Main Signatures Research Articles

Patients with Alzheimer's disease have an increased removal rate of soluble beta-amyloid-42.

Senile plaques, which are mostly composed of beta-amyloid peptide, are the main signature of Alzheimer's disease (AD). Two main forms of beta-amyloid in humans are 40 and 42-amino acid, long; the latter is considered more relevant to AD etiology. The concentration of soluble beta-amyloid-42 (Aβ42) in cerebrospinal fluid (CSF-Aβ42) and the density of amyloid depositions have a strong negative correlation. However, AD patients have lower CSF-Aβ42 levels compared to individuals with normal cognition (NC), even after accounting for this correlation. The goal of this study was to infer deviations of Aβ42 metabolism parameters that underlie this difference using data from the Alzheimer's Disease Neuroimaging Initiative cohort. Aβ42 is released to the interstitial fluid (ISF) by cells and is removed by several processes. First, growth of insoluble fibrils by aggregation decreases the concentration of soluble beta-amyloid in the ISF. Second, Aβ42 is physically transferred from the brain to the CSF and removed with the CSF flow. Finally, there is an intratissue removal of Aβ42 ending in proteolysis, which can occur either in the ISF or inside the cells after the peptide is endocytosed. Unlike aggregation, which preserves the peptide in the brain, transfer to the CSF and intratissue proteolysis together represent amyloid removal. Using a kinetic model of Aβ42 turnover, we found that compared to NC subjects, AD patients had dramatically increased rates of amyloid removal. A group with late-onset mild cognitive impairment (LMCI) also exhibited a higher rate of amyloid removal; however, this was less pronounced than in the AD group. Estimated parameters in the early-onset MCI group did not differ significantly from those in the NC group. We hypothesize that increased amyloid removal is mediated by Aβ42 cellular uptake; this is because CSF flow is not increased in AD patients, while most proteases are intracellular. Aβ cytotoxicity depends on both the amount of beta-amyloid internalized by cells and its intracellular conversion into toxic products. We speculate that AD and LMCI are associated with increased cellular amyloid uptake, which leads to faster disease progression. The early-onset MCI (EMCI) patients do not differ from the NC participants in terms of cellular amyloid uptake. Therefore, EMCI may be mediated by the increased production of toxic amyloid metabolites.

Evaluation of the thermal contrast of low-temperature ground-based objects

Subject of study. The thermal contrast of low-temperature passive terrain objects is the difference in radiant temperatures of an object and background in operating spectral regions of air- and ground-based thermal imaging devices for surveillance. Aim of study. The study attempted to provide the designers of thermal imaging devices with initial data for signature features of ground-based objects. Method. The study employed a theoretical analysis on the physical dependences of the formation of thermal contrast in ground-based objects using the previously published model of thermal radiation of the atmosphere, which, in addition to temperature contrast owing to the different thermal inertias of the object and background upon alterations in meteorological conditions, considers the optical properties of the object, solar and environmental (of the Earth’s surface and atmosphere) radiation reflected from the object, and viewing direction of three-dimensional objects. Main results. A methodological approach and corresponding mathematical model were proposed for the quick engineering evaluation of the main signature feature of low-temperature ground-based objects, particularly vehicles surveilled using thermal imaging devices from the upper hemisphere against the background of the Earth’s surface at different cloud coverage, i.e., their thermal contrast in the spectral regions of 3–5 and 8–12 µm corresponding to the atmospheric windows. Accordingly, we presented the analytical expressions for this evaluation considering environmental thermal radiation, direct and scattered solar radiation reflected by the diffuse spherical surface imitating the surveilled object, and its viewing direction. The possibility of thermal contrast variation in the rather wide range and its inversion was demonstrated even for a fixed temperature contrast. An example of a practical application of the proposed model was considered. Practical significance. The developed engineering method for calculating the thermal contrast of ground-based objects can be applied to quickly estimate effectiveness, including the operating range of air- and ground-based thermal imaging devices, and validate the requirements on the main technical parameters of prospective devices of this type.

Genomic landscape of multiple Bowen's disease using whole-exome sequencing.

