsoon and global climate. Here, using our new speleothem data, we extend the Chinese record to cover the full uranium/thorium dating range, that is, the past 640,000 years. The record's length and temporal precision allow us to test the idea that insolation changes caused by the Earth's precession drove the terminations of each of the last seven ice ages as well as the millennia-long intervals of reduced monsoon rainfall associated with each of the terminations. On the basis of our record's timing, the terminations are separated by four or five precession cycles, supporting the idea that the '100,000-year' ice age cycle is an average of discrete numbers of precession cycles. Furthermore, the suborbital component of monsoon rainfall variability exhibits power in both the precession and obliquity bands, and is nearly in anti-phase with summer boreal insolation. These observations indicate that insolation, in part, sets the pace of the occurrence of millennial-scale events, including those associated with terminations and 'unfinished terminations'.

Early Neanderthal constructions deep in Bruniquel Cave in southwestern France.

Very little is known about Neanderthal cultures, particularly early ones. Other than lithic implements and exceptional bone tools, very few artefacts have been preserved. While those that do remain include red and black pigments and burial sites, these indications of modernity are extremely sparse and few have been precisely dated, thus greatly limiting our knowledge of these predecessors of modern humans. Here we report the dating of annular constructions made of broken stalagmites found deep in Bruniquel Cave in southwest France. The regular geometry of the stalagmite circles, the arrangement of broken stalagmites and several traces of fire demonstrate the anthropogenic origin of these constructions. Uranium-series dating of stalagmite regrowths on the structures and on burnt bone, combined with the dating of stalagmite tips in the structures, give a reliable and replicated age of 176.5 thousand years (±2.1 thousand years), making these edifices among the oldest known well-dated constructions made by humans. Their presence at 336 metres from the entrance of the cave indicates that humans from this period had already mastered the underground environment, which can be considered a major step in human modernity.

Lytic to temperate switching of viral communities.

Microbial viruses can control host abundances via density-dependent lytic predator-prey dynamics. Less clear is how temperate viruses, which coexist and replicate with their host, influence microbial communities. Here we show that virus-like particles are relatively less abundant at high host densities. This suggests suppressed lysis where established models predict lytic dynamics are favoured. Meta-analysis of published viral and microbial densities showed that this trend was widespread in diverse ecosystems ranging from soil to freshwater to human lungs. Experimental manipulations showed viral densities more consistent with temperate than lytic life cycles at increasing microbial abundance. An analysis of 24 coral reef viromes showed a relative increase in the abundance of hallmark genes encoded by temperate viruses with increased microbial abundance. Based on these four lines of evidence, we propose the Piggyback-the-Winner model wherein temperate dynamics become increasingly important in ecosystems with high microbial densities; thus 'more microbes, fewer viruses'.

Intra-operative neurophysiological mapping to identify distorted functional anatomy of the 4th ventricle in a 5-month-old infant.

BACKGROUND: Neurophysiological brainstem mapping techniques facilitate the intra-operative localisation of cranial nerve nuclei amidst distorted anatomy. Neurophysiological recording in young infants can be limited due to immature myelination and synaptogenesis, as well as an increased sensitivity to anaesthetic agents. CASE REPORT: A 5-month-old boy was diagnosed with a cystic brainstem lesion located dorsally within the pons and upper medulla. An open surgical biopsy was undertaken via a posterior fossa craniotomy, revealing a grossly distorted fourth ventricular floor. Intra-operative neurophysiological mapping produced oculomotor, facial, glossopharyngeal and vagal muscle responses allowing a deviated functional midline to be identified. Direct stimulation was used to identify an area in the floor of the fourth ventricle eliciting no cranial nerve responses and allow safe entry into the tumour cavity and biopsy. Transcranial motor evoked responses (TcMEPs), short-latency somatosensory evoked potentials (SSEPs) and brainstem auditory evoked potentials (BAEPs) were all successfully recorded throughout the procedure, despite the use of halogenated gaseous anaesthesia. CONCLUSIONS: We describe the use of brainstem mapping techniques for identification of a distorted midline on the floor of the 4th ventricle in an infant, with reproducible recordings of intra-operative TcMEPs, SSEPs and BAEPs.

