Comparative single-cell genomics of Atribacterota JS1 in the Japan Trench hadal sedimentary biosphere.

Deep-sea and subseafloor sedimentary environments host heterotrophic microbial communities that contribute to Earth's carbon cycling. However, the potential metabolic functions of individual microorganisms and their biogeographical distributions in hadal ocean sediments remain largely unexplored. In this study, we conducted single-cell genome sequencing on sediment samples collected from six sites (7,445-8,023 m water depth) along an approximately 500 km transect of the Japan Trench during the International Ocean Discovery Program Expedition 386. A total of 1,886 single-cell amplified genomes (SAGs) were obtained, offering comprehensive genetic insights into sedimentary microbial communities in surface sediments (<1 m depth) above the sulfate-methane transition zone along the Japan Trench. Our genome data set included 269 SAGs from Atribacterota JS1, the predominant bacterial clade in these hadal environments. Phylogenetic analysis classified SAGs into nine distinct phylotypes, whereas metagenome-assembled genomes were categorized into only two phylotypes, advancing JS1 diversity coverage through a single cell-based approach. Comparative genomic analysis of JS1 lineages from different habitats revealed frequent detection of genes related to organic carbon utilization, such as extracellular enzymes like clostripain and α-amylase, and ABC transporters of oligopeptide from Japan Trench members. Furthermore, specific JS1 phylotypes exhibited a strong correlation with in situ methane concentrations and contained genes involved in glycine betaine metabolism. These findings suggest that the phylogenomically diverse and novel Atribacterota JS1 is widely distributed in Japan Trench sediment, playing crucial roles in carbon cycling within the hadal sedimentary biosphere.IMPORTANCEThe Japan Trench represents tectonically active hadal environments associated with Pacific plate subduction beneath the northeastern Japan arc. This study, for the first time, documented a large-scale single-cell and metagenomic survey along an approximately 500 km transect of the Japan Trench, obtaining high-quality genomic information on hadal sedimentary microbial communities. Single-cell genomics revealed the predominance of diverse JS1 lineages not recoverable through conventional metagenomic binning. Their metabolic potential includes genes related to the degradation of organic matter, which contributes to methanogenesis in the deeper layers. Our findings enhance understanding of sedimentary microbial communities at water depths exceeding 7,000 m and provide new insights into the ecological role of biogeochemical carbon cycling in the hadal sedimentary biosphere.

Single-cell gene set scoring with nearest neighbor graph smoothed data (gssnng).

Summary: Gene set scoring (or enrichment) is a common dimension reduction task in bioinformatics that can be focused on the differences between groups or at the single sample level. Gene sets can represent biological functions, molecular pathways, cell identities, and more. Gene set scores are context dependent values that are useful for interpreting biological changes following experiments or perturbations. Single sample scoring produces a set of scores, one for each member of a group, which can be analyzed with statistical models that can include additional clinically important factors such as gender or age. However, the sparsity and technical noise of single-cell expression measures create difficulties for these methods, which were originally designed for bulk expression profiling (microarrays, RNAseq). This can be greatly remedied by first applying a smoothing transformation that shares gene measure information within transcriptomic neighborhoods. In this work, we use the nearest neighbor graph of cells for matrix smoothing to produce high quality gene set scores on a per-cell, per-group, level which is useful for visualization and statistical analysis. Availability and implementation: The gssnng software is available using the python package index (PyPI) and works with Scanpy AnnData objects. It can be installed using "pip install gssnng." More information and demo notebooks: see https://github.com/IlyaLab/gssnng.

Earthquake-enhanced dissolved carbon cycles in ultra-deep ocean sediments.