The genomic landscape of Bowen's disease (BD), with multiple manifestations, has not yet been determined. This study aimed to investigate the genomic alterations in multiple BD. We performed whole-exome sequencing of BD lesions (n=9) and matched germlines collected from three patients with multiple (≥3) BD to detect somatic and germline mutations. We found a median of 64 somatic mutations in each sample (range 20-267). UV-signature mutations accounted for 64.9% (median, range 26.0%-82.1%) of point mutations. Putative driver mutations were found in five BDs (RB1 p.R445*, ARID2 p.R274*, TP53 p.Y163D/p.Y205D/p.R342*, KMT2C p.R4549C) but not in the other four lesions. Somatic mutations were not shared between multiple BD lesions collected from the same patient, indicating a different clonal origin. We also found no known pathogenic germline mutations in cancer-related genes. The mutational signature analysis revealed that UV signatures (SBS7a/7b) and age-related signatures (SBS1/5) were the main active signatures. Copy number alterations (CNAs) were found in two BDs: one with extensive CNA regions (21.7% of the genome), including driver genes (PIK3CA/SOX2/TP63 and MYC gain, and CDKN2A loss), and the other with 1q gain. Our study revealed that multiple BD lesions harbor distinct genomic landscapes, suggesting that they have different risks of malignant progression.

Geochemical characteristics of gases associated with natural gas hydrate

With more natural gas hydrate samples recovered and more research approaches applied to hydrate-associated gas studies, data concerning the geochemical characteristics of hydrate-associated gases have been increased significantly in the past decades. Although systematic reviews of hydrocarbons are available, fewer studies have focused on the systematic classification of gas hydrates, yet. In this study, the primary origins and secondary processes that affect the geochemical characteristics of the gases are discussed. The primary origins are affected mainly by the type and /or maturity of the organic matter, which determine the main signature of the gas is microbial gas or thermogenic gas in a broad scheme. Apart from primary origins, secondary processes after gas generation such as migration, mixing, biodegradation and oxidation occur during the migration and/or storage of gases can significantly alter their primary features. Traditional methods such as stable isotope and molecular ratios are basic proxies, which have been widely adopted to identify these primary origins and secondary processes. Isotopic compositions of C2+ gases have been employed to identify the precursor of the gases or source rocks in recent years. Data from novel techniques such as methane clumped isotope and noble gases bring additional insights into the gas origins and sources by providing information about the formation temperature of methane or proxies of mantle contribution. A combination of these multiple geochemical approaches can help to elucidate an accurate delineation of the generation and accumulation processes of gases in a gas hydrate reservoir.

A Raman spectroscopy–compositional–structural investigation of lunar surface materials and analogues

AbstractWe investigated the Raman spectroscopy of 35 rock and mineral samples of composition relevant to the lunar surface: pyroxenes, olivine, plagioclase feldspars and oxides. The Raman spectra were analysed in the context of their compositional and structural properties to develop robust correlations to enable their detection on the lunar surface by Raman spectroscopy. We developed and implemented a spectral deconvolution program to model the fluorescence background and various Raman peaks to extract their positions in wavenumber space. Relations were developed between the Raman peak positions of pyroxenes around 325, 670 and 1000 cm−1 with their compositions in terms of enstatite, ferrosilite and wollastonite components. For olivines, we verified previously determined correlations between the positions of the olivine‐related peak doublet between 800 and 880 cm−1 with forsterite content. We also discuss the main signatures detected in the Raman spectra of plagioclases and oxides. The derived relationships were examined using Raman spectra of the matrix and several inclusions of the lunar meteorite NWA12593. We were able to identify the main endmembers of the selected surface spots as pyroxenes, plagioclase feldspars and olivine. We used the previous correlations to separate orthopyroxene from clinopyroxene signatures and to propose a composition of the inclusions of the meteorite. The results of this study demonstrate the utility of Raman spectroscopy for determining the mineralogy of the lunar surface.

Impaired Amino Acid Metabolism and Its Correlation with Diabetic Kidney Disease Progression in Type 2 Diabetes Mellitus.

