Millennium Science Initiative

The gut microbiota is emerging as a promising target for the management or prevention of inflammatory and metabolic disorders in humans. Many of the current research efforts are focused on the identification of specific microbial signatures, more particularly for those associated with obesity, type 2 diabetes, and cardiovascular diseases. Some studies have described that the gut microbiota of obese animals and humans exhibits a higher Firmicutes/Bacteroidetes ratio compared with normal-weight individuals, proposing this ratio as an eventual biomarker. Accordingly, the Firmicutes/Bacteroidetes ratio is frequently cited in the scientific literature as a hallmark of obesity. The aim of the present review was to discuss the validity of this potential marker, based on the great amount of contradictory results reported in the literature. Such discrepancies might be explained by the existence of interpretative bias generated by methodological differences in sample processing and DNA sequence analysis, or by the generally poor characterization of the recruited subjects and, more particularly, the lack of consideration of lifestyle-associated factors known to affect microbiota composition and/or diversity. For these reasons, it is currently difficult to associate the Firmicutes/Bacteroidetes ratio with a determined health status and more specifically to consider it as a hallmark of obesity.

BACKGROUND: Mass vaccination campaigns to prevent coronavirus disease 2019 (Covid-19) are occurring in many countries; estimates of vaccine effectiveness are urgently needed to support decision making. A countrywide mass vaccination campaign with the use of an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine (CoronaVac) was conducted in Chile starting on February 2, 2021. METHODS: We used a prospective national cohort, including participants 16 years of age or older who were affiliated with the public national health care system, to assess the effectiveness of the inactivated SARS-CoV-2 vaccine with regard to preventing Covid-19 and related hospitalization, admission to the intensive care unit (ICU), and death. We estimated hazard ratios using the extension of the Cox proportional-hazards model, accounting for time-varying vaccination status. We estimated the change in the hazard ratio associated with partial immunization (≥14 days after receipt of the first dose and before receipt of the second dose) and full immunization (≥14 days after receipt of the second dose). Vaccine effectiveness was estimated with adjustment for individual demographic and clinical characteristics. RESULTS: The study was conducted from February 2 through May 1, 2021, and the cohort included approximately 10.2 million persons. Among persons who were fully immunized, the adjusted vaccine effectiveness was 65.9% (95% confidence interval [CI], 65.2 to 66.6) for the prevention of Covid-19 and 87.5% (95% CI, 86.7 to 88.2) for the prevention of hospitalization, 90.3% (95% CI, 89.1 to 91.4) for the prevention of ICU admission, and 86.3% (95% CI, 84.5 to 87.9) for the prevention of Covid-19-related death. CONCLUSIONS: Our results suggest that the inactivated SARS-CoV-2 vaccine effectively prevented Covid-19, including severe disease and death, a finding that is consistent with results of phase 2 trials of the vaccine. (Funded by Agencia Nacional de Investigación y Desarrollo and others.).

The identification of human artifacts at the early archaeological site of Monte Verde in southern Chile has raised questions of when and how people reached the tip of South America without leaving much other evidence in the New World. Remains of nine species of marine algae were recovered from hearths and other features at Monte Verde II, an upper occupational layer, and were directly dated between 14,220 and 13,980 calendar years before the present ( approximately 12,310 and 12,290 carbon-14 years ago). These findings support the archaeological interpretation of the site and indicate that the site's inhabitants used seaweed from distant beaches and estuarine environments for food and medicine. These data are consistent with the ideas that an early settlement of South America was along the Pacific coast and that seaweeds were important to the diet and health of early humans in the Americas.

Mutations in superoxide dismutase-1 (SOD1) cause familial amyotrophic lateral sclerosis (fALS). Recent evidence implicates adaptive responses to endoplasmic reticulum (ER) stress in the disease process via a pathway known as the unfolded protein response (UPR). Here, we investigated the contribution to fALS of X-box-binding protein-1 (XBP-1), a key UPR transcription factor that regulates genes involved in protein folding and quality control. Despite expectations that XBP-1 deficiency would enhance the pathogenesis of mutant SOD1, we observed a dramatic decrease in its toxicity due to an enhanced clearance of mutant SOD1 aggregates by macroautophagy, a cellular pathway involved in lysosome-mediated protein degradation. To validate these observations in vivo, we generated mutant SOD1 transgenic mice with specific deletion of XBP-1 in the nervous system. XBP-1-deficient mice were more resistant to developing disease, correlating with increased levels of autophagy in motoneurons and reduced accumulation of mutant SOD1 aggregates in the spinal cord. Post-mortem spinal cord samples from patients with sporadic ALS and fALS displayed a marked activation of both the UPR and autophagy. Our results reveal a new function of XBP-1 in the control of autophagy and indicate critical cross-talk between these two signaling pathways that can provide protection against neurodegeneration.

