Browse Articles

Mutations to transcription factor MAX allosterically increase DNA selectivity by altering folding and binding pathways

Exploring the impact of entrepreneurial orientation and market orientation on entrepreneurial performance in the context of environmental uncertainty

Fundamental constraints and questions from the study of Martian meteorites and the need for returned samples

Physical materials from planetary bodies are crucial for understanding fundamental processes that constrain the evolution of the solar system, as samples can be analyzed at high precision and accuracy in Earth-based laboratories. Mars is the only planet outside of Earth from which we possess samples in the form of meteorites. Martian meteorites (n > 350) have enabled constraints to be placed on various aspects of the red planet’s formation and evolution, notably: that Mars accreted and differentiated rapidly; that the planet has a complex volatile element evolution; and that it has always been volcanically active with a rich and diverse magmatic history. Meteorites have limitations, however, with lack of field context, restricted lithological diversity compared to the martian surface, and with no sampling of a major portion of Mars’ history between 4.1 and 2.4 billion years ago. Returned samples from Mars have the potential to fill these gaps and answer many open questions driven by the study of meteorites, as well as reveal new fundamental research questions. Key questions that Mars Sample Return is likely to answer regard the basic evolution of the martian interior and surface, its potential for habitability and the possibility of past life, and calibration of age dating of the martian surface. Samples of various lithologies and different ages collected at Jezero crater by the Perseverance rover will aid in better understanding our own planet and will answer outstanding questions regarding Mars’ future geological evolution and habitability.

Inhalable biohybrid microrobots: a non-invasive approach for lung treatment

Abstract Amidst the rising prevalence of respiratory diseases, the importance of effective lung treatment modalities is more critical than ever. However, current drug delivery systems face significant limitations that impede their efficacy and therapeutic outcome. Biohybrid microrobots have shown considerable promise for active in vivo drug delivery, especially for pulmonary applications via intratracheal routes. However, the invasive nature of intratracheal administration poses barriers to its clinical translation. Herein, we report on an efficient non-invasive inhalation-based method of delivering microrobots to the lungs. A nebulizer is employed to encapsulate picoeukaryote algae microrobots within small aerosol particles, enabling them to reach the lower respiratory tract. Post nebulization, the microrobots retain their motility (~55 μm s-1) to help achieve a homogeneous lung distribution and long-term retention exceeding five days in the lungs. Therapeutic efficacy is demonstrated in a mouse model of acute methicillin-resistant Staphylococcus aureus pneumonia using this pulmonary inhalation approach to deliver microrobots functionalized with platelet membrane-coated polymeric nanoparticles loaded with vancomycin. These promising findings underscore the benefits of inhalable biohybrid microrobots in a setting that does not require anesthesia, highlighting the substantial translational potential of this delivery system for routine clinical applications.

Proteomic, metabolomic and lipidomic profiles in community acquired pneumonia for differentiating viral and bacterial infections

Abstract Community-acquired pneumonia (CAP) has a significant impact on public health, especially in light of the recent SARS-CoV-2 pandemic. To enhance disease characterization and improve understanding of the underlying mechanisms, a comprehensive analysis of the plasma lipidome, metabolome and proteome was conducted in patients with viral and bacterial CAP infections, including those induced by SARS-CoV-2. Lipidomic, metabolomic and proteomic profiling were conducted on plasma samples of 69 patients suffering either from viral or bacterial CAP. Lipid and metabolite analyses were LC-MS-based, while proteomic analyses were performed using multiple panels of the Olink platform. Statistical methods, machine learning and pathway analyses were conducted investigating differences between the infection types. Through comparison of the bacterial and viral pathogen groups, distinct signatures were observed in the plasma profiles. Notably, linoleic acid-derived inflammation signaling metabolites (EpOME and DiHOME) were increased in viral CAP compared to bacterial CAP. Similarly, proteins involved in cellular immune response and apoptosis (LAG-3 and TRAIL) showed elevated levels in viral CAP, while bacterial CAP exhibited notable elevation in pattern-recognizing receptors (CLEC4D and EN-RAGE). Additionally, within the lipidomic profile at baseline, several lipids displayed notable differences between viral and bacterial pneumonia, including bile acids (GCA, TCA, TCDCA), various tri- and diglycerides (TGs and DGs), and several phosphatidylcholines (PCs). These findings hold promise for facilitating the differential diagnosis of viral and bacterial pulmonary infections based on the systemic lipidome, metabolome and proteome, enabling timely treatment decisions. Additionally, they highlight potential targets for drug research, advancing therapeutic interventions in CAP. By providing valuable insights into the molecular characterization of CAP, this study contributes to the improvement of understanding the disease and, ultimately, the development of effective treatment strategies.