Hadal trenches are unique geological and ecological systems located along subduction zones. Earthquake-triggered turbidites act as efficient transport pathways of organic carbon (OC), yet remineralization and transformation of OC in these systems are not comprehensively understood. Here we measure concentrations and stable- and radiocarbon isotope signatures of dissolved organic and inorganic carbon (DOC, DIC) in the subsurface sediment interstitial water along the Japan Trench axis collected during the IODP Expedition 386. We find accumulation and aging of DOC and DIC in the subsurface sediments, which we interpret as enhanced production of labile dissolved carbon owing to earthquake-triggered turbidites, which supports intensive microbial methanogenesis in the trench sediments. The residual dissolved carbon accumulates in deep subsurface sediments and may continue to fuel the deep biosphere. Tectonic events can therefore enhance carbon accumulation and stimulate carbon transformation in plate convergent trench systems, which may accelerate carbon export into the subduction zones.

Concerted epithelial and stromal changes during progression of Barrett's Esophagus to invasive adenocarcinoma exposed by multi-scale, multi-omics analysis.

Esophageal adenocarcinoma arises from Barrett's esophagus, a precancerous metaplastic replacement of squamous by columnar epithelium in response to chronic inflammation. Multi-omics profiling, integrating single-cell transcriptomics, extracellular matrix proteomics, tissue-mechanics and spatial proteomics of 64 samples from 12 patients' paths of progression from squamous epithelium through metaplasia, dysplasia to adenocarcinoma, revealed shared and patient-specific progression characteristics. The classic metaplastic replacement of epithelial cells was paralleled by metaplastic changes in stromal cells, ECM and tissue stiffness. Strikingly, this change in tissue state at metaplasia was already accompanied by appearance of fibroblasts with characteristics of carcinoma-associated fibroblasts and of an NK cell-associated immunosuppressive microenvironment. Thus, Barrett's esophagus progresses as a coordinated multi-component system, supporting treatment paradigms that go beyond targeting cancerous cells to incorporating stromal reprogramming.

Apposition of Fibroblasts With Metaplastic Gastric Cells Promotes Dysplastic Transition.

BACKGROUND & AIMS: Elements of field cancerization, including atrophic gastritis, metaplasia, and dysplasia, promote gastric cancer development in association with chronic inflammation. However, it remains unclear how stroma changes during carcinogenesis and how the stroma contributes to progression of gastric preneoplasia. Here we investigated heterogeneity of fibroblasts, one of the most important elements in the stroma, and their roles in neoplastic transformation of metaplasia. METHODS: We used single-cell transcriptomics to evaluate the cellular heterogeneity of mucosal cells from patients with gastric cancer. Tissue sections from the same cohort and tissue microarrays were used to identify the geographical distribution of distinct fibroblast subsets. We further evaluated the role of fibroblasts from pathologic mucosa in dysplastic progression of metaplastic cells using patient-derived metaplastic gastroids and fibroblasts. RESULTS: We identified 4 subsets of fibroblasts within stromal cells defined by the differential expression of PDGFRA, FBLN2, ACTA2, or PDGFRB. Each subset was distributed distinctively throughout stomach tissues with different proportions at each pathologic stage. The PDGFRα+ subset expanded in metaplasia and cancer compared with normal, maintaining a close proximity with the epithelial compartment. Co-culture of metaplasia- or cancer-derived fibroblasts with gastroids showing the characteristics of spasmolytic polypeptide-expressing metaplasia-induced disordered growth, loss of metaplastic markers, and increases in markers of dysplasia. Culture of metaplastic gastroids with conditioned media from metaplasia- or cancer-derived fibroblasts also promoted dysplastic transition. CONCLUSIONS: These findings indicate that fibroblast associations with metaplastic epithelial cells can facilitate direct transition of metaplastic spasmolytic polypeptide-expressing metaplasia cell lineages into dysplastic lineages.

Genetic Variants Determine Treatment Response in Autoimmune Hepatitis.