Shallow particulate organic carbon regeneration in the South Pacific Ocean.

Particulate organic carbon (POC) produced in the surface ocean sinks through the water column and is respired at depth, acting as a primary vector sequestering carbon in the abyssal ocean. Atmospheric carbon dioxide levels are sensitive to the length (depth) scale over which respiration converts POC back to inorganic carbon, because shallower waters exchange with the atmosphere more rapidly than deeper ones. However, estimates of this carbon regeneration length scale and its spatiotemporal variability are limited, hindering the ability to characterize its sensitivity to environmental conditions. Here, we present a zonal section of POC fluxes at high vertical and spatial resolution from the GEOTRACES GP16 transect in the eastern tropical South Pacific, based on normalization to the radiogenic thorium isotope 230Th. We find shallower carbon regeneration length scales than previous estimates for the oligotrophic South Pacific gyre, indicating less efficient carbon transfer to the deep ocean. Carbon regeneration is strongly inhibited within suboxic waters near the Peru coast. Canonical Martin curve power laws inadequately capture POC flux profiles at suboxic stations. We instead fit these profiles using an exponential function with flux preserved at depth, finding shallow regeneration but high POC sequestration below 1,000 m. Both regeneration length scales and POC flux at depth closely track the depths at which oxygen concentrations approach zero. Our findings imply that climate warming will result in reduced ocean carbon storage due to expanding oligotrophic gyres, but opposing effects on ocean carbon storage from expanding suboxic waters will require modeling and future work to disentangle.

Archaic human remains from Hualongdong, China, and Middle Pleistocene human continuity and variation.

Middle to Late Pleistocene human evolution in East Asia has remained controversial regarding the extent of morphological continuity through archaic humans and to modern humans. Newly found ∼300,000-y-old human remains from Hualongdong (HLD), China, including a largely complete skull (HLD 6), share East Asian Middle Pleistocene (MPl) human traits of a low vault with a frontal keel (but no parietal sagittal keel or angular torus), a low and wide nasal aperture, a pronounced supraorbital torus (especially medially), a nonlevel nasal floor, and small or absent third molars. It lacks a malar incisure but has a large superior medial pterygoid tubercle. HLD 6 also exhibits a relatively flat superior face, a more vertical mandibular symphysis, a pronounced mental trigone, and simple occlusal morphology, foreshadowing modern human morphology. The HLD human fossils thus variably resemble other later MPl East Asian remains, but add to the overall variation in the sample. Their configurations, with those of other Middle and early Late Pleistocene East Asian remains, support archaic human regional continuity and provide a background to the subsequent archaic-to-modern human transition in the region.

Rainfall variations in central Indo-Pacific over the past 2,700 y.

Tropical rainfall variability is closely linked to meridional shifts of the Intertropical Convergence Zone (ITCZ) and zonal movements of the Walker circulation. The characteristics and mechanisms of tropical rainfall variations on centennial to decadal scales are, however, still unclear. Here, we reconstruct a replicated stalagmite-based 2,700-y-long, continuous record of rainfall for the deeply convective northern central Indo-Pacific (NCIP) region. Our record reveals decreasing rainfall in the NCIP over the past 2,700 y, similar to other records from the northern tropics. Notable centennial- to decadal-scale dry climate episodes occurred in both the NCIP and the southern central Indo-Pacific (SCIP) during the 20th century [Current Warm Period (CWP)] and the Medieval Warm Period (MWP), resembling enhanced El Niño-like conditions. Further, we developed a 2,000-y-long ITCZ shift index record that supports an overall southward ITCZ shift in the central Indo-Pacific and indicates southward mean ITCZ positions during the early MWP and the CWP. As a result, the drying trend since the 20th century in the northern tropics is similar to that observed during the past warm period, suggesting that a possible anthropogenic forcing of rainfall remains indistinguishable from natural variability.