A critical procedure in diagnosing atrial fibrillation is the creation of electro-anatomic activation maps. Current methods generate these mappings from interpolation using a few sparse data points recorded inside the atria; they neither include prior knowledge of the underlying physics nor uncertainty of these recordings. Here we propose a physics-informed neural network for cardiac activation mapping that accounts for the underlying wave propagation dynamics and we quantify the epistemic uncertainty associated with these predictions. These uncertainty estimates not only allow us to quantify the predictive error of the neural network, but also help to reduce it by judiciously selecting new informative measurement locations via active learning. We illustrate the potential of our approach using a synthetic benchmark problem and a personalized electrophysiology model of the left atrium. We show that our new method outperforms linear interpolation and Gaussian process regression for the benchmark problem and linear interpolation at clinical densities for the left atrium. In both cases, the active learning algorithm achieves lower error levels than random allocation. Our findings open the door towards physics-based electro-anatomic mapping with the ultimate goals to reduce procedural time and improve diagnostic predictability for patients affected by atrial fibrillation. Open source code is available at https://github.com/fsahli/EikonalNet.

Amyotrophic lateral sclerosis (ALS) is a fatal motoneuron disease with no current effective treatment. Accumulation of abnormal protein inclusions containing SOD1, TARDBP, FUS, among other proteins, is a pathological hallmark of ALS. Autophagy is the major degradation pathway involved in the clearance of damaged organelles and protein aggregates. Although autophagy has been shown to efficiently degrade ALS-linked mutant protein in cell culture models, several studies suggest that autophagy impairment may also contribute to disease pathogenesis. In this report, we tested the potential use of trehalose, a disaccharide that induces MTOR-independent autophagy, in the development of experimental ALS. Administration of trehalose to mutant SOD1 transgenic mice significantly prolonged life span and attenuated the progression of disease signs. These effects were associated with decreased accumulation of SOD1 aggregates and enhanced motoneuron survival. The protective effects of trehalose were associated with increased autophagy levels in motoneurons. Cell culture experiments demonstrated that trehalose led to mutant SOD1 degradation by autophagy in NSC34 motoneuron cells and also protected primary motoneurons against the toxicity of conditioned media from mutant SOD1 transgenic astrocytes. At the mechanistic level, trehalose treatment led to a significant upregulation in the expression of key autophagy-related genes at the mRNA level including Lc3, Becn1, Sqstm1 and Atg5. Consistent with these changes, trehalose administration enhanced the nuclear translocation of FOXO1, an important transcription factor involved in the activation of autophagy in neurons. This study suggests a potential use of trehalose and enhancers of MTOR-independent autophagy for the treatment of ALS.

The relevance of the β-proteobacterial Burkholderiales order in the degradation of a vast array of aromatic compounds, including several priority pollutants, has been largely assumed. In this review, the presence and organization of genes encoding oxygenases involved in aromatics biodegradation in 80 Burkholderiales genomes is analysed. This genomic analysis underscores the impressive catabolic potential of this bacterial lineage, comprising nearly all of the central ring-cleavage pathways reported so far in bacteria and most of the peripheral pathways involved in channelling of a broad diversity of aromatic compounds. The more widespread pathways in Burkholderiales include protocatechuate ortho ring-cleavage, catechol ortho ring-cleavage, homogentisate ring-cleavage and phenylacetyl-CoA ring-cleavage pathways found in at least 60% of genomes analysed. In general, a genus-specific pattern of positional ordering of biodegradative genes is observed in the catabolic clusters of these pathways indicating recent events in its evolutionary history. In addition, a significant bias towards secondary chromosomes, now termed chromids, is observed in the distribution of catabolic genes across multipartite genomes, which is consistent with a genus-specific character. Strains isolated from environmental sources such as soil, rhizosphere, sediment or sludge show a higher content of catabolic genes in their genomes compared with strains isolated from human, animal or plant hosts, but no significant difference is found among Alcaligenaceae, Burkholderiaceae and Comamonadaceae families, indicating that habitat is more of a determinant than phylogenetic origin in shaping aromatic catabolic versatility.

