Ruthenium isotopes show the Chicxulub impactor was a carbonaceous-type asteroid.

An impact at Chicxulub, Mexico, occurred 66 million years ago, producing a global stratigraphic layer that marks the boundary between the Cretaceous and Paleogene eras. That layer contains elevated concentrations of platinum-group elements, including ruthenium. We measured ruthenium isotopes in samples taken from three Cretaceous-Paleogene boundary sites, five other impacts that occurred between 36 million to 470 million years ago, and ancient 3.5-billion- to 3.2-billion-year-old impact spherule layers. Our data indicate that the Chicxulub impactor was a carbonaceous-type asteroid, which had formed beyond the orbit of Jupiter. The five other impact structures have isotopic signatures that are more consistent with siliceous-type asteroids, which formed closer to the Sun. The ancient spherule layer samples are consistent with impacts of carbonaceous-type asteroids during Earth's final stages of accretion.

Ontogeny of the malleus in Mesocricetus auratus (Mammalia, Rodentia): Systematic and functional implications for the muroid middle ear.

The three mammalian auditory ossicles enhance sound transmission from the tympanic membrane to the inner ear. The anterior anchoring of the malleus is one of the key characters for functional classification of the auditory ossicles. Previous studies revealed a medial outgrowth of the mallear anterior process, the processus internus praearticularis, which serves as an anchor for the auditory ossicle chain but has been often missed due to its delicate nature. Here we describe the development and morphology of the malleus and its processus internus praearticularis in the cricetine rodent Mesocricetus auratus, compared to selected muroid species (Cricetus cricetus, Peromyscus maniculatus, and Mus musculus). Early postnatal stages of Mesocricetus show the formation of the malleus by fusion of the prearticular and mallear main body. The processus internus praearticularis forms an increasing broad lamina fused anteriorly to the ectotympanic in adult stages of all studied species. Peromyscus and Mus show a distinct orbicular apophysis that increases inertia of the malleus and therefore these species represent the microtype of auditory ossicles. In contrast, the center of mass of the malleus in the studied Cricetinae is close to the anatomical axis of rotation and their auditory ossicles represent the transitional type. The microtype belongs to the grundplan of Muroidea and is plesiomorphic for Cricetidae, whereas the transitional type evolved several times within Muroidea and represents an apomorphic feature of Cricetinae.

Profiles of met and unmet care needs in the oldest-old primary care patients with cognitive disorders and dementia - results of the AgeCoDe and AgeQualiDe study.

INTRODUCTION: The prevalence of MCI and dementia is increasing as the oldest-old population grows, requiring a nuanced understanding of their care needs. Few studies have examined need profiles of oldest-old patients with MCI or dementia. Therefore, this study aims to identify patients' need profiles. METHODS: The data analysis included cross-sectional baseline data from N = 716 primary care patients without cognitive impairment (n = 575), with MCI (n = 97), and with dementia (n = 44) aged 85+ years from the multicenter cohort AgeQualiDe study "Needs, Health Service Use, Costs and Health-Related Quality of Life in a Large Sample of Oldest-Old Primary Care Patients [85+]". Patients' needs were assessed using the Camberwell Assessment of Need for the Elderly (CANE), and latent class analysis identified need profiles. Multinomial logistic regression analyzed the association of MCI and dementia with need profiles, adjusting for sociodemographic factors, social network (Lubben Social Network Scale, LSNS-6), and frailty (Clinical Frailty Scale, CSHA-CFS). RESULTS: Results indicated three profiles: 'no needs', 'met physical and environmental needs', and 'unmet physical and environmental needs'. MCI was associated with the met and unmet physical and environmental needs profiles; dementia was associated with the unmet physical and environmental needs profile. Patients without MCI or dementia had larger social networks (LSNS-6). Frailty was associated with dementia. CONCLUSIONS: Integrated care should address the needs of the oldest-old and support social networks for people with MCI or dementia. Assessing frailty can help clinicians to identify the most vulnerable patients and develop beneficial interventions for cognitive disorders.

Dactylfungins and Tetralones: Bioactive Metabolites from a Nematode-Associated Laburnicola nematophila.