Perspectives on Mars Sample Return: A critical resource for planetary science and exploration

Mars Sample Return (MSR) has been the highest flagship mission priority in the last two Planetary Decadal Surveys of the National Academies of Science, Engineering, and Medicine (hereafter, “the National Academies”) and was the highest priority flagship for Mars in the Decadal Survey that preceded them. This inspirational and challenging campaign, like the Apollo program’s returned lunar samples, will potentially revolutionize our understanding of Mars and help inform how other planets are explored. MSR’s technological advances will keep the NASA and European Space Agency at the forefront of planetary exploration, and data on returned samples will fill knowledge gaps for future human exploration. Investigations of the ancient rocks collected in and around Jezero crater, as well as samples of the regolith and atmosphere, will be fundamentally different in scope, depth, and certainty from what is achievable with spaceborne observations. Returned Mars samples can address critical science issues including the discovery and characterization of ancient extraterrestrial life, prebiotic organic chemistry, the history of habitable planetary environments, planetary geological, geochemical, and geophysical evolution, orbital dynamics of bodies in the early Solar System, and the formation and evolution of atmospheres.

Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling

Abstract Investigating the genetic factors influencing human birth weight may lead to biological insights into fetal growth and long-term health. We report analyses of rare variants that impact birth weight when carried by either fetus or mother, using whole exome sequencing data in up to 234,675 participants. Rare protein-truncating and deleterious missense variants are collapsed to perform gene burden tests. We identify 9 genes; 5 with fetal-only effects on birth weight, 1 with maternal-only effects, 3 with both, and observe directionally concordant associations in an independent sample. Four of the genes were previously implicated by GWAS of birth weight. IGF1R and PAPPA2 (fetal and maternal-acting) have known roles in insulin-like growth factor bioavailability and signalling. PPARG, INHBE and ACVR1C (fetal-acting) are involved in adipose tissue regulation, and the latter two also show associations with favourable adiposity patterns in adults. We highlight the dual role of PPARG (fetal-acting) in adipocyte differentiation and placental angiogenesis. NOS3 (fetal and maternal-acting) , NRK (fetal), and ADAMTS8 (maternal-acting) have been implicated in placental function and hypertension. To conclude, our analysis of rare coding variants identifies regulators of fetal adipose tissue and fetoplacental angiogenesis as determinants of birth weight, and further evidence for the role of insulin-like growth factors.

Variational graph autoencoder for reconstructed transcriptomic data associated with NLRP3 mediated pyroptosis in periodontitis

Systems immunology integrates the complex endotypes of recessive dystrophic epidermolysis bullosa

Abstract Endotypes are characterized by the immunological, inflammatory, metabolic, and remodelling pathways that explain the mechanisms underlying the clinical presentation (phenotype) of a disease. Recessive dystrophic epidermolysis bullosa (RDEB) is a severe blistering disease caused by COL7A1 pathogenic variants. Although underscored by animal studies, the endotypes of human RDEB are poorly understood. To fill this gap, we apply systems immunology approaches using single-cell high-dimensional techniques to capture the signature of peripheral immune cells and the diversity of metabolic profiles in RDEB adults, sampled outside of any opportunistic infection and active cancer. Our study, demonstrates the particular inflammation and immunity characteristics of RDEB adults, with activated / effector T and dysfunctional natural killer cell signatures, concomitant with an overall pro-inflammatory lipid signature. Artificial intelligence prediction models and principal component analysis stress that RDEB is not solely confined to cutaneous issues but has complex systemic endotypes marked by immune dysregulation and hyperinflammation. By characterising the phenotype-endotype association in RDEB adults, our study lays the groundwork for translational interventions that could by lessening inflammation, alleviate the everlasting suffering of RDEB patients, while awaiting curative genetic therapies.