Nitrogen (N) is the mineral nutrient required in the greatest amount and its availability is a major factor limiting growth and development of plants. As sessile organisms, plants have evolved different strategies to adapt to changes in the availability and distribution of N in soils. These strategies include mechanisms that act at different levels of biological organization from the molecular to the ecosystem level. At the molecular level, plants can adjust their capacity to acquire different forms of N in a range of concentrations by modulating the expression and function of genes in different N uptake systems. Modulation of plant growth and development, most notably changes in the root system architecture, can also greatly impact plant N acquisition in the soil. At the organism and ecosystem levels, plants establish associations with diverse microorganisms to ensure adequate nutrition and N supply. These different adaptive mechanisms have been traditionally discussed separately in the literature. To understand plant N nutrition in the environment, an integrated view of all pathways contributing to plant N acquisition is required. Towards this goal, in this review the different mechanisms that plants utilize to maintain an adequate N supply are summarized and integrated.

There is evidence in Xenopus and zebrafish embryos that the neural crest/neural folds are specified at the border of the neural plate by a precise threshold concentration of a Bmp gradient. In order to understand the molecular mechanism by which a gradient of Bmp is able to specify the neural crest, we analyzed how the expression of Bmp targets, the Msx genes, is regulated and the role that Msx genes has in neural crest specification. As Msx genes are directly downstream of Bmp, we analyzed Msx gene expression after experimental modification in the level of Bmp activity by grafting a bead soaked with noggin into Xenopus embryos, by expressing in the ectoderm a dominant-negative Bmp4 or Bmp receptor in Xenopus and zebrafish embryos, and also through Bmp pathway component mutants in the zebrafish. All the results show that a reduction in the level of Bmp activity leads to an increase in the expression of Msx genes in the neural plate border. Interestingly, by reaching different levels of Bmp activity in animal cap ectoderm, we show that a specific concentration of Bmp induces msx1 expression to a level similar to that required to induce neural crest. Our results indicate that an intermediate level of Bmp activity specifies the expression of Msx genes in the neural fold region. In addition, we have analyzed the role that msx1 plays on neural crest specification. As msx1 has a role in dorsoventral pattering, we have carried out conditional gain- and loss-of-function experiments using different msx1 constructs fused to a glucocorticoid receptor element to avoid an early effect of this factor. We show that msx1 expression is able to induce all other early neural crest markers tested (snail, slug, foxd3) at the time of neural crest specification. Furthermore, the expression of a dominant negative of Msx genes leads to the inhibition of all the neural crest markers analyzed. It has been previously shown that snail is one of the earliest genes acting in the neural crest genetic cascade. In order to study the hierarchical relationship between msx1 and snail/slug we performed several rescue experiments using dominant negatives for these genes. The rescuing activity by snail and slug on neural crest development of the msx1 dominant negative, together with the inability of msx1 to rescue the dominant negatives of slug and snail strongly argue that msx1 is upstream of snail and slug in the genetic cascade that specifies the neural crest in the ectoderm. We propose a model where a gradient of Bmp activity specifies the expression of Msx genes in the neural folds, and that this expression is essential for the early specification of the neural crest.

Migration of neural crest cells is an elaborate process that requires the delamination of cells from an epithelium and cell movement into an extracellular matrix. In this work, it is shown for the first time that the non-canonical Wnt signalling [planar cell polarity (PCP) or Wnt-Ca2+] pathway controls migration of neural crest cells. By using specific Dsh mutants, we show that the canonical Wnt signalling pathway is needed for neural crest induction, while the non-canonical Wnt pathway is required for neural crest migration. Grafts of neural crest tissue expressing non-canonical Dsh mutants, as well as neural crest cultured in vitro, indicate that the PCP pathway works in a cell-autonomous manner to control neural crest migration. Expression analysis of non-canonical Wnt ligands and their putative receptors show that Wnt11 is expressed in tissue adjacent to neural crest cells expressing the Wnt receptor Frizzled7 (Fz7). Furthermore, loss- and gain-of-function experiments reveal that Wnt11 plays an essential role in neural crest migration. Inhibition of neural crest migration by blocking Wnt11 activity can be rescued by intracellular activation of the non-canonical Wnt pathway. When Wnt11 is expressed opposite its normal site of expression, neural crest migration is blocked. Finally, time-lapse analysis of cell movement and cell protrusion in neural crest cultured in vitro shows that the PCP or Wnt-Ca2+ pathway directs the formation of lamellipodia and filopodia in the neural crest cells that are required for their delamination and/or migration.

