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Recently, engineered bacterial cells have been shown to behave as optically-active photonic devices comparable to industrially fabricated microlenses . Bacterial cells can be encapsulated within a layer of polysilicate through surface display of the sea sponge enzyme silicatein, which mineralizes a polysilicate coating. The addition of this polysilicate layer significantly enhances the ability of these cells to guide, scatter, and focus light . However, this previous technique was limited to creating rod-shaped microlenses, which are not ideal for all applications. Here we expand upon this technology by engineering the shapes of silicatein-displaying bacterial cells. Through the overexpression of the genes and or through the use of the drug A22 , we are able to alter cells from their characteristic rod-like shape to either spherical or filamentous forms. Round cells encapsulated in polysilicate were shown to scatter light more intensely and symmetrically than rod-shaped cells, while encapsulated filamentous cells were shown to guide light similarly to an optical fiber. This control over the size and shape of optically-active cells is a major advancement towards developing bio-engineered photonic devices such as nanophotonic waveguides, spherical microlens arrays, and advanced biosensors.

Current methods used for measuring amino acid side-chain reactivity lack the throughput needed to screen large chemical libraries for interactions across the proteome. Here we redesigned the workflow for activity-based protein profiling of reactive cysteine residues by using a smaller desthiobiotin-based probe, sample multiplexing, reduced protein starting amounts and software to boost data acquisition in real time on the mass spectrometer. Our method, streamlined cysteine activity-based protein profiling (SLC-ABPP), achieved a 42-fold improvement in sample throughput, corresponding to profiling library members at a depth of >8,000 reactive cysteine sites at 18 min per compound. We applied it to identify proteome-wide targets of covalent inhibitors to mutant Kirsten rat sarcoma (KRAS) G12C and Bruton’s tyrosine kinase (BTK). In addition, we created a resource of cysteine reactivity to 285 electrophiles in three human cell lines, which includes >20,000 cysteines from >6,000 proteins per line. The goal of proteome-wide profiling of cysteine reactivity across thousand-member libraries under several cellular contexts is now within reach. An improved workflow enables a 42-fold higher throughput of activity-based protein profiling.

The human Y chromosome has been notoriously difficult to sequence and assemble because of its complex repeat structure that includes long palindromes, tandem repeats and segmental duplications 1 – 3 . As a result, more than half of the Y chromosome is missing from the GRCh38 reference sequence and it remains the last human chromosome to be finished 4 , 5 . Here, the Telomere-to-Telomere (T2T) consortium presents the complete 62,460,029-base-pair sequence of a human Y chromosome from the HG002 genome (T2T-Y) that corrects multiple errors in GRCh38-Y and adds over 30 million base pairs of sequence to the reference, showing the complete ampliconic structures of gene families TSPY , DAZ and RBMY ; 41 additional protein-coding genes, mostly from the TSPY family; and an alternating pattern of human satellite 1 and 3 blocks in the heterochromatic Yq12 region. We have combined T2T-Y with a previous assembly of the CHM13 genome 4 and mapped available population variation, clinical variants and functional genomics data to produce a complete and comprehensive reference sequence for all 24 human chromosomes. We present the complete 62,460,029-base-pair sequence of a human Y chromosome from the HG002 genome (T2T-Y) that corrects multiple errors in GRCh38-Y and adds over 30 million base pairs of sequence to the reference.

Anti-amyloid treatments for early symptomatic Alzheimer disease have recently become clinically available in some countries, which has greatly increased the need for biomarker confirmation of amyloid pathology. Blood biomarker (BBM) tests for amyloid pathology are more acceptable, accessible and scalable than amyloid PET or cerebrospinal fluid (CSF) tests, but have highly variable levels of performance. The Global CEO Initiative on Alzheimer’s Disease convened a BBM Workgroup to consider the minimum acceptable performance of BBM tests for clinical use. Amyloid PET status was identified as the reference standard. For use as a triaging test before subsequent confirmatory tests such as amyloid PET or CSF tests, the BBM Workgroup recommends that a BBM test has a sensitivity of ≥90% with a specificity of ≥85% in primary care and ≥75–85% in secondary care depending on the availability of follow-up testing. For use as a confirmatory test without follow-up tests, a BBM test should have performance equivalent to that of CSF tests — a sensitivity and specificity of ~90%. Importantly, the predictive values of all biomarker tests vary according to the pre-test probability of amyloid pathology and must be interpreted in the complete clinical context. Use of BBM tests that meet these performance standards could enable more people to receive an accurate and timely Alzheimer disease diagnosis and potentially benefit from new treatments.Anti-amyloid treatments for early symptomatic Alzheimer disease have greatly increased the need for biomarker confirmation of amyloid pathology and blood biomarker tests offer an accessible and scalable biomarker test. This Consensus Statement provides recommendations for the minimum acceptable performance of blood biomarker tests for clinical use.

