julilili42/papers huggingface dataset:
Characterization of the blood oxygen level dependent hemodynamic response function in human subcortical regions with high spatiotemporal resolution
2022-10-11

Subcortical brain regions are absolutely essential for normal human function. These phylogenetically early brain regions play critical roles in human behaviors such as the orientation of attention, arousal, and the modulation of sensory signals to cerebral cortex. Despite the critical health importance of subcortical brain regions, there has been a dearth of research on their neurovascular responses. Blood oxygen level dependent (BOLD) functional MRI (fMRI) experiments can help fill this gap in our understanding. The BOLD hemodynamic response function (HRF) evoked by brief (&amp;lt;4 s) neural activation is crucial for the interpretation of fMRI results because linear analysis between neural activity and the BOLD response relies on the HRF. Moreover, the HRF is a consequence of underlying local blood flow and oxygen metabolism, so characterization of the HRF enables understanding of neurovascular and neurometabolic coupling. We measured the subcortical HRF at 9.4T and 3T with high spatiotemporal resolution using protocols that enabled reliable delineation of HRFs in individual subjects. These results were compared with the HRF in visual cortex. The HRF was faster in subcortical regions than cortical regions at both field strengths. There was no significant undershoot in subcortical areas while there was a significant post-stimulus undershoot that was tightly coupled with its peak amplitude in cortex. The different BOLD temporal dynamics indicate different vascular dynamics and neurometabolic responses between cortex and subcortical nuclei.
Towards the human nasal microbiome: Simulating D. pigrum and S. aureus
2022-10-11

The human nose harbors various microbes that decisively influence the wellbeing and health of their host. Among the most threatening pathogens in this habitat is Staphylococcus aureus . Multiple epidemiological studies identify Dolosigranulum pigrum as a likely beneficial bacterium based on its positive association with health, including negative associations with S. aureus . Carefully curated GEMs are available for both bacterial species that reliably simulate their growth behavior in isolation. To unravel the mutual effects among bacteria, building community models for simulating co-culture growth is necessary. However, modeling microbial communities remains challenging. This article illustrates how applying the NCMW fosters our understanding of two microbes’ joint growth conditions in the nasal habitat and their intricate interplay from a metabolic modeling perspective. The resulting community model combines the latest available curated GEMs of D. pigrum and S. aureus . This uses case illustrates how to incorporate genuine GEM of participating microorganisms and creates a basic community model mimicking the human nasal environment. Our analysis supports the role of negative microbe–microbe interactions involving D. pigrum examined experimentally in the lab. By this, we identify and characterize metabolic exchange factors involved in a specific interaction between D. pigrum and S. aureus as an in silico candidate factor for a deep insight into the associated species. This method may serve as a blueprint for developing more complex microbial interaction models. Its direct application suggests new ways to prevent disease-causing infections by inhibiting the growth of pathogens such as S. aureus through microbe–microbe interactions.
Prognostic impact of tumour budding in squamous cell carcinoma of the lung: a systematic review and meta‐analysis
2022-10-11

Tumour budding is an established prognostic factor in various solid tumours, including colorectal cancers and oral squamous cell carcinomas. However, its role is unclear and needs to be defined for squamous cell carcinoma of the lung (LSCC). Hence, we conducted a systematic review and meta‐analysis investigating the prognostic role of tumour budding in LSCC. PubMed, Embase and Scopus were searched for peer‐reviewed literature investigating the association between tumour budding and survival outcomes or clinicopathological variables in LSCC. The primary outcomes were pooled estimates for overall and recurrence‐free survival with hazard ratio (HR) as the effect measure. The association between tumour budding and clinicopathological parameters was also investigated. Of 243 studies, nine were included, comprising 2546 patients. An increased risk of death [HR = 1.76, 95% confidence interval (CI) = 1.50–2.05, P &lt; 0.00001] and recurrence (HR = 1.37, 95% CI = 1.12–1.68, P = 0.003) was evident in patients with high‐grade tumour budding. Sensitivity and subgroup analyses revealed consistent results. Pathological stage II, lymph node metastasis, lymphovascular and pleural invasion were associated with high‐grade tumour budding. Tumour budding is a new and promising prognostic factor in patients with LSCC. However, pervasive heterogeneity and publication bias reduces the credibility of these findings and the applicability of tumour budding in clinical practice. Future studies are required to standardise reporting on tumour budding in LSCC.
The digital blender: conceptualizing the political economic nexus of digital technologies and authoritarian practices
2022-10-11