Background: Metabolomics is useful in elucidating the progression of diabetes; however, the follow-up changes in metabolomics among health, diabetes mellitus, and diabetic kidney disease (DKD) have not been reported. This study was aimed to reveal metabolomic signatures in diabetes development and progression. Methods: In this cross-sectional study, we compared healthy (n = 30), type 2 diabetes mellitus (T2DM) (n = 30), and DKD (n = 30) subjects with the goal of identifying gradual altering metabolites. Then, a prospective study was performed in T2DM patients to evaluate these altered metabolites in the onset of DKD. Logistic regression was conducted to predict rapid eGFR decline in T2DM subjects using altered metabolites. The prospective association of metabolites with the risk of developing DKD was examined using logistic regression and restricted cubic spline regression models. Results: In this cross-sectional study, impaired amino acid metabolism was the main metabolic signature in the onset and development of diabetes, which was characterized by increased N-acetylaspartic acid, L-valine, isoleucine, asparagine, betaine, and L-methionine levels in both the T2DM and DKD groups. These candidate metabolites could distinguish the DKD group from the T2DM group. In the follow-up study, higher baseline levels of L-valine and isoleucine were significantly associated with an increased risk of rapid eGFR decline in T2DM patients. Of these, L-valine and isoleucine were independent risk factors for the development of DKD. Notably, nonlinear associations were also observed for higher baseline levels of L-valine and isoleucine, with an increased risk of DKD among patients with T2DM. Conclusion: Amino acid metabolism was disturbed in diabetes, and N-acetylaspartic acid, L-valine, isoleucine, asparagine, betaine, and L-methionine could be biomarkers for the onset and progression of diabetes. Furthermore, high levels of L-valine and isoleucine may be risk factors for DKD development.

Scoring personalized molecular portraits identify Systemic Lupus Erythematosus subtypes and predict individualized drug responses, symptomatology and disease progression.

ObjectivesSystemic Lupus Erythematosus is a complex autoimmune disease that leads to significant worsening of quality of life and mortality. Flares appear unpredictably during the disease course and therapies used are often only partially effective. These challenges are mainly due to the molecular heterogeneity of the disease, and in this context, personalized medicine-based approaches offer major promise. With this work we intended to advance in that direction by developing MyPROSLE, an omic-based analytical workflow for measuring the molecular portrait of individual patients to support clinicians in their therapeutic decisions.MethodsImmunological gene-modules were used to represent the transcriptome of the patients. A dysregulation score for each gene-module was calculated at the patient level based on averaged z-scores. Almost 6100 Lupus and 750 healthy samples were used to analyze the association among dysregulation scores, clinical manifestations, prognosis, flare and remission events and response to Tabalumab. Machine learning-based classification models were built to predict around 100 different clinical parameters based on personalized dysregulation scores.ResultsMyPROSLE allows to molecularly summarize patients in 206 gene-modules, clustered into nine main lupus signatures. The combination of these modules revealed highly differentiated pathological mechanisms. We found that the dysregulation of certain gene-modules is strongly associated with specific clinical manifestations, the occurrence of relapses or the presence of long-term remission and drug response. Therefore, MyPROSLE may be used to accurately predict these clinical outcomes.ConclusionsMyPROSLE (https://myprosle.genyo.es) allows molecular characterization of individual Lupus patients and it extracts key molecular information to support more precise therapeutic decisions.

Aspartic Acid-Modified Phospholipids Regulate Cell Response and Rescue Memory Deficits in APP/PS1 Transgenic Mice.

Misfolding and accumulation of amyloid-β (Aβ) to form senile plaques are the main neuropathological signatures of Alzheimer's disease (AD). Decreasing Aβ production, inhibiting Aβ aggregation, and clearing Aβ plaques are thus considered an important strategy for AD treatment. However, numerous drugs cannot enter the AD clinical trials due to unsatisfactory biocompatibility, poor blood-brain barrier penetration, little biomarker impact, and/or low therapeutic indicators. Here, a pair of chiral aspartic acid-modified 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (l- and d-Asp-DPPE) are prepared to build stabilized chiral liposomes. We find that both l- and d-liposomes are able to rescue Aβ aggregation-induced apoptosis, oxidative stress, and calcium homeostasis, in which the effect of d-liposomes is more obvious than that of l-ones. Furthermore, in AD model mice (APPswe/PS1d9 double-transgenic mice), chiral liposomes not only show biosafety but also strongly improve cognitive deficits and reduce Aβ deposition in the brain. Our results suggest that chiral liposomes, particularly, d-liposomes, could be a potential therapeutic approach for AD treatment. This study opens new horizons by showing that liposomes will be used for drug development in addition to delivery and targeting functions.