Nitrous oxide (N2O) is a long-lived potent greenhouse gas and stratospheric ozone-depleting substance that has been accumulating in the atmosphere since the preindustrial period. The mole fraction of atmospheric N2O has increased by nearly 25 % from 270 ppb (parts per billion) in 1750 to 336 ppb in 2022, with the fastest annual growth rate since 1980 of more than 1.3 ppb yr−1 in both 2020 and 2021. According to the Sixth Assessment Report of the Intergovernmental Panel on Climate Change (IPCC AR6), the relative contribution of N2O to the total enhanced effective radiative forcing of greenhouse gases was 6.4 % for 1750–2022. As a core component of our global greenhouse gas assessments coordinated by the Global Carbon Project (GCP), our global N2O budget incorporates both natural and anthropogenic sources and sinks and accounts for the interactions between nitrogen additions and the biogeochemical processes that control N2O emissions. We use bottom-up (BU: inventory, statistical extrapolation of flux measurements, and process-based land and ocean modeling) and top-down (TD: atmospheric measurement-based inversion) approaches. We provide a comprehensive quantification of global N2O sources and sinks in 21 natural and anthropogenic categories in 18 regions between 1980 and 2020. We estimate that total annual anthropogenic N2O emissions have increased 40 % (or 1.9 Tg N yr−1) in the past 4 decades (1980–2020). Direct agricultural emissions in 2020 (3.9 Tg N yr−1, best estimate) represent the large majority of anthropogenic emissions, followed by other direct anthropogenic sources, including fossil fuel and industry, waste and wastewater, and biomass burning (2.1 Tg N yr−1), and indirect anthropogenic sources (1.3 Tg N yr−1) . For the year 2020, our best estimate of total BU emissions for natural and anthropogenic sources was 18.5 (lower–upper bounds: 10.6–27.0) Tg N yr−1, close to our TD estimate of 17.0 (16.6–17.4) Tg N yr−1. For the 2010–2019 period, the annual BU decadal-average emissions for both natural and anthropogenic sources were 18.2 (10.6–25.9) Tg N yr−1 and TD emissions were 17.4 (15.8–19.20) Tg N yr−1. The once top emitter Europe has reduced its emissions by 31 % since the 1980s, while those of emerging economies have grown, making China the top emitter since the 2010s. The observed atmospheric N2O concentrations in recent years have exceeded projected levels under all scenarios in the Coupled Model Intercomparison Project Phase 6 (CMIP6), underscoring the importance of reducing anthropogenic N2O emissions. To evaluate mitigation efforts and contribute to the Global Stocktake of the United Nations Framework Convention on Climate Change, we propose the establishment of a global network for monitoring and modeling N2O from the surface through to the stratosphere. The data presented in this work can be downloaded from https://doi.org/10.18160/RQ8P-2Z4R (Tian et al., 2023).

One-third of all Neotropical forests are secondary forests that regrow naturally after agricultural use through secondary succession. We need to understand better how and why succession varies across environmental gradients and broad geographic scales. Here, we analyze functional recovery using community data on seven plant characteristics (traits) of 1,016 forest plots from 30 chronosequence sites across the Neotropics. By analyzing communities in terms of their traits, we enhance understanding of the mechanisms of succession, assess ecosystem recovery, and use these insights to propose successful forest restoration strategies. Wet and dry forests diverged markedly for several traits that increase growth rate in wet forests but come at the expense of reduced drought tolerance, delay, or avoidance, which is important in seasonally dry forests. Dry and wet forests showed different successional pathways for several traits. In dry forests, species turnover is driven by drought tolerance traits that are important early in succession and in wet forests by shade tolerance traits that are important later in succession. In both forests, deciduous and compound-leaved trees decreased with forest age, probably because microclimatic conditions became less hot and dry. Our results suggest that climatic water availability drives functional recovery by influencing the start and trajectory of succession, resulting in a convergence of community trait values with forest age when vegetation cover builds up. Within plots, the range in functional trait values increased with age. Based on the observed successional trait changes, we indicate the consequences for carbon and nutrient cycling and propose an ecologically sound strategy to improve forest restoration success.

There is currently a debate about the timing and drivers of former glacier behaviour and climate change in the tropical Andes. Using 10 Be dating we determined the ages of 21 boulders on moraines in the Santa Cruz Valley, Peru (∼10°S, altitudes ~ 4100 to ~ 4300 m a.s.l.). Former glacier extent is marked by a suite of nested outer lateral and terminal moraines. These moraines are dated to 11.1 ka, 11.6 ka, 11.8 ka and 12.0 ka, falling within the Younger Dryas Chronozone (YDC; ∼12.9–11.6 ka). Nine 10 Be samples from the Lake Arhuaycocha catchment document a period of glacier thinning and lateral contraction between 12.0 ka and 11.8 ka. Reconstructed glacier Equilibrium Line Altitudes (ELA) at 11.0 to 12.0 ka with an area–altitude balance ratio (AABR) of 1.00-2.50 are between 4675 and 4835 m a.s.l. for the Arhuaycocha glacier, between 4692 and 4832 m a.s.l. for the Taullicocha glacier and between 4800 and 4940 m a.s.l. for the Artizon glacier. These values represent a depression of 300–400 m in elevation compared to contemporary values for the ELA. We infer that the glacier advances at this time were driven by increased precipitation and that these changes were most likely a response to seasonal changes in the position of the ITCZ.