BACKGROUND: Autoimmune hepatitis (AIH) is a rare entity; in addition, single-nucleotide polymorphisms (SNPs) may impact its course and outcome. We investigated liver-related SNPs regarding its activity, as well as in relation to its stage and treatment response in a Central European AIH cohort. METHODS: A total of 113 AIH patients (i.e., 30 male/83 female, median 57.9 years) were identified. In 81, genotyping of PNPLA3-rs738409, MBOAT7-rs626238, TM6SF2-rs58542926, and HSD17B13-rs72613567:TA, as well as both biochemical and clinical data at baseline and follow-up, were available. RESULTS: The median time of follow-up was 2.8 years; five patients died and one underwent liver transplantation. The PNPLA3-G/G homozygosity was linked to a worse treatment response when compared to wildtype [wt] (ALT 1.7 vs. 0.6 × ULN, p < 0.001). The MBOAT7-C/C homozygosity was linked to non-response vs. wt and heterozygosity (p = 0.022). Male gender was associated with non-response (OR 14.5, p = 0.012) and a higher prevalence of PNPLA3 (G/G vs. C/G vs. wt 41.9/40.0/15.0% males, p = 0.03). The MBOAT7 wt was linked to less histological fibrosis (p = 0.008), while no effects for other SNPs were noted. A polygenic risk score was utilized comprising all the SNPs and correlated with the treatment response (p = 0.04). CONCLUSIONS: Our data suggest that genetic risk variants impact the treatment response of AIH in a gene-dosage-dependent manner. Furthermore, MBOAT7 and PNPLA3 mediated most of the observed effects, the latter explaining, in part, the predisposition of male subjects to worse treatment responses.

Validation of seismic hazard curves using a calibrated 14 ka lacustrine record in the Eastern Alps, Austria.

Seismic hazard maps are crucial for earthquake mitigation and mostly rely on probabilistic seismic hazard analysis (PSHA). However, the practise and value of PSHA are under debate because objective testing procedures for seismic hazard maps are scarce. We present a lacustrine turbidite record revealing 44 earthquakes over the last ~ 14 ka and use it to test seismic hazard curves in southern Austria. We derive local seismic intensities for paleo-earthquakes by applying scaling relationships between the sedimentary imprint and seismic intensity of well-documented historical earthquakes. The last ~ 2.8 ka of the record agree with a Poissonian recurrence behaviour and therefore a constant hazard rate, which is the modelling choice for standard PSHA. The lacustrine data are consistent with the intensity-frequency relationship of the local seismic hazard curve, confirming the current PSHA approach for this part of Austria. On longer timescales, distinct phases of enhanced regional seismicity occurred, indicating a potential increase of seismic hazard after large earthquakes-a factor hitherto disregarded in the PSHA of the Eastern Alps. Our new method forms an independent procedure to test hazard maps in any setting where suitable lake systems are available.

PNPLA3 is the dominant SNP linked to liver disease severity at time of first referral to a tertiary center.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in genes including PNPLA3, TM6SF2, HSD17B13 and SERPINA1 have been identified as risk modifiers of progression in chronic liver disease (CLD). However, it is unclear whether genotyping for these risk variants is useful in clinical routine. METHODS: Liver disease severity was assessed by liver stiffness measurement (LSM) and by presence of clinical manifestations of advanced-chronic liver disease (ACLD) in 779 consecutive CLD patients at the time of referral to a tertiary center. The associations of risk variants with CLD severity were calculated individually and in a combined model using a polygenic risk-score. RESULTS: Non-alcoholic fatty liver disease (NAFLD) was the most common etiology (n = 511, 65.6%), and ACLD was present in 217 (27.9%) patients. The PNPLA3-G-allele remained independently associated with higher LSM (adjusted-B: 2.508 [95%CI: 0.887-4.130], P = 0.002) or the presence of ACLD (aOR: 1.562 [95%CI: 1.097-2.226], P = 0.013). SERPINA1-Z-allele was also independently associated with LSM (adjusted-B: 4.558 [95%CI: 1.182-7.934], P = 0.008), while the other risk alleles did not attain statistical significance. Combining these risk alleles into a polygenic risk-score was significantly associated with LSM (adjusted-B: 0.948 [95%CI: 0.153-1.743], P = 0.020). CONCLUSION: PNPLA3 risk-variants are linked to liver disease severity at the time of first referral to an outpatient hepatology clinic.

Hepatitis D virus (HDV) prevalence in Austria is low but causes considerable morbidity due to fast progression to cirrhosis.