We present PATICE, a GIS database of Patagonian glacial geomorphology and recalibrated chronological data. PATICE includes 58,823 landforms and 1,669 geochronological ages, and extends from 38°S to 55°S in southern South America. We use these data to generate new empirical reconstructions of the Patagonian Ice Sheet (PIS) and subsequent ice masses and ice-dammed palaeolakes at 35 ka, 30 ka, 25 ka, 20 ka, 15 ka, 13 ka (synchronous with the Antarctic Cold Reversal), 10 ka, 5 ka, 0.2 ka and 2011 AD. At 35 ka, the PIS covered of 492.6 x103 km2, had a sea level equivalent of ~1,496 mm, was 350 km wide and 2090 km long, and was grounded on the Pacific continental shelf edge. Outlet glacier lobes remained topographically confined and the largest generated the suites of subglacial streamlined bedforms characteristic of ice streams. The PIS reached its maximum extent by 33 – 28 ka from 38°S to 48°S, and earlier, around 47 ka from 48°S southwards. Net retreat from maximum positions began by 25 ka, with ice-marginal stabilisation then at 21 – 18 ka, which was then followed by rapid, irreversible deglaciation. By 15 ka, the PIS had separated into disparate ice masses, draining into large ice-dammed lakes along the eastern margin, which strongly influenced rates of recession. Glacial readvances or stabilisations occurred at least at 14 – 13 ka, 11 ka, 6 – 5 ka, 2 – 1 ka, and 0.5 – 0.2 ka. We suggest that 20th century glacial recession (% a-1) is occurring faster than at any time documented during the Holocene.

This is a tutorial-style introduction to the field of molecular polaritons. We describe the basic physical principles and consequences of strong light-matter coupling common to molecular ensembles embedded in UV-visible or infrared cavities. Using a microscopic quantum electrodynamics formulation, we discuss the competition between the collective cooperative dipolar response of a molecular ensemble and local dynamical processes that molecules typically undergo, including chemical reactions. We highlight some of the observable consequences of this competition between local and collective effects in linear transmission spectroscopy, including the formal equivalence between quantum mechanical theory and the classical transfer matrix method, under specific conditions of molecular density and indistinguishability. We also overview recent experimental and theoretical developments on strong and ultrastrong coupling with electronic and vibrational transitions, with a special focus on cavity-modified chemistry and infrared spectroscopy under vibrational strong coupling. We finally suggest several opportunities for further studies that may lead to novel applications in chemical and electromagnetic sensing, energy conversion, optoelectronics, quantum control, and quantum technology.

Abstract The eighteenth data release (DR18) of the Sloan Digital Sky Survey (SDSS) is the first one for SDSS-V, the fifth generation of the survey. SDSS-V comprises three primary scientific programs or “Mappers”: the Milky Way Mapper (MWM), the Black Hole Mapper (BHM), and the Local Volume Mapper. This data release contains extensive targeting information for the two multiobject spectroscopy programs (MWM and BHM), including input catalogs and selection functions for their numerous scientific objectives. We describe the production of the targeting databases and their calibration and scientifically focused components. DR18 also includes ∼25,000 new SDSS spectra and supplemental information for X-ray sources identified by eROSITA in its eFEDS field. We present updates to some of the SDSS software pipelines and preview changes anticipated for DR19. We also describe three value-added catalogs (VACs) based on SDSS-IV data that have been published since DR17, and one VAC based on the SDSS-V data in the eFEDS field.