Microvascular and proteomic signatures overlap in COVID-19 and bacterial sepsis: the MICROCODE study

AimsAlthough coronavirus disease 2019 (COVID-19) and bacterial sepsis are distinct conditions, both are known to trigger endothelial dysfunction with corresponding microcirculatory impairment. The purpose of this study was to compare microvascular injury patterns and proteomic signatures in COVID-19 and bacterial sepsis patients.Methods and resultsThis multi-center, observational study included 22 hospitalized adult COVID-19 patients, 43 hospitalized bacterial sepsis patients, and 10 healthy controls from 4 hospitals. Microcirculation and glycocalyx dimensions were quantified via intravital sublingual microscopy. Plasma proteins were measured using targeted proteomics (Olink). Coregulation and cluster analysis of plasma proteins was performed using a training-set and confirmed in a test-set. An independent external cohort of 219 COVID-19 patients was used for validation and outcome analysis. Microcirculation and plasma proteome analysis found substantial overlap between COVID-19 and bacterial sepsis. Severity, but not disease entity explained most data variation. Unsupervised correlation analysis identified two main coregulated plasma protein signatures in both diseases that strictly counteract each other. They were associated with microvascular dysfunction and several established markers of clinical severity. The signatures were used to derive new composite biomarkers of microvascular injury that allow to predict 28-day mortality or/and intubation (area under the curve 0.90, p < 0.0001) in COVID-19.ConclusionOur data imply a common biological host response of microvascular injury in both bacterial sepsis and COVID-19. A distinct plasma signature correlates with endothelial health and improved outcomes, while a counteracting response is associated with glycocalyx breakdown and high mortality. Microvascular health biomarkers are powerful predictors of clinical outcomes.Graphical abstract

UNIPROT DATABASE - UNIVERSAL INFORMATION RESOURCE OF PROTEIN SEQUENCES

Protein sequences are stored in public databases such as the UniProt Knowledgebase (UniProtKB), where curators add bioinformatics data, including prediction of structure and function of biomolecules and experimental results. Protein function prediction can be done using sequence similarity searches, but an alternative approach is to use protein signatures that classify proteins into families and domains. The main protein signature databases are accessible through the integrated InterPro database, which provides the UniProtKB sequence classification. In addition to characterizing proteins through protein families, many researchers are interested in analyzing the complete set of proteins from the genome (i.e., the proteome), and there are databases and resources providing unreduced sets of proteomes and analyzes of proteins from organisms with fully sequenced genomes. This article reviews the tools and resources available on the Internet for characterizing both individual proteins and analysis of the entire proteome.

Insights into the Devonian–Carboniferous transition and Hangenberg Event from δ13Ccarb and 87Sr/86Sr chemostratigraphy of shallow platform carbonate strata of northwestern Colorado

ABSTRACTPaired chemostratigraphic and biostratigraphic data suggest that the Devonian–Carboniferous boundary and the Hangenberg extinction event are recorded in the Coffee Pot Member of the Dyer Formation of the White River uplift region of northwestern Colorado. The Hangenberg isotopic excursion interval occurs in biostratigraphically depauperate shallow platform micritic dolostone and limestone representing the aculeatus–?ultimus–kockeli? Zone. The Hangenberg interval strata have δ13Ccarb values up to 7.69‰, and locally contain ooids, stromatolites, and other microbial structures. In three sections, there is a short-lived &amp;gt; 4‰ “pre-Hangenberg” positive excursion that is associated with the presence of detrital dolomite siltstone. The main Hangenberg isotopic signature exists in overlying strata, and is replicated in four different sections of the Dyer Formation across an area ~300 km2. In each section, the excursion interval is preceded by, and in one location is interrupted by, evidence of meteoric diagenesis and/or emergence characterized by macroscopic dissolution features and pronounced negative δ13Ccarb values (to ca. -6‰). Conodont 87Sr/86Sr ratios through the Dyer Formation dip to nearly 0.708 during the onset of the Hangenberg Event, consistent with the brachiopod based 87Sr/86Sr nadir from the same interval in Missouri, France, and Germany. The least-radiogenic trendline through the Dyer 87Sr/86Sr record matches the global minimum 87Sr/86Sr trendline through the Famennian–Tournaisian transition and infills several gaps in the global record.