BACKGROUND: Hepatitis D virus (HDV) coinfection aggravates the course of hepatitis B virus (HBV). The prevalence of HDV in Austria is unknown. OBJECTIVE: This national study aimed at (i) recording the prevalence of HDV-infection in Austria and (ii) characterizing the "active" HDV cohort in Austria. METHODS: A total of 10 hepatitis treatment centers in Austria participated in this multicenter study and retrospectively collected their HDV patients between Q1/2010 and Q4/2020. Positive anti-HDV and/or HDV-RNA-polymerase chain reaction (PCR) results were retrieved from local database queries. Disease severity was assessed by individual chart review. Viremic HDV patients with clinical visits in/after Q1/2019 were considered as the "active" HDV cohort. RESULTS: A total of 347 anti-HDV positive patients were identified. In 202 (58.2%) patients, HDV-RNA-PCR test was performed, and 126/202 (62.4%) had confirmed viremia. Hepatocellular carcinoma was diagnosed in 7 (5.6%) patients, 7 (5.6%) patients underwent liver transplantation, and 11 (8.7%) patients died during follow-up. The "active" Austrian HDV cohort included 74 (58.7%) patients: Evidence for advanced chronic liver disease (ACLD, i.e., histological F3/F4 fibrosis, liver stiffness ≥10 kPa, varices, or hepatic venous pressure gradient ≥6 mmHg) was detected in 38 (51.4%) patients, including 2 (5.3%) with decompensation (ascites/hepatic encephalopathy). About 37 (50.0%) patients of the "active" HDV cohort had previously received interferon treatment. Treatment with the sodium-taurocholate cotransporting polypeptide inhibitor bulevirtide was initiated in 20 (27.0%) patients. CONCLUSION: The number of confirmed HDV viremic cases in Austria is low (<1% of HBV patients) but potentially underestimated. Testing all HBV patients will increase the diagnostic yield. More than half of viremic HDV patients had ACLD. Improved HDV testing and workup strategies will facilitate access to novel antiviral therapies.

A tsunamigenic delta collapse and its associated tsunami deposits in and around Lake Sils, Switzerland.

Large lacustrine mass movements and delta collapses are increasingly being considered as potential tsunamigenic sources and therefore hazardous for the population and infrastructure along lakeshores. Although historical reports document tsunami events in several lakes in Switzerland, and although the propagation of lake tsunamis has been studied by numerical wave modeling, only little is known about on- and offshore lacustrine tsunami deposits. In Lake Sils, Switzerland, a large prehistoric mass-movement deposit originating from the Isola Delta with a minimum estimated volume of 6.5 × 106 m3 and a basinal thickness of > 6 m in the seismic record has been identified by previous studies and radiocarbon dated to around 700 Common Era. Here, we combine (i) comprehensive sedimentological investigation of sediment cores recovered from the on- and offshore settings, (ii) mineralogical fingerprinting of the inflows from key catchments to characterize sediment provenance, and (iii) numerical tsunami modeling, to test the hypothesis of a tsunamigenic delta collapse in Lake Sils. We observe a clastic event deposit consisting of coarse-grained, fining-upward sand overlying an organic-rich peat deposit in the shallow water. This layer thins and fines landward on the coastal plain. Toward the deeper water (20-40 m), the deposit transforms into a thicker and more heterogeneous sediment package with multiple sequences of fining-upward sand and a well-pronounced clay cap at the top. Radiocarbon dating of the peat underlying the event deposit yields a maximum age of 225-419 calibrated  Common Era. The tsunami models, which indicate wave heights reaching up to 5 m, simulate areas of inundation that coincide with the location of event deposits. Based on our results, we propose that the historically undocumented Isola Delta collapse generated a basin-wide tsunami that inundated the lakeshore, transporting large amounts of unconsolidated sediment along the lakeshore toward the coastal plain and into the deeper lake basin. SUPPLEMENTARY INFORMATION: The online version of this article (10.1007/s11069-021-04533-y) contains supplementary material, which is available to authorized users.