Hemodynamic assessment is an integral part of the diagnosis and management of cardiovascular disease. Four-dimensional cardiovascular magnetic resonance flow imaging (4D Flow CMR) allows comprehensive and accurate assessment of flow in a single acquisition. This consensus paper is an update from the 2015 '4D Flow CMR Consensus Statement'. We elaborate on 4D Flow CMR sequence options and imaging considerations. The document aims to assist centers starting out with 4D Flow CMR of the heart and great vessels with advice on acquisition parameters, post-processing workflows and integration into clinical practice. Furthermore, we define minimum quality assurance and validation standards for clinical centers. We also address the challenges faced in quality assurance and validation in the research setting. We also include a checklist for recommended publication standards, specifically for 4D Flow CMR. Finally, we discuss the current limitations and the future of 4D Flow CMR. This updated consensus paper will further facilitate widespread adoption of 4D Flow CMR in the clinical workflow across the globe and aid consistently high-quality publication standards.

Many aspects of plant development, including patterning and tropisms, are largely dependent on the asymmetric distribution of the plant signaling molecule auxin. Auxin transport inhibitors (ATIs), which interfere with directional auxin transport, have been essential tools in formulating this concept. However, despite the use of ATIs in plant research for many decades, the mechanism of ATI action has remained largely elusive. Using real-time live-cell microscopy, we show here that prominent ATIs such as 2,3,5-triiodobenzoic acid (TIBA) and 2-(1-pyrenoyl) benzoic acid (PBA) inhibit vesicle trafficking in plant, yeast, and mammalian cells. Effects on micropinocytosis, rab5-labeled endosomal motility at the periphery of HeLa cells and on fibroblast mobility indicate that ATIs influence actin cytoskeleton. Visualization of actin cytoskeleton dynamics in plants, yeast, and mammalian cells show that ATIs stabilize actin. Conversely, stabilizing actin by chemical or genetic means interferes with endocytosis, vesicle motility, auxin transport, and plant development, including auxin transport-dependent processes. Our results show that a class of ATIs act as actin stabilizers and advocate that actin-dependent trafficking of auxin transport components participates in the mechanism of auxin transport. These studies also provide an example of how the common eukaryotic process of actin-based vesicle motility can fulfill a plant-specific physiological role.

The complex sequence of inductive events responsible for the generation of the neural crest at the border between the neural plate and the epidermis, triggers a genetic cascade involving several families of transcription factors. Two members of the Snail family, Snail and Slug, have both been implicated in this cascade. In chick and Xenopus, loss- and gain-of-function experiments have provided evidence that Slug plays a key role in neural crest development. However, in contrast to the chick, Snail rather than Slug is expressed in the premigratory neural crest in the mouse and, in Xenopus, Snail precedes Slug expression in this population. Thus, in order to study the function of Snail in neural crest development in Xenopus, we have carried out conditional gain- and loss-of-function experiments using different Snail constructs fused to a glucocorticoid receptor element. We show that Snail is able to induce the expression of Slug and all other neural crest markers tested (Zic5, FoxD3, Twist and Ets1) at the time of specification. This activation is observed in whole embryos and in animal caps, in the absence of neural plate and mesodermal markers. We show that Snail is required for neural crest specification and migration and that it works as a transcriptional repressor. These functions have been previously attributed to SLUG: However, Slug alone is unable to induce other neural crest markers in animal cap assays, and we show that Snail and Slug can be functionally equivalent when tested in overexpression studies. This suggests that, in Xenopus embryos, at least some of the functions previously attributed to Slug can be carried out by SNAIL: This is additionally supported by rescue experiments in embryos injected with dominant-negative constructs that indicate that Snail lies upstream of Slug in the genetic cascade leading to neural crest formation and that it plays a key role in crest development.

Reaction-rate modifications for chemical processes due to strong coupling between reactant molecular vibrations and the cavity vacuum have been reported; however, no currently accepted mechanisms explain these observations. In this work, reaction-rate constants were extracted from evolving cavity transmission spectra, revealing resonant suppression of the intracavity reaction rate for alcoholysis of phenyl isocyanate with cyclohexanol. We observed up to an 80% suppression of the rate by tuning cavity modes to be resonant with the reactant isocyanate (NCO) stretch, the product carbonyl (CO) stretch, and cooperative reactant-solvent modes (CH). These results were interpreted using an open quantum system model that predicted resonant modifications of the vibrational distribution of reactants from canonical statistics as a result of light-matter quantum coherences, suggesting links to explore between chemistry and quantum science.