A benchmark activity on the fatigue life assessment of AlSi10Mg components manufactured by L-PBF

One of the challenges associated with additive manufacturing (AM) is the definition of an assessment route which considers the main process signatures of the AM process. To this end, this work presents a complete benchmark activity for the assessment of an AlSi10Mg component produced by a laser powder bed fusion process, aimed at advancing the understanding of the fatigue resistance of AM materials with particular focus on the comparison between the fatigue performances of small coupons and demonstrators. Four builds of AlSi10Mg specimen geometries were manufactured to: (i) determine the fatigue curves for both as-built and machined conditions; (ii) measure the fatigue crack growth rate; (iii) produce and test under fatigue a benchmark component used as a reference for the validation of the fatigue assessment procedure. Tools and concepts of flaw tolerance were then used to perform the fatigue assessment of the benchmark component and were shown to be successful in the life prediction. Results obtained from this wide database (related to internal defects and surface features) show that only a fracture-based fatigue assessment is able to provide precise life estimates consistent with material crack growth properties. Eventually, all the experimental results including specimens design, analysis of fracture surfaces and raw tests’ data will be made available in a database which can be accessed and used by the industrial and scientific communities to calibrate and validate alternative fatigue assessment procedures of AM parts.

Systematic evaluation of colorectal cancer organoid system by single-cell RNA-Seq analysis

BackgroundPatient-derived organoid culture is a powerful system for studying the molecular mechanisms of cancers, especially colorectal cancer (CRC), one of the most prevalent cancers worldwide. There are two main types of 3D culture methods for colonic cells, but the similarities and differences between gene expression patterns in different culture media remain largely unexplored.ResultsHere, we establish patient-derived organoids from colorectal cancer patients and perform single-cell RNA-Seq for pairwise samples from seven patients for both organoids and their corresponding tumor and normal tissues in vivo. We find that organoids derived from tumor tissues faithfully recapitulate the main gene expression signatures of cancer cells in vivo. On the other hand, organoids derived from normal tissues exhibited some tumor-like features at the whole transcriptome level but retained normal genomic features, such as CNVs, point mutations, and normal global DNA methylation levels, for both cultural media. More importantly, we show that conditioned medium outperforms chemical-defined medium in long-term culture of tumor epithelial cells. Finally, we mutually exchange the culture medium for the organoids and find that after interchanging the medium, the organoid cells basically maintain the transcriptome characteristics of the original medium.ConclusionsOur work gives a thorough evaluation of both the cultural conditions and the biological features of organoids of CRC patients.

A persistent ultraviolet outflow from an accreting neutron star binary transient.

All disc-accreting astrophysical objects produce powerful disc winds. In compact binaries containing neutron stars or black holes, accretion often takes place during violent outbursts. The main disc wind signatures during these eruptions are blue-shifted X-ray absorption lines, which are preferentially seen in disc-dominated 'soft states'1,2. By contrast, optical wind-formed lines have recently been detected in 'hard states', when a hot corona dominates the luminosity3. The relationship between these signatures is unknown, and no erupting system has as yet revealed wind-formed lines between the X-ray and optical bands, despite the many strong resonance transitions in this ultraviolet (UV) region4. Here we report that the transient neutron star binary Swift J1858.6-0814 exhibits wind-formed, blue-shifted absorption linesassociated with C IV, N Vand He IIin time-resolved UV spectroscopy during a luminous hard state, which we interpret as a warm, moderately ionized outflow component in this state. Simultaneously observed optical lines also display transient blue-shifted absorption. Decomposing the UV data into constant and variable components, the blue-shifted absorption is associated with the former. This implies that the outflow is not associated with the luminous flares in the data. The joint presence of UV and optical wind features reveals a multi-phase and/or spatially stratified evaporative outflow from the outer disc5. This type of persistent mass loss across all accretion states has been predicted by radiation-hydrodynamic simulations6 and helps to explain the shorter-than-expected duration of outbursts7.