What controls the remobilization and deformation of surficial sediment by seismic shaking? Linking lacustrine slope stratigraphy to great earthquakes in South-Central Chile.

Remobilization and deformation of surficial subaqueous slope sediments create turbidites and soft sediment deformation structures, which are common features in many depositional records. Palaeoseismic studies have used seismically-induced turbidites and soft sediment deformation structures preserved in sedimentary sequences to reconstruct recurrence patterns and - in some cases - allow quantifying rupture location and magnitude of past earthquakes. However, current understanding of earthquake-triggered remobilization and deformation lacks studies targeting where these processes take place, the subaqueous slope and involving direct comparison of sedimentary fingerprint with well-documented historical earthquakes. This study investigates the sedimentary imprint of six megathrust earthquakes with varying rupture characteristics in 17 slope sediment cores from two Chilean lakes, Riñihue and Calafquén, and evaluates how it links to seismic intensity, peak ground acceleration, bracketed duration and slope angle. Centimetre-scale stratigraphic gaps ranging from ca 1 to 20 cm - caused by remobilization of surficial slope sediment - were identified using high-resolution multi-proxy core correlation of slope to basin cores, and six types of soft sediment deformation structures ranging from ca 1 to 25 cm thickness using high-resolution three-dimensional X-ray computed tomography data. Stratigraphic gaps occur on slope angles of ≥2.3°, whereas deformation already occurs from slope angle 0.2°. The thickness of both stratigraphic gaps and soft sediment deformation structures increases with slope angle, suggesting that increased gravitational shear stress promotes both surficial remobilization and deformation. Seismic shaking is the dominant trigger for surficial remobilization and deformation at the studied lakes. Total remobilization depth correlates best with bracketed duration and is highest in both lakes for the strongest earthquakes (M w ca 9.5). In lake Riñihue, soft sediment deformation structure thickness and type correlate best with peak ground acceleration providing the first field-based evidence of progressive soft sediment deformation structure development with increasing peak ground acceleration for soft sediment deformation structures caused by Kelvin-Helmholtz instability. The authors propose that long duration and low frequency content of seismic shaking favours surficial remobilization, whereas ground motion amplitude controls Kelvin-Helmholtz instability-related soft sediment deformation structure development.

Liver-related Mortality is Increased in Lean Subjects with Non- alcoholic Fatty Liver Disease Compared to Overweight and Obese Subjects.

BACKGROUND AND AIMS: Although non-alcoholic fatty liver disease (NAFLD) is linked to obesity, a proportion of lean subjects also have NAFLD with potentially distinct clinical features. We studied the outcome of lean NAFLD subjects. METHODS: 299 consecutive patients (215 male, 84 female, 49.5 ± 13.5years) with biopsy-proven NAFLD and a follow-up of 8.4 years (±4.1; range: 0.9-18.0) were stratified by body mass index (BMI) at the time of liver biopsy: lean (BMI ≤25.0 kg/m, n=38), overweight (BMI 25.0-29.9 kg/m2, n=165), obese (BMI ≥30.0 kg/m2, n=93). A control group of 1,013 subjects (547 male, 52.4 ± 5.8) was used for comparison. The time to the event was recorded. Multivariable Cox regression analyses were performed to assess associations with 10-year-mortality. Hazard ratios (HR) and adjusted hazard ratios (aHR) with 95% confidence intervals (CI) were calculated. RESULTS: Age and gender were similar, while components of the metabolic syndrome were less frequent in lean subjects. The proportion of subjects with significant fibrosis and the number of subjects with cirrhosis was increased in lean subjects while the proportion of non-alcoholic steatohepatitis was not different. Mortality in the NAFLD groups was significantly higher than in the control group. Multivariable analysis adjusting for age, gender, and glucose confirmed lower mortality in overweight (aHR 0.21; 95% CI 0.07-0.62, p=0.005) and in obese (aHR 0.22; 95% CI 0.06-0.76, p=0.02) compared to lean subjects. Further adjustment for fibrosis weakened the difference between lean and obese (p=0.12) while the difference to overweight subjects remained intact (p=0.01). CONCLUSION: Lean subjects with NAFLD have a high risk of liver-related death. Our data support that lean NAFLD subjects deserve particular attention with regard to clinical follow-up.