A chemical investigation of Laburnicola nematophila, isolated from cysts of the plant parasitic nematode Heterodera filipjevi, affored three dactylfungin derivatives (1-3) and three tetralone congeners (4-6). Dactylfungin C (1), laburnicolin (4), and laburnicolenone (5) are previously undescribed natural products. Chemical structures of the isolated compounds were determined based on 1D and 2D NMR spectroscopic analyses together with HR-ESI-MS spectrometry and comparison with data reported in the literature. The relative configurations of compounds 1, 2, and 4-6 were determined based on their ROESY data and analysis of their coupling constants (J values). The absolute configurations of 4-6 were determined through the comparison of their measured and calculated TDDFT-ECD spectra. Compounds 1-3 were active against azole-resistant Aspergillus fumigatus.

Metabolic activity of CYP2C19 and CYP2D6 on antidepressant response from 13 clinical studies using genotype imputation: a meta-analysis.

Cytochrome P450 enzymes including CYP2C19 and CYP2D6 are important for antidepressant metabolism and polymorphisms of these genes have been determined to predict metabolite levels. Nonetheless, more evidence is needed to understand the impact of genetic variations on antidepressant response. In this study, individual clinical and genetic data from 13 studies of European and East Asian ancestry populations were collected. The antidepressant response was clinically assessed as remission and percentage improvement. Imputed genotype was used to translate genetic polymorphisms to metabolic phenotypes (poor, intermediate, normal, and rapid+ultrarapid) of CYP2C19 and CYP2D6. CYP2D6 structural variants cannot be imputed from genotype data, limiting the determination of metabolic phenotypes, and precluding testing for association with response. The association of CYP2C19 metabolic phenotypes with treatment response was examined using normal metabolizers as the reference. Among 5843 depression patients, a higher remission rate was found in CYP2C19 poor metabolizers compared to normal metabolizers at nominal significance but did not survive after multiple testing correction (OR = 1.46, 95% CI [1.03, 2.06], p = 0.033, heterogeneity I2 = 0%, subgroup difference p = 0.72). No metabolic phenotype was associated with percentage improvement from baseline. After stratifying by antidepressants primarily metabolized by CYP2C19, no association was found between metabolic phenotypes and antidepressant response. Metabolic phenotypes showed differences in frequency, but not effect, between European- and East Asian-ancestry studies. In conclusion, metabolic phenotypes imputed from genetic variants using genotype were not associated with antidepressant response. CYP2C19 poor metabolizers could potentially contribute to antidepressant efficacy with more evidence needed. Sequencing and targeted pharmacogenetic testing, alongside information on side effects, antidepressant dosage, depression measures, and diverse ancestry studies, would more fully capture the influence of metabolic phenotypes.

Next-Generation Sequencing of the Human Aqueous Humour Microbiome.

The microbiome of the ocular surface has been characterised, but only limited information is available on a possible silent intraocular microbial colonisation in normal eyes. Therefore, we performed next-generation sequencing (NGS) of 16S rDNA genes in the aqueous humour. The aqueous humour was sampled from three patients during cataract surgery. Air swabs, conjunctival swabs from patients as well as from healthy donors served as controls. Following DNA extraction, the V3 and V4 hypervariable regions of the 16S rDNA gene were amplified and sequenced followed by denoising. The resulting Amplicon Sequence Variants were matched to a subset of the Ribosomal Database Project 16S database. The deduced bacterial community was then statistically analysed. The DNA content in all samples was low (0-1.49 ng/µL) but sufficient for analysis. The main phyla in the samples were Acinetobacteria (48%), Proteobacteria (26%), Firmicutes (14%), Acidobacteria (8%), and Bacteroidetes (2%). Patients' conjunctival control samples and anterior chamber fluid showed similar patterns of bacterial species containing many waterborne species. Non-disinfected samples showed a different bacterial spectrum than the air swab samples. The data confirm the existence of an ocular surface microbiome. Meanwhile, a distinct intraocular microbiome was not discernible from the background, suggesting the absence of an intraocular microbiome in normal eyes.

Age-specific risk factors of depression among the oldest-old - evidence from the multicenter AgeCoDe-AgeQualiDe study.