Folic acid and sodium folate salts: Thermal behavior and spectroscopic (IR, Raman, and solid-state 13C NMR) characterization

Folic acid (FA; vitamin B9) and its associated sodium salts, strongly relevant for many scientific and technological applications - from nutrition to pharmacology and nanomedicine, suffer from a lack of characterization combining experimental and theoretical. In this work, a spectroscopic investigation of FA and its synthesized sodium salts in the form of dianion (Na2HFol) or trianion (Na3Fol) was scrutinized in their solid state. The spectroscopic (infrared, Raman, and solid state 13C-nuclear magnetic resonance) data interpretation was supported by theoretical calculations using the Density Functional Theory (DFT). Additionally, the compounds were characterized by UV–VIS diffuse-reflectance spectroscopy, combined thermal analysis (TG/DTG-DSC) coupled to mass spectrometry, and X-ray diffractometry. The main signatures of each species were identified, as well as the influence of the protonation level on their physicochemical properties. These distinct properties for the three compounds are mainly based on signals assigned to glutamic acid (glutamate) and pterin (neutral or anionic) moieties. This work should help developing new products based on FA or its anionic forms, such as theragnostic/drug delivery systems, supramolecular structures, nanocarbons, or metal complexes.

Analytic modeling of recurrent Forbush decreases caused by corotating interaction regions

Context.On scales of days, the galactic cosmic ray (GCR) flux is affected by coronal mass ejections and corotating interaction regions (CIRs), causing so-called Forbush decreases and recurrent Forbush decreases (RFDs), respectively.Aims.We explain the properties and behavior of RFDs recorded at about 1 au that are caused by CIRs generated by solar wind high-speed streams (HSSs) that emanate from coronal holes.Methods.We employed a convection-diffusion GCR propagation model based on the Fokker-Planck equation and applied it to solar wind and interplanetary magnetic field properties at 1 au.Results.Our analysis shows that the only two effects that are relevant for a plausible overall explanation of the observations are the enhanced convection effect caused by the increased velocity of the HSS and the reduced diffusion effect caused by the enhanced magnetic field and its fluctuations within the CIR and HSS structure. These two effects that we considered in the model are sufficient to explain not only the main signatures of RFDs, but also the sometimes observed “over-recovery” and secondary dips in RFD profiles. The explanation in terms of the convection-diffusion GCR propagation hypothesis is tested by applying our model to the observations of a long-lived CIR that recurred over 27 rotations in 2007–2008.Conclusions.Our analysis demonstrates a very good match of the model results and observations.

Xenoliths Evidence of Alkaline Magmatic Infiltrations Beneath Lake Nyos (Cameroon Volcanic Line, West Africa)

Xenoliths enclosed in Lavas of the Nyos volcano (Cameroon Volcanic Line, continental sector) range from fertile lherzolites to harzburgites. One spinel-free wehrlite has been also sampled. The occurrence of phlogopites and pargasites in some harzburgites together with specific textural rock-type (lherzolites transitional porphyroclastic to equigranular), including major and trace element compositions both in peridotites bulk rocks and minerals point out interactions between the mantle and basaltic magmas responsible for the formation of wehrlites beneath the Nyos volcano. Hydrous minerals (phlogopites and pargasites) and metasomatic events are their main petrogeochemical signatures different from group 1 samples which are characterized by spoon-shaped REE patterns. Later on, hydrous phases, Ti-rich Cpx, CaO rich Ol, Ti, and V rich Ol wehrlite precipitated from melt enrichments due to the percolation of the mantle by basaltic magmas of alkaline affinity. The metasomatic liquid which percolates the Nyos mantle column was a dense alkaline silicate rich in volatile, displaying low HFSE abundances in the metasomatic hydrous melts compared to the LILE. It is suggested that Nyos mantle peridotites have experienced: 1) variable metasomatic events related to the percolating of the depleted mantle by a alkaline silicate liquid, 2) the spinel-free wehrlite is a group 2 sample corresponding to a cumulate of a similar melt, 3) amphibole may be a potassium-bearing mineral instead of or in addition to phlogopite at shallower levels of Nyos upper mantle and 4) transitional textural rock facies express also the fingerprint of rising mantle plume which were percolated by alkaline magma during their transit to the surface.