PNPLA3 and SERPINA1 Variants Are Associated with Severity of Fatty Liver Disease at First Referral to a Tertiary Center.

Single nucleotide polymorphisms (SNPs), including PNPLA3 rs738409 and SERPINA1 rs17580, have been identified as risk modifiers in the progression fatty liver disease (alcoholic (ALD) or non-alcoholic (NAFLD)). While PNPLA3 has been studied in various settings, the value of both SNPs has so far not been addressed in a real-world cohort of subjects referred for a diagnostic work-up of liver disease. Thus, liver disease severity was assessed in 1257 consecutive patients with suspected ALD or NAFLD at the time of referral to a tertiary center. Advanced chronic liver disease (ACLD) was present in 309 (24.6%) patients and clinically significant portal hypertension (CSPH) was present in 185 (14.7%) patients. The PNPLA3 G-allele was independently associated with a higher liver stiffness measurement (LSM; adjusted B: 2.707 (1.435-3.979), p < 0.001), and higher odds of ACLD (adjusted odds ratio (aOR): 1.971 (1.448-2.681), p < 0.001) and CSPH (aOR: 1.685 (1.180-2.406), p = 0.004). While the SERPINA1 Z-allele was not associated with a higher LSM or the presence of ACLD, it was independently associated with higher odds of CSPH (aOR: 2.122 (1.067-4.218), p = 0.032). Associations of the PNPLA3 G-allele and the SERPINA1 Z-allele with CSPH were maintained independently of each other. The presence of both risk variants further increased the likelihood of ACLD and CSPH.

Seismic control of large prehistoric rockslides in the Eastern Alps.

Large prehistoric rockslides tend to occur within spatio-temporal clusters suggesting a common trigger such as earthquake shaking or enhanced wet periods. Yet, trigger assessment remains equivocal due to the lack of conclusive observational evidence. Here, we use high-resolution lacustrine paleoseismology to evaluate the relation between past seismicity and a spatio-temporal cluster of large prehistoric rockslides in the Eastern Alps. Temporal and spatial coincidence of paleoseismic evidence with multiple rockslides at ~4.1 and ~3.0 ka BP reveals that severe earthquakes (local magnitude ML 5.5-6.5; epicentral intensity I0 VIII»-X¾) have triggered these rockslides. A series of preceding severe earthquakes is likely to have progressively weakened these rock slopes towards critical state. These findings elucidate the role of seismicity in preparing and triggering large prehistoric rockslides in the European Alps, where rockslides and earthquakes typically occur in clusters. Such integration of multiple datasets in other formerly glaciated regions with low to moderate seismicity will improve our understanding of catastrophic rockslide drivers.

Similar clinical outcome of AMA immunoblot-M2-negative compared to immunoblot-positive subjects over six years of follow-up.

Background: The detection of anti-mitochondrial antibodies (AMA) is considered a hallmark in diagnosing primary biliary cholangitis (PBC). The most important AMA-subtype is AMA-M2 directed against the E2-subunit of pyruvate dehydrogenase. It is common clinical interpretation that lack of M2 due to immunoblotting (IB) indicates absence of specific auto-reactivity. We aimed to define whether M2-IB confirmation is linked to clinical outcomes.Methods: Our cohort comprised 302 patients who tested positive for AMA with indirect immunofluorescence between 2006 and 2015. One hundred and eighty-four subjects (60.9%; male n = 29 [15.8%]) were tested M2-positive by confirmatory IB, whereas 118 subjects were IB-M2-negative (39.1%; male n = 25 [21.2%]). The natural history of 236 patients (78.1%) was evaluated by clinical follow-up (FU) assessing causes of death, leading health condition and response to PBC standard therapy if applicable.Results: Mean time to FU was 6.8 years. Twenty-eight M2-positive patients (15.2% of 184) and 28 M2-negative patients (23.7% of 118) had died (p = 0.0958). Thirty-four M2-positives (18.5%) and 32 M2-negatives (27.1%) were not available for FU. According to the clinical course by the time of FU, subjects were allocated to one of four groups: a) 34 patients had known PBC with n = 16 having an adequate and 18 an inadequate treatment response, b) 1 de novo PBC was detected, c) 13 were AMA-positive without biochemical evidence of PBC and d) 9 subjects were tested AMA-negative at FU. These numbers were comparable to M2-positive subjects with similar long-term clinical outcome.Conclusion: Our data suggest that the clinical value of confirmatory M2 immunoblotting in the diagnostic routine of PBC is overestimated as the clinical course appears not to be related to the test result.