Purpose: The present study aimed to investigate age-group-specific incidence rates and risk factors for depressive symptoms in the highest age groups. Methods: Data were derived from a prospective multicenter cohort study conducted in primary care - the AgeCoDe/AgeQualiDe study. In total, 2,436 patients 75 years and older were followed from baseline to ninth follow-up. To assess depressive symptoms, the short version of the Geriatric Depression Scale (GDS-15, cutoff score 6) was used. Age-specific competing risk regressions were performed to analyze risk factors for incident depressive symptoms in different age groups (75 to 79, 80 to 84, 85+ years), taking into account the accumulated mortality. Results: The age-specific incidence rate of depression was 33 (95% CI 29-38), 46 (95% CI 40-52) and 63 (95% CI 45-87) per 1,000 person years for the initial age groups 75 to 79, 80 to 84 and 85+ years, respectively. In competing risk regression models, female sex, mobility as well as vision impairment, and subjective cognitive decline (SCD) were found to be risk factors for incident depression for age group 75 to 79, female sex, single/separated marital status, mobility as well as hearing impairment, and SCD for age group 80 to 84, and mobility impairment for age group 85+. Conclusion: Depressive symptoms in latest life are common and the incidence increases with increasing age. Modifiable and differing risk factors across the highest age groups open up the possibility of specifically tailored prevention concepts.

Laburnicolamine: A Rare Penillic Acid Congener from the Nematode Cyst-Associated Fungus Laburnicola nematophila.

A chemical investigation of a methanol extract derived from a solid-state rice culture of the nematode-cyst associated fungus Laburnicola nematophila K01 led to the isolation and characterization of a previously undescribed penillic acid analogue named laburnicolamine (1). The chemical structure was elucidated through comprehensive 1D and 2D NMR spectroscopic analyses in methanol-d4 and DMSO-d6, alongside with HR-ESI-MS spectrometry. The absolute configuration of 1 was concluded through the electronic circular dichroism (ECD) and time-dependent density functional theory-ECD (TDDFT-ECD) computations compared to its acquired spectrum. Biological assays revealed that compound 1 exhibited no significant cytotoxic, antimicrobial, or nematicidal activity.

Laburnicotides A-F: Acyclic N-Acetyl Oligopeptides from the Nematode-Cyst-Associated Fungus Laburnicola nematophila.

Nematode-associated fungi revealed the potential to produce a broad spectrum of chemical scaffolds. In this study, a mycelial extract of Laburnicola nematophila, a fungal strain derived from the cereal cyst nematode Heterodera filipjevi, was chemically explored and afforded six unprecedentedly reported acylic N-acetyl oligopeptides, laburnicotides A-F (1-6). Structure elucidation of the isolated compounds was established based on comprehensive 1D and 2D NMR spectroscopic analyses together with the acquired HR-ESI-MS spectrometric data. The absolute configuration of amino acid residues in 1-6 was established by performing advanced Marfey's derivatization method. All isolated compounds were assessed for their cytotoxic, antimicrobial, antiviral, and nematicidal activities with no potential activity observed.

Recommendations for Uniform Variant Calling of SARS-CoV-2 Genome Sequence across Bioinformatic Workflows.

Genomic sequencing of clinical samples to identify emerging variants of SARS-CoV-2 has been a key public health tool for curbing the spread of the virus. As a result, an unprecedented number of SARS-CoV-2 genomes were sequenced during the COVID-19 pandemic, which allowed for rapid identification of genetic variants, enabling the timely design and testing of therapies and deployment of new vaccine formulations to combat the new variants. However, despite the technological advances of deep sequencing, the analysis of the raw sequence data generated globally is neither standardized nor consistent, leading to vastly disparate sequences that may impact identification of variants. Here, we show that for both Illumina and Oxford Nanopore sequencing platforms, downstream bioinformatic protocols used by industry, government, and academic groups resulted in different virus sequences from same sample. These bioinformatic workflows produced consensus genomes with differences in single nucleotide polymorphisms, inclusion and exclusion of insertions, and/or deletions, despite using the same raw sequence as input datasets. Here, we compared and characterized such discrepancies and propose a specific suite of parameters and protocols that should be adopted across the field. Consistent results from bioinformatic workflows are fundamental to SARS-CoV-2 and future pathogen surveillance efforts, including pandemic preparation, to allow for a data-driven and timely public health response.