BACKGROUND: Bortezomib is a potent, reversible proteasome inhibitor that has been approved for the treatment of recurrent and/or refractory multiple myeloma, but its activity in patients with renal impairment has not been studied to date. METHODS: Response rates, safety, and 20S proteasome activity were assessed in relation to baseline creatinine clearance (CrCl) among patients with recurrent and/or refractory myeloma (n = 256 patients) who were treated with bortezomib in 2 Phase II trials. Bortezomib was administered by intravenous bolus on Days 1, 4, 8, and 11 of a 21-day cycle at 2 doses, 1.0 mg/m2 (n = 28 patients) and 1.3 mg/m2 (n = 228 patients). RESULTS: Of 10 patients with CrCl < or = 30 mL/minute, 7 patients completed the protocol-specified 8 cycles of treatment; 4 patients received the 1.3 mg/m2 bortezomib dose, and 3 patients received the 1.0 mg/m2 bortezomib dose. Using the European Group for Blood and Marrow Transplantation criteria, responses were assigned by an independent committee to 3 of the 10 patients (2 partial responses and 1 minimal response), a response rate similar to that of the overall treated population. Patients with CrCl > 80 mL/minute (n = 105 patients), 51-80 mL/minute (n = 99 patients), and < or = 50 mL/minute (n = 52 patients) had similar rates of discontinuation and similar adverse event profiles. Renal function did not appear to affect the 1-hour postdose proteasome inhibition or its recovery. CONCLUSIONS: Clinical experience in a limited number of patients with impaired renal function suggests that bortezomib provides clinical benefit with manageable toxicities in this high-risk population.

We introduce the Ophiuchus DIsc Survey Employing ALMA (ODISEA), a project aiming to study the entire population of Spitzer-selected protoplanetary discs in the Ophiuchus Molecular Cloud (~300 objects) from both millimetre continuum and CO isotopologues data. Here we present 1.3 mm/230 GHz continuum images of 147 targets at 0.2 arcsec (28 au) resolution and a typical rms of 0.15 mJy. We detect a total of 133 discs, including the individual components of 11 binary systems and 1 triple system. 60 of these discs are spatially resolved. We find clear substructures (inner cavities, rings, gaps, and/or spiral arms) in eight of the sources and hints of such structures in another four discs. We construct the disc luminosity function for our targets and perform preliminary comparisons to other regions. A simple conversion between flux and dust mass (adopting standard assumptions) indicates that all discs detected at 1.3 mm are massive enough to form one or more rocky planets. In contrast, only ~50 discs (~1/3 of the sample) have enough mass in the form of dust to form the canonical 10 M&lt;SUB&gt;‚äï&lt;/SUB&gt; core needed to trigger runaway gas accretion and the formation of gas giant planets, although the total mass of solids already incorporated into bodies larger than cm scales is mostly unconstrained. The distribution in continuum disc sizes in our sample is heavily weighted towards compact discs: most detected discs have radii &amp;lt; 15 au, while only 23 discs ({~ }15{{ per cent}} of the targets) have radii &amp;gt; 30 au.

High energy collisions at the High-Luminosity Large Hadron Collider (LHC) produce a large number of particles along the beam collision axis, outside of the acceptance of existing LHC experiments. The proposed Forward Physics Facility (FPF), to be located several hundred meters from the ATLAS interaction point and shielded by concrete and rock, will host a suite of experiments to probe standard model (SM) processes and search for physics beyond the standard model (BSM). In this report, we review the status of the civil engineering plans and the experiments to explore the diverse physics signals that can be uniquely probed in the forward region. FPF experiments will be sensitive to a broad range of BSM physics through searches for new particle scattering or decay signatures and deviations from SM expectations in high statistics analyses with TeV neutrinos in this low-background environment. High statistics neutrino detection will also provide valuable data for fundamental topics in perturbative and non-perturbative QCD and in weak interactions. Experiments at the FPF will enable synergies between forward particle production at the LHC and astroparticle physics to be exploited. We report here on these physics topics, on infrastructure, detector, and simulation studies, and on future directions to realize the FPF’s physics potential.