Differentiation between multiple sclerosis and neuromyelitis optic spectrum disorders with multilevel fMRI features: A machine learning analysis

The scientific value of Mars Sample Return

Increased but not pristine soil organic carbon stocks in restored ecosystems

Deficits in reaching movements under visual interference as a novel diagnostic marker for mild cognitive impairment

Activation of three targets by a TAL effector confers susceptibility to bacterial blight of cotton

Propensity score matched cohort study on magnesium supplementation and mortality in critically ill patients with HFpEF

Distinct and interdependent functions of three RING proteins regulate recombination during mammalian meiosis

During meiosis, each pair of homologous chromosomes becomes connected by at least one crossover, as required for accurate segregation, and adjacent crossovers are widely separated thereby limiting total numbers. In coarsening models, this crossover patterning results from nascent recombination sites competing to accrue a limiting pro-crossover RING-domain protein (COR) that diffuses between synapsed chromosomes. Here, we delineate the localization dynamics of three mammalian CORs in the mouse and determine their interdependencies. RNF212, HEI10, and the newest member RNF212B show divergent spatiotemporal dynamics along synapsed chromosomes, including profound differences in spermatocytes and oocytes, that are not easily reconciled by elementary coarsening models. Contrasting mutant phenotypes and genetic requirements indicate that RNF212B, RNF212, and HEI10 play distinct but interdependent functions in regulating meiotic recombination and coordinating the events of meiotic prophase-I by integrating signals from DNA breaks, homolog synapsis, the cell-cycle, and incipient crossover sites.

Coordinated representations for naturalistic memory encoding and retrieval in hippocampal neural subspaces

Nationwide cohort study of primary open angle glaucoma risk and cardiovascular factors among in Korean glaucoma suspects

Organic matter and biomarkers: Why are samples required?

The search for evidence of past prebiotic or biotic activity on Mars will be enhanced by the return of samples to Earth laboratories. While impressive analytical feats have been accomplished by in situ missions on the red planet, accessing the capabilities of Earth’s global laboratories will present a step change in data acquisition. Highly diagnostic markers of past life are biomarkers, organic molecules whose architecture can be attributed to once living organisms. Similar organic molecular structures can also be used to identify the prebiotic steps that preceded any emergence of life. The style of modification or degradation of such organic structures indicates their agents of change, including oxidants, radiation, heating, water, and pressure. For biomarker analysis, sample return provides enhanced opportunities for sample preparation and analyte isolation. The augmentation of biomarker data with spatial information provides the opportunity for confirmatory data but is a multistep and multitechnique process best achieved here on Earth. Efficient use of returned samples will benefit from lessons learned on Earth’s ancient records and meteorites from Mars. The next decade is a time when analytical capabilities can be improved as we prepare for the delivery of carefully selected and collected extraterrestrial samples containing potential evidence of the development or even emergence of past life on Mars.

Principled neuromorphic reservoir computing

Abstract Reservoir computing advances the intriguing idea that a nonlinear recurrent neural circuit—the reservoir—can encode spatio-temporal input signals to enable efficient ways to perform tasks like classification or regression. However, recently the idea of a monolithic reservoir network that simultaneously buffers input signals and expands them into nonlinear features has been challenged. A representation scheme in which memory buffer and expansion into higher-order polynomial features can be configured separately has been shown to significantly outperform traditional reservoir computing in prediction of multivariate time-series. Here we propose a configurable neuromorphic representation scheme that provides competitive performance on prediction, but with significantly better scaling properties than directly materializing higher-order features as in prior work. Our approach combines the use of randomized representations from traditional reservoir computing with mathematical principles for approximating polynomial kernels via such representations. While the memory buffer can be realized with standard reservoir networks, computing higher-order features requires networks of ‘Sigma-Pi’ neurons, i.e., neurons that enable both summation as well as multiplication of inputs. Finally, we provide an implementation of the memory buffer and Sigma-Pi networks on Loihi 2, an existing neuromorphic hardware platform.