Omnipolyphilins A and B: Chlorinated Cyclotetrapeptides and Naphtho-α-pyranones from the Plant Nematode-Derived Fungus Polyphilus sieberi.

Chemical exploration for two isolates of the recently described ascomycete species Polyphilus sieberi, derived from the eggs of the plant parasitic nematode Heterodera filipjevi, afforded the identification of many compounds that belong to various metabolite families: two previously undescribed chlorinated cyclotetrapeptides, omnipolyphilins A (1) and B (2), one new pyranonaphthoquinone, ventiloquinone P (3), a 6,6'-binaphto-α-pyranone dimer, talaroderxine D (4) in addition to nine known metabolites (5-13) were isolated from this biocontrol candidate. All isolated compounds were characterized by comprehensive 1D, 2D NMR, and HR-ESI-MS analyses. The absolute configurations of the cyclotetrapeptides were determined by a combination of advanced Marfey's method, ROE correlation aided by conformational analysis, and TDDFT-ECD calculations, while ECD calculations, Mosher's method, and experimental ECD spectra were used for ventiloquinone P (3) and talaroderxine D (4). Among the isolated compounds, talaroderxine D (4) showed potent antimicrobial activities against Bacillus subtilis and Staphylococcus aureus with MIC values of 2.1 and 8.3 µg mL-1, respectively. Additionally, promising inhibitory effects on talaroderxine D (4) against the formation of S. aureus biofilms were observed up to a concentration of 0.25 µg mL-1. Moreover, ophiocordylongiiside A (10) showed activity against the free-living nematode Caenorhabditis elegans.

Mobilisation and analyses of publicly available SARS-CoV-2 data for pandemic responses.

The COVID-19 pandemic has seen large-scale pathogen genomic sequencing efforts, becoming part of the toolbox for surveillance and epidemic research. This resulted in an unprecedented level of data sharing to open repositories, which has actively supported the identification of SARS-CoV-2 structure, molecular interactions, mutations and variants, and facilitated vaccine development and drug reuse studies and design. The European COVID-19 Data Platform was launched to support this data sharing, and has resulted in the deposition of several million SARS-CoV-2 raw reads. In this paper we describe (1) open data sharing, (2) tools for submission, analysis, visualisation and data claiming (e.g. ORCiD), (3) the systematic analysis of these datasets, at scale via the SARS-CoV-2 Data Hubs as well as (4) lessons learnt. This paper describes a component of the Platform, the SARS-CoV-2 Data Hubs, which enable the extension and set up of infrastructure that we intend to use more widely in the future for pathogen surveillance and pandemic preparedness.

Profiles of met and unmet care needs in the oldest-old primary care patients with depression - results of the AgeMooDe study.

BACKGROUND: Unmet care needs have been associated with an increased risk of depression in old age. Currently, the identification of profiles of met and unmet care needs associated with depressive symptoms is pending. Therefore, this exploratory study aimed to identify profiles of care needs and analyze associated factors in oldest-old patients with and without depression. METHODS: The sample of 1092 GP patients aged 75+ years is based on the multicenter study "Late-life depression in primary care: needs, health care utilization and costs (AgeMooDe)". Depression (i.e. clinically meaningful depressive symptoms) was determined using the Geriatric Depression Scale (GDS) (cutoff score ≥ 4). Needs of patients were assessed using the Camberwell Assessment of Need for the Elderly (CANE). Associated sociodemographic and clinical factors were examined, and latent class analysis identified the need profiles. RESULTS: The main result of the study indicates three need profiles: 'no needs', 'met physical needs', and 'unmet social needs'. Members of the 'met physical needs' (OR = 3.5, 95 %-CI: 2.5-4.9) and 'unmet social needs' (OR = 17.4, 95 %-CI: 7.7-39.7) profiles were significantly more likely to have depression compared to members of the 'no needs' profile. LIMITATIONS: Based on the cross-sectional design, no conclusions can be drawn about the causality or direction of the relationships between the variables. CONCLUSIONS: The study results provide important insights for the establishment of needs-based interventions for GPs. Particular attention should be paid to the presence of unmet social needs in the oldest-old GP patients with underlying depressive symptoms.