This article develops the concept of the digital blender to comprehensively address the extent to which digital technologies further authoritarian practices and power beyond the state. By focusing on the primarily commercial nature of digital technologies, and their reciprocal transformational political economic embeddedness, the digital blender allows to highlight the role of private companies in enabling practices that are detrimental to democratic values and processes, irrespective of the formal regime-type context of a given polity, and less confined by national borders. While previous discussions primarily focus on digital technologies as mere tools at the discretion of their master, this relational perspective allows for the incorporation of transnational non-state actors and dynamics in constituting and contesting manifestations of authoritarian power beyond the state. These dynamics will be illustrated and discussed in light of insights into recent incidents involving companies such as Cambridge Analytica, Meta Platforms Inc., and the NSO Group.
Evaluation of Adnexal Masses: The IOTA Concept
2022-10-11

Abstract Ovarian lesions have a wide range of sonomorphological features with numerous different underlying benign and malignant histologies. Based on the studies conducted by the International Ovarian Tumor Analysis (IOTA) group, ovarian masses can currently be reliably characterized by ultrasound. In the following article, we explain how to use the IOTA terms and definitions and we provide insight into how to safely triage patients with an ovarian mass.
“All mimsy were the borogoves” – a discriminative learning model of morphological knowledge in pseudo-word inflection
2022-10-11

Grammatical knowledge has often been investigated in wug tests, in which participants inflect pseudo-words. It was argued that in inflecting these pseudo-words, speakers apply their knowledge of word formation. However, it remains unclear what exactly this knowledge is and how it is learned. According to one theory, the knowledge is best characterised as abstractions that specify how units are combined. Another theory maintains that it is best characterised by memory-based analogy. In both cases the knowledge is learned by association based on positive evidence alone. In this paper, we model the classification of pseudo-words to Maltese plurals using a shallow neural network trained with an error-driven learning algorithm. We demonstrate that the classifications mirror those of Maltese speakers in a wug test. Our results indicate that speakers rely on gradient knowledge of a relation between the phonetics of whole words and plural classes, which is learned in an error-driven way.
Identification of macrocyclic peptides which allosterically activate bacterial cylindrical proteases
2022-10-11

The caseinolytic protease complex ClpXP is an important house-keeping enzyme in prokaryotes charged with the removal and degradation of misfolded and aggregated proteins and performing regulatory proteolysis. Dysregulation of its function, particularly by inhibition or allosteric activation of the proteolytic core ClpP, has proven to be a promising strategy to reduce virulence and eradicate persistent bacterial infections. Here, we report a rational drug-design approach to identify macrocyclic peptides which allosterically increase proteolysis by ClpP. This work expands the understanding of ClpP dynamics and sheds light on the conformational control exerted by its binding partner, the chaperone ClpX, by means of a chemical approach. The identified macrocyclic peptide ligands may, in the future, serve as a starting point for the development of ClpP activators for antibacterial applications.
Inflammatory CSF profiles and longitudinal development of cognitive decline in sporadic and GBA-associated PD
2022-10-11

Abstract Inflammation modifies incidence and progression of Parkinson’s disease (PD). By using 30 inflammatory markers in CSF in 498 people with PD and 67 people with Dementia with Lewy Bodies (DLB) we show that: 1) levels of ICAM-1, Interleukin-8, MCP-1, MIP-1 beta, SCF and VEGF were associated with clinical scores and neurodegenerative CSF biomarkers (Aβ1–42, t-Tau, p181-Tau, NFL and α-synuclein). 2) PD patients with GBA mutations show similar levels of inflammatory markers compared to PD patients without GBA mutations, even when stratified by mutation severity. 3) PD patients who longitudinally developed cognitive impairment during the study had higher levels of TNF-alpha at baseline compared to patients without development of cognitive impairment. 4) Higher levels of VEGF and MIP-1 beta were associated with a longer duration until development of cognitive impairment. We conclude that the majority of inflammatory markers is limited in robustly predicting longitudinal trajectories of developing cognitive impairment.
Booster dose of mRNA vaccine augments waning T cell and antibody responses against SARS-CoV-2
2022-10-12

A gradual decay in humoral and cellular immune responses over time upon SAR1S-CoV-2 vaccination may cause a lack of protective immunity. We conducted a longitudinal analysis of antibodies, T cells, and monocytes in 25 participants vaccinated with mRNA or ChAdOx1-S up to 12 weeks after the 3 rd (booster) dose with mRNA vaccine. We observed a substantial increase in antibodies and CD8 T cells specific for the spike protein of SARS-CoV-2 after vaccination. Moreover, vaccination induced activated T cells expressing CD69, CD137 and producing IFN-γ and TNF-α. Virus-specific CD8 T cells showed predominantly memory phenotype. Although the level of antibodies and frequency of virus-specific T cells reduced 4-6 months after the 2 nd dose, they were augmented after the 3 rd dose followed by a decrease later. Importantly, T cells generated after the 3 rd vaccination were also reactive against Omicron variant, indicated by a similar level of IFN-γ production after stimulation with Omicron peptides. Breakthrough infection in participants vaccinated with two doses induced more SARS-CoV-2-specific T cells than the booster vaccination. We found an upregulation of PD-L1 expression on monocytes but no accumulation of myeloid cells with MDSC-like immunosuppressive phenotype after the vaccination. Our results indicate that the 3 rd vaccination fosters antibody and T cell immune response independently from vaccine type used for the first two injections. However, such immune response is attenuated over time, suggesting thereby the need for further vaccinations.
Age‐related macular degeneration: A disease of extracellular complement amplification
2022-10-12