Andrew Wilkie and colleagues report that mutations in TCF12 cause coronal craniosynostosis. They found heterozygous mutations in 38 unrelated families. Craniosynostosis, the premature fusion of the cranial sutures, is a heterogeneous disorder with a prevalence of ∼1 in 2,200 (refs. 1 , 2 ). A specific genetic etiology can be identified in ∼21% of cases 3 , including mutations of TWIST1 , which encodes a class II basic helix-loop-helix (bHLH) transcription factor, and causes Saethre-Chotzen syndrome, typically associated with coronal synostosis 4 , 5 , 6 . Using exome sequencing, we identified 38 heterozygous TCF12 mutations in 347 samples from unrelated individuals with craniosynostosis. The mutations predominantly occurred in individuals with coronal synostosis and accounted for 32% and 10% of subjects with bilateral and unilateral pathology, respectively. TCF12 encodes one of three class I E proteins that heterodimerize with class II bHLH proteins such as TWIST1. We show that TCF12 and TWIST1 act synergistically in a transactivation assay and that mice doubly heterozygous for loss-of-function mutations in Tcf12 and Twist1 have severe coronal synostosis. Hence, the dosage of TCF12-TWIST1 heterodimers is critical for normal coronal suture development.

BackgroundDemand for same-day discharge pathways and early ambulation following knee arthroplasty continues to increase. While spinal anesthesia with mepivacaine versus bupivacaine may promote return of motor function and ambulation, there are limited randomized trials evaluating this in knee arthroplasty patients. This study hypothesized that spinal mepivacaine would result in earlier return of motor function, promoting ambulation and same-day discharge.MethodsPatients undergoing primary total knee arthroplasty (n=163) were enrolled and randomized patients to mepivacaine (60 mg) or isobaric bupivacaine (10 mg) for spinal anesthesia. The primary outcome was time to return of motor function. Additional outcomes included time to first ambulation, distance at first ambulation, same-day discharge rate, length of stay, postoperative pain, opioid consumption, and side effects.ResultsPatients receiving a mepivacaine spinal anesthetic had faster median (95% CI) time to return of motor function, (210 min (200, 216) vs 229 (223, 237) min, p<0.001) and lower rates of urinary retention (36% vs 57%, p=0.007). Mepivacaine patients exhibited higher pain scores in the post-anesthesia care unit (32.4 vs 9.5 mm, p<0.001) but no differences at 6, 24, or 48 hours postoperative. Opioid consumption did not differ at any time point (p=0.769). There were no differences in time to first ambulation, distance at first ambulation, same-day discharge rate, length of stay, nausea, vomiting, pruritus, or transient neurological symptoms between groups.ConclusionsAlthough mepivacaine expedited return of motor function after knee arthroplasty, a clinically relevant 20% reduction was not observed. Ambulation times and same-day discharge rates did not differ.Trial registration numberNCT05765682.

For decades, most critical care patients have survived hospitalisation, supporting increased attention on the long-term critical illness recovery. The term ‘Post-Intensive Care Syndrome’ was coined in 2012 to raise awareness of long-term impairment in physical, cognitive and/or mental health after critical illness. However, the incidence of these impairments has persisted over the past decade, reaching as high as 60% and remains a major public health problem.Aiming to set a research agenda to address evidence gaps in critical illness recovery over the next 10 years, we invited key international opinion leaders from diverse clinical and methodological backgrounds to a roundtable meeting in June 2024 to assess the progress of post-critical illness recovery research and outline a future research agenda to address the unmet needs of critical illness survivors over the next decade.An early outcome from the meeting was to conduct a thematic analysis of critical care recovery literature, which highlighted the need for effective expectation management, ongoing patient support and education throughout recovery, integration between inpatient and community care, caregiver support and opportunities to reconnect with the intensive care unit.Participants identified conceptual challenges concerning current terminology and scope, population heterogeneity and phenotyping, and outcome definitions. Methodological challenges were identified around study design, with a call to shift to contemporary trial designs, incorporating qualitative methods. Translation into clinical practice will require interdisciplinary engagement.The roundtable concluded that a roadmap should be developed to guide clinical and research efforts over the coming decade, with the aim of developing a precision recovery approach.