Mesenchymal iron deposition is associated with adverse long-term outcome in non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Approximately one-third of patients with non-alcoholic fatty liver disease (NAFLD) show signs of mild-to-moderate iron overload. The impact of histological iron deposition on the clinical course of patients with NAFLD has not been established. METHODS & RESULTS: For this retrospective study, 299 consecutive patients with biopsy-proven NAFLD and a mean follow-up of 8.4 (±4.1; range: 0.3-18.0) years were allocated to one of four groups according to presence of hepatic iron in the reticuloendothelial system (RES) and/or hepatocytes (HC): 156 subjects (52%) showed no stainable iron (NONE), 58 (19%) exclusively reticuloendothelial (xRES), 19 (6%) exclusively hepatocellular (xHC) and 66 (22%) showed a mixed (HC/RES) pattern of iron deposition. A long-term analysis for overall survival, hepatic, cardiovascular or extrahepatic-malignant events was conducted. Based on multivariate Cox proportional hazards models any reticuloendothelial iron was associated with fatal and non-fatal hepatic events. Specifically, xRES showed a cause-specific hazard ratio (csHR) of 2.4 (95%-CI, 1.0-5.8; P = .048) for hepatic as well as cardiovascular fatal and non-fatal events combined (csHR 3.2; 95%-CI, 1.2-8.2; P = .015). Furthermore, the mixed HC/RES iron pattern showed a higher rate of combined hepatic fatal and non-fatal events (csHR 3.6; 95%-CI, 1.4-9.5; P = .010), while xHC iron deposition was not associated with any defined events. CONCLUSIONS: The presence of reticuloendothelial-accentuated hepatic iron distribution patterns is associated with detrimental long-term outcomes reflected in a higher rate of both liver-related and cardiovascular fatal and non-fatal events.

Earthquake Impact on Active Margins: Tracing Surficial Remobilization and Seismic Strengthening in a Slope Sedimentary Sequence.

Strong earthquakes at active ocean margins can remobilize vast amounts of surficial slope sediments and dynamically strengthen the margin sequences. Current process understanding is obtained from resulting event deposits and low-resolution shear strength data, respectively. Here we directly target a site offshore Japan where both processes are expected to initiate, that is, at the uppermost part (15 cm) of a sedimentary slope sequence. Based on a novel application of short-lived radionuclide data, we identified, dated, and quantified centimeter-scale gaps related to surficial remobilization. Temporal correlation to the three largest regional earthquakes attest triggering by strong earthquakes (M w >8). Also, extremely elevated shear strength values suggest a strong influence of seismic strengthening on shallow sediments. We show that despite enhanced slope stability by seismic strengthening, earthquake-induced sediment transport can occur through surficial remobilization, which has large implications for the assessment of turbidite paleoseismology and carbon cycling at active margins.

Cancer cell population growth kinetics at low densities deviate from the exponential growth model and suggest an Allee effect.