The effect of depressive symptoms on quality of life and its different facets in the oldest age population: evidence from the AgeQualiDe prospective cohort study.

PURPOSE: The present study aims to investigate the prospective effect of depressive symptoms on overall QoL in the oldest age group, taking into account its different facets. METHODS: Data were derived from the multicenter prospective AgeCoDe/AgeQualiDe cohort study, including data from follow-up 7-9 and n = 580 individuals 85 years of age and older. Overall QoL and its facets were assessed using the WHOQOL-OLD instrument. The short form of the geriatric depression scale (GDS-15) was applied to assess depressive symptoms. Cognitively impaired individuals were excluded. Linear mixed-effects models were used to assess the effect of depressive symptoms on QoL. RESULTS: Depressive symptoms were significantly associated with overall QoL and each of the different facets of WHOQOL-OLD, also after adjustment for time and sociodemographic characteristics such as age, gender, education, marital status, living situation, and cognitive status. Higher age and single as well as divorced marital status were also associated with a lower QoL. CONCLUSION: This work provides comprehensive longitudinal results on the relationship between depressive symptoms and QoL in the oldest age population. The results underscore the relevance of tailored and targeted care planning and the development of customized interventions.

Global and local functions of the Fused kinase ortholog CdaH in intracellular patterning in Tetrahymena.

Ciliates assemble numerous microtubular structures into complex cortical patterns. During ciliate division, the pattern is duplicated by intracellular segmentation that produces a tandem of daughter cells. In Tetrahymena thermophila, the induction and positioning of the division boundary involves two mutually antagonistic factors: posterior CdaA (cyclin E) and anterior CdaI (Hippo kinase). Here, we characterized the related cdaH-1 allele, which confers a pleiotropic patterning phenotype including an absence of the division boundary and an anterior-posterior mispositioning of the new oral apparatus. CdaH is a Fused or Stk36 kinase ortholog that localizes to multiple sites that correlate with the effects of its loss, including the division boundary and the new oral apparatus. CdaH acts downstream of CdaA to induce the division boundary and drives asymmetric cytokinesis at the tip of the posterior daughter. CdaH both maintains the anterior-posterior position of the new oral apparatus and interacts with CdaI to pattern ciliary rows within the oral apparatus. Thus, CdaH acts at multiple scales, from induction and positioning of structures on the cell-wide polarity axis to local organelle-level patterning.

Family History of Dementia in Old-Age Participants with Subjective Memory Complaints Predicts Own Risk for Dementia in a Longitudinal Multi-Center Cohort Study.

BACKGROUND: Subjective memory complaints and family history of dementia are possibly intertwined risk factors for the own subsequent dementia risk and Alzheimer's disease. However, their interaction has rarely been studied. OBJECTIVE: To study the association between subjective memory complaints and family history of dementia with regard to the own subsequent risk of dementia. METHODS: Cross-sectional and longitudinal analyses over a follow-up period of up to 13 years were conducted in a population sample of participants without dementia at baseline (n = 3,256, mean age = 79.62 years), using group comparisons and Cox proportional hazards models. RESULTS: Cross-sectionally, participants with subjective memory complaints were significantly more likely to report family history of dementia. Longitudinally, family history of dementia (FH) was significantly associated with subsequent dementia in the subjective memory complaints (SMC) group, but not in those without SMC. A relative excess risk due to interaction analysis confirmed a significant FHxSMC-interaction. CONCLUSIONS: Family history of dementia was a predictor of incident dementia in those with SMC, which can serve as an additional, clinically relevant criterion to gauge the risk of dementia in older-aged subjects with SMC with and without objective cognitive impairment.

Bioactive Naphtho-α-Pyranones from Two Endophytic Fungi of the Genus Polyphilus.