Gene-environment-gut interactions in Huntington's disease mice are associated with environmental modulation of the gut microbiome

SummaryGut dysbiosis in Huntington's disease (HD) has recently been reported using microbiome profiling in R6/1 HD mice and replicated in clinical HD. In HD mice, environmental enrichment (EE) and exercise (EX) were shown to have therapeutic impacts on the brain and associated symptoms. We hypothesize that these housing interventions modulate the gut microbiome, configuring one of the mechanisms that mediate their therapeutic effects observed in HD. We exposed R6/1 mice to a protocol of either EE or EX, relative to standard-housed control conditions, before the onset of gut dysbiosis and motor deficits. We characterized gut structure and function, as well as gut microbiome profiling using 16S rRNA sequencing. Multivariate analysis identified specific orders, namely Bacteroidales, Lachnospirales and Oscillospirales, as the main bacterial signatures that discriminate between housing conditions. Our findings suggest a promising role for the gut microbiome in mediating the effects of EE and EX exposures, and possibly other environmental interventions, in HD mice.

Applications of Machine Learning in Process Monitoring and Controls of L-PBF Additive Manufacturing: A Review

One of the main issues hindering the adoption of parts produced using laser powder bed fusion (L-PBF) in safety-critical applications is the inconsistencies in quality levels. Furthermore, the complicated nature of the L-PBF process makes optimizing process parameters to reduce these defects experimentally challenging and computationally expensive. To address this issue, sensor-based monitoring of the L-PBF process has gained increasing attention in recent years. Moreover, integrating machine learning (ML) techniques to analyze the collected sensor data has significantly improved the defect detection process aiming to apply online control. This article provides a comprehensive review of the latest applications of ML for in situ monitoring and control of the L-PBF process. First, the main L-PBF process signatures are described, and the suitable sensor and specifications that can monitor each signature are reviewed. Next, the most common ML learning approaches and algorithms employed in L-PBFs are summarized. Then, an extensive comparison of the different ML algorithms used for defect detection in the L-PBF process is presented. The article then describes the ultimate goal of applying ML algorithms for in situ sensors, which is closing the loop and taking online corrective actions. Finally, some current challenges and ideas for future work are also described to provide a perspective on the future directions for research dealing with using ML applications for defect detection and control for the L-PBF processes.

Molecular Evolution of Classical Hodgkin Lymphoma Revealed Though Whole Genome Sequencing of Hodgkin and Reed-Sternberg Cells