Most models of cancer cell population expansion assume exponential growth kinetics at low cell densities, with deviations to account for observed slowing of growth rate only at higher densities due to limited resources such as space and nutrients. However, recent preclinical and clinical observations of tumor initiation or recurrence indicate the presence of tumor growth kinetics in which growth rates scale positively with cell numbers. These observations are analogous to the cooperative behavior of species in an ecosystem described by the ecological principle of the Allee effect. In preclinical and clinical models, however, tumor growth data are limited by the lower limit of detection (i.e., a measurable lesion) and confounding variables, such as tumor microenvironment, and immune responses may cause and mask deviations from exponential growth models. In this work, we present alternative growth models to investigate the presence of an Allee effect in cancer cells seeded at low cell densities in a controlled in vitro setting. We propose a stochastic modeling framework to disentangle expected deviations due to small population size stochastic effects from cooperative growth and use the moment approach for stochastic parameter estimation to calibrate the observed growth trajectories. We validate the framework on simulated data and apply this approach to longitudinal cell proliferation data of BT-474 luminal B breast cancer cells. We find that cell population growth kinetics are best described by a model structure that considers the Allee effect, in that the birth rate of tumor cells increases with cell number in the regime of small population size. This indicates a potentially critical role of cooperative behavior among tumor cells at low cell densities with relevance to early stage growth patterns of emerging and relapsed tumors.

Lean Patients with Non-Alcoholic Fatty Liver Disease Have a Severe Histological Phenotype Similar to Obese Patients.

A small proportion of lean patients develop non-alcoholic fatty liver disease (NAFLD). We aimed to report the histological picture of lean NAFLD in comparison to overweight and obese NAFLD patients. Biopsy and clinical data from 466 patients diagnosed with NAFLD were stratified to groups according to body mass index (BMI): lean (BMI ≤ 25.0 kg/m², n confirmed to be appropriate = 74), overweight (BMI > 25.0 ≤ 30.0 kg/m², n = 242) and obese (BMI > 30.0 kg/m², n = 150). Lean NAFLD patients had a higher rate of lobular inflammation compared to overweight patients (12/74; 16.2% vs. 19/242; 7.9%; p = 0.011) but were similar to obese patients (25/150; 16.7%). Ballooning was observed in fewer overweight patients (38/242; 15.7%) compared to lean (19/74; 25.7%; p = 0.014) and obese patients (38/150; 25.3%; p = 0.006). Overweight patients had a lower rate of portal and periportal fibrosis (32/242; 13.2%) than lean (19/74; 25.7%; p = 0.019) and obese patients (37/150; 24.7%; p = 0.016). The rate of cirrhosis was higher in lean patients (6/74; 8.1%) compared to overweight (4/242; 1.7%; p = 0.010) and obese patients (3/150; 2.0% p = 0.027). In total, 60/466; 12.9% patients were diagnosed with non-alcoholic steatohepatitis (NASH). The rate of NASH was higher in lean (14/74; 18.9% p = 0.01) and obese (26/150; 17.3%; p = 0.007) compared to overweight patients (20/242; 8.3%)). Among lean patients, fasting glucose, INR and use of thyroid hormone replacement therapy were independent predictors of NASH in a multivariate model. Lean NAFLD patients were characterized by a severe histological picture similar to obese patients but are more progressed compared to overweight patients. Fasting glucose, international normalized ratio (INR) and the use of thyroid hormone replacement may serve as indicators for NASH in lean patients.

Increasing Neural Stem Cell Division Asymmetry and Quiescence Are Predicted to Contribute to the Age-Related Decline in Neurogenesis.

Adult murine neural stem cells (NSCs) generate neurons in drastically declining numbers with age. How cellular dynamics sustain neurogenesis and how alterations with age may result in this decline are unresolved issues. We therefore clonally traced NSC lineages using confetti reporters in young and middle-aged adult mice. To understand the underlying mechanisms, we derived mathematical models that explain observed clonal cell type abundances. The best models consistently show self-renewal of transit-amplifying progenitors and rapid neuroblast cell cycle exit. In middle-aged mice, we identified an increased probability of asymmetric stem cell divisions at the expense of symmetric differentiation, accompanied by an extended persistence of quiescence between activation phases. Our model explains existing longitudinal population data and identifies particular cellular properties underlying adult NSC homeostasis and the aging of this stem cell compartment.