In the course of our survey to study the metabolic potential of two species of a new helotialean genus Polyphilus, namely P. frankenii and P. sieberi, their crude extracts were obtained using different cultivation techniques, which led to the isolation and characterization of two new naphtho-α-pyranone derivatives recognized as a monomer (1) and its 6,6'-homodimer (2) together with two known diketopiperazine congeners, outovirin B (3) and (3S,6S)-3,6-dibenzylpiperazine-2,5-dione (4). The structures of isolated compounds were determined based on extensive 1D and 2D NMR and HRESIMS. The absolute configuration of new naphtho-α-pyranones was determined using a comparison of their experimental ECD spectra with those of related structural analogues. 6,6'-binaphtho-α-pyranone talaroderxine C (2) exhibited potent cytotoxic activity against different mammalian cell lines with IC50 values in the low micromolar to nanomolar range. In addition, talaroderxine C unveiled stronger antimicrobial activity against Bacillus subtilis rather than Staphylococcus aureus with MIC values of 0.52 µg mL-1 (0.83 µM) compared to 66.6 µg mL-1 (105.70 µM), respectively.

Social isolation in the oldest-old: determinants and the differential role of family and friends.

PURPOSE: To examine the association of sociodemographic and health-related determinants with social isolation in relation to family and friends in the oldest-old. METHODS: Database was the multi-center prospective AgeCoDe/AgeQualiDe cohort study assessed at follow-up wave 5 (N = 1148; mean age 86.6 years (SD 3.0); 67% female). Social isolation was assessed using the short form of the Lubben Social Network Scale (LSNS-6). The LSNS-6 contains two sets of items establishing psychometrically separable subscales for isolation from family and friends (ranges 0-15 points), with lower scores indicating higher isolation. Cross-sectional linear (OLS) regression analyses were used to examine multivariate associations of sociodemographic and health-related determinants with social isolation from family and friends. RESULTS: Overall, n = 395 participants (34.6%) were considered socially isolated. On average, isolation was higher from friends (mean 6.0, SD 3.8) than from family (mean 8.0, SD 3.5). Regression results revealed that in relation to family, males were more socially isolated than females (ß = - 0.68, 95% CI - 1.08, - 0.28). Concerning friends, increased age led to more isolation (ß = - 0.12, 95% CI - 0.19, - 0.05) and functional activities of daily living to less isolation (ß = 0.36, 95% CI 0.09, 0.64). Independent of the social context, depression severity was associated with more social isolation, whereas cognitive functioning was associated with less social isolation. CONCLUSIONS: Different determinants unequally affect social isolation in relation to family and friends. The context of the social network should be incorporated more strongly regarding the detection and prevention of social isolation to sustain mental and physical health.

Meta-analysis of CYP2C19 and CYP2D6 metabolic activity on antidepressant response from 13 clinical studies using genotype imputation.

Cytochrome P450 enzymes including CYP2C19 and CYP2D6 are important for antidepressant metabolism and polymorphisms of these genes have been determined to predict metabolite levels. Nonetheless, more evidence is needed to understand the impact of genetic variations on antidepressant response. In this study, individual clinical and genetic data from 13 studies of European and East Asian ancestry populations were collected. The antidepressant response was clinically assessed as remission and percentage improvement. Imputed genotype was used to translate genetic polymorphisms to metabolic phenotypes (poor, intermediate, normal, and rapid+ultrarapid) of CYP2C19 and CYP2D6. The association of CYP2C19 and CYP2D6 metabolic phenotypes with treatment response was examined using normal metabolizers as the reference. Among 5843 depression patients, a higher remission rate was found in CYP2C19 poor metabolizers compared to normal metabolizers at nominal significance but did not survive after multiple testing correction (OR=1.46, 95% CI [1.03, 2.06], p=0.033, heterogeneity I2=0%, subgroup difference p=0.72). No metabolic phenotype was associated with percentage improvement from baseline. After stratifying by antidepressants primarily metabolized by CYP2C19 and CYP2D6, no association was found between metabolic phenotypes and antidepressant response. Metabolic phenotypes showed differences in frequency, but not effect, between European- and East Asian-ancestry studies. In conclusion, metabolic phenotypes imputed from genetic variants using genotype were not associated with antidepressant response. CYP2C19 poor metabolizers could potentially contribute to antidepressant efficacy with more evidence needed. CYP2D6 structural variants cannot be imputed from genotype data, limiting inference of pharmacogenetic effects. Sequencing and targeted pharmacogenetic testing, alongside information on side effects, antidepressant dosage, depression measures, and diverse ancestry studies, would more fully capture the influence of metabolic phenotypes.