Introduction: Classical Hodgkin lymphoma (cHL) is characterized by a small fraction of Hodgkin and Reed-Sternberg (HRS) tumor cells (~1%) which are surrounded by an extensive immune infiltrate. The rare nature of HRS cells limits the ability to study the genomics of cHL using standard platforms. To circumvent this, our group has optimized fluorescence-activated cell sorting to isolate HRS cells and intratumor B- and T- cells and to perform whole exome sequencing (WES; Reichel, Blood 2015). To date, however, there have been no reports on whole genome sequencing (WGS) of cHL.Methods: We performed flow-sorting of HRS cells and WGS to define the genomic landscape of cHL including: i) mutational processes involved in pathogenesis, ii) large and focal copy number variants, iii) structural variants including complex events, iv) the sequence and evolution of molecular events in cHL. We interrogated WGS from 25 cases of cHL: 10 pediatric patients (age<18), 9 adolescents and young adults (AYA, age 18-40), and 6 older adults (age>40). Intra-tumoral T-cells were used as germline control. An additional 36 cHL cases were evaluated by WES.Results: The average depth of coverage among the 25 WGS cases was 27.5x. After having identified and removed amplification-based palindromic sequencing artifacts, we observed a median of 5006 single base substitutions (SBS; range 1763-18436). Pediatric and AYA patients had a higher SBS burden compared to older adults (median 5279 vs. 2945, p=0.009). Five main SBS signatures were identified: SBS1 and SBS5 (aging), SBS2 and SBS13 (APOBEC), and SBS25 (chemotherapy, in a relapsed case). A dNdScv driver discovery analysis performed on the combined WES and WGS cases identified 24 driver genes including BCL7A and CISH which had not been previously reported as drivers in cHL.An investigation of copy number alterations (CNAs) confirmed high ploidy in cHL (median 2.95, range 1.66-5.33). Whole genome duplication was identified in 64% cases. We also observed clear evidence of complex events such as chromothripsis (n=4), double minutes (dm, n=2), breakage-fusion-bridge (bfb; n=4). Some of these events were responsible for the acquisition of distinct drivers. For example, we observed one dm and one bfb responsible for CD274 and REL gains, respectively (>10 copies).Leveraging the high prevalence of large chromosomal gains, we performed an investigation of the relative timing of acquisition of driver mutations. Clonal mutations within chromosomal gains can be defined as duplicated (VAF~66%; acquired before the gain) or non-duplicated (VAF~33%; acquired before or after the gain). Sixty-one percent (152/249) of driver genes were duplicated suggesting that they were acquired prior to large chromosomal gains. Next, we used the corrected ratio between duplicated and non-duplicated mutations within large chromosomal gains to estimate the molecular time of each duplicated segment (Rustad, Nat Comm 2020). In 11/22 genomes the final CNA profile was acquired through at least two temporally distinct events. To convert these relative estimations into absolute timing (i.e., the age at which events occurred), we leveraged the clock-like mutation signatures (SBS1, SBS5). We first confirmed that the SBS1 and SBS5 mutation rate were constant over time (R 2=0.84; p<0.0001 in Peds/AYA; R 2 =0.82; p=0.002 in older adults). We observed a higher mutation rate in Pediatric/AYA cases compared to older adults (p=0.01), which is consistent with the higher mutational burden observed in this age group. By estimating the SBS1- and SBS5-based molecular time for large chromosomal gains and converting relative estimates to absolute time, we are able to estimate the age in years at the time of the first multi-chromosomal gain event. We observed that the first multi-chromosomal gain in cHL is often acquired several years before the diagnosis/sample collection: median latency of 19.5 (range 12-27) and 5.6 (range 1.8-16) years in older adults and pediatric/AYA patients respectively.Conclusion: Here we report the first WGS in cHL. We identify novel drivers and genomic mechanisms involved in cHL pathogenesis. We found that mutations in driver genes are often acquired earlier then chromosomal gains, potentially preceding the cHL diagnosis by several years. In addition, we observed key differences in biology of cHL across age groups including accelerated mutagenesis and increased mutational burden among younger patients. DisclosuresMaura: OncLive: Honoraria; Medscape: Consultancy, Honoraria. Oberley: Caris LIfe Science: Current Employment. Lim: EUSA Pharma: Honoraria. Landgren: Janssen: Other: IDMC; Celgene: Research Funding; Janssen: Honoraria; Amgen: Honoraria; Janssen: Research Funding; Amgen: Research Funding; Takeda: Other: IDMC; GSK: Honoraria. Moskowitz: Merck & Co., Inc.: Research Funding. Roshal: Celgene: Other: Provision of services; Auron Therapeutics: Other: Ownership / Equity interests; Provision of services; Physicians' Education Resource: Other: Provision of services. Elemento: Owkin: Consultancy, Other: Current equity holder; AstraZeneca: Research Funding; Champions Oncology: Consultancy; Volastra Therapeutics: Consultancy, Other: Current equity holder, Research Funding; One Three Biotech: Consultancy, Other: Current equity holder; Eli Lilly: Research Funding; Johnson and Johnson: Research Funding; Freenome: Consultancy, Other: Current equity holder in a privately-held company; Janssen: Research Funding. Roth: Janssen: Consultancy; Merck: Consultancy.