Summary Age‐related macular degeneration (AMD) is a major cause of vision impairment in the Western World, and with the aging world population, its incidence is increasing. As of today, for the majority of patients, no treatment exists. Multiple genetic and biochemical studies have shown a strong association with components in the complement system and AMD, and evidence suggests a major role of remodeling of the extracellular matrix underlying the outer blood/retinal barrier. As part of the innate immune system, the complement cascade acts as a first‐line defense against pathogens, and upon activation, its amplification loop ensures a strong, rapid, and sustained response. Excessive activation, however, can lead to host tissue damage and cause complement‐associated diseases like AMD. AMD patients present with aberrant activation of the alternative pathway, especially in ocular tissues but also on a systemic level. Here, we review the latest findings of complement activation in AMD, and we will discuss in vivo observations made in human tissue, cellular models, the potential synergy of different AMD‐associated pathways, and conclude on current clinical trials and the future outlook.
Genetic and environmental drivers of large-scale epigenetic variation in Thlaspi arvense
2022-10-12

Natural plant populations often harbour substantial heritable variation in DNA methylation. However, a thorough understanding of the genetic and environmental drivers of this epigenetic variation requires large-scale and high-resolution data, which currently exist only for a few model species. Here, we studied 207 lines of the annual weed Thlaspi arvense (field pennycress), collected across a large latitudinal gradient in Europe and propagated in a common environment. By screening for variation in DNA sequence and DNA methylation using whole-genome (bisulfite) sequencing, we found significant epigenetic population structure across Europe. Average levels of DNA methylation were strongly context-dependent, with highest DNA methylation in CG context, particularly in transposable elements and in intergenic regions. Residual DNA methylation variation within all contexts was associated with genetic variants, which often co-localized with annotated methylation machinery genes but also with new candidates. Variation in DNA methylation was also significantly associated with climate of origin, with methylation levels being lower in colder regions and in more variable climates. Finally, we used variance decomposition to assess genetic versus environmental associations with differentially methylated regions (DMRs). We found that while genetic variation was generally the strongest predictor of DMRs, the strength of environmental associations increased from CG to CHG and CHH, with climate-of-origin as the strongest predictor in about one third of the CHH DMRs. In summary, our data show that natural epigenetic variation in Thlaspi arvense is significantly associated with both DNA sequence and environment of origin, and that the relative importance of the two factors strongly depends on the sequence context of DNA methylation. T . arvense is an emerging biofuel and winter cover crop; our results may hence be relevant for breeding efforts and agricultural practices in the context of rapidly changing environmental conditions.
Intravascular Large B-Cell Lymphoma Genomic Profile Is Characterized by Alterations in Genes Regulating NF-κB and Immune Checkpoints
2022-10-12

Intravascular large B-cell lymphoma (IVLBCL) is an uncommon lymphoma with an aggressive clinical course characterized by selective growth of tumor cells within the vessels. Its pathogenesis is still uncertain and there is little information on the underlying genomic alterations. In this study, we performed a clinicopathologic and next-generation sequencing analysis of 15 cases of IVLBCL using a custom panel for the detection of alterations in 68 recurrently mutated genes in B-cell lymphomagenesis. Six patients had evidence of hemophagocytic syndrome. Four patients presented concomitantly a solid malignancy. Tumor cells outside the vessels were observed in 7 cases, 2 with an overt diffuse large B-cell cell lymphoma. In 4 samples, tumor cells infiltrated lymphatic vessel in addition to blood capillaries. Programmed death-ligand 1 (PD-L1) was positive in tumor cells in 4 of 11 evaluable samples and in macrophages intermingled with tumor cells in 8. PD-L1 copy number gains were identified in a higher proportion of cases expressing PD-L1 than in negative tumors. The most frequently mutated gene was PIM1 (9/15, 60%), followed by MYD88 L265P and CD79B (8/15, 53% each). In 6 cases, MYD88 L265P and CD79B mutations were detected concomitantly. We also identified recurrent mutations in IRF4 , TMEM30A , BTG2 , and ETV6 loci (4/15, 27% each) and novel driver mutations in NOTCH2 , CCND3 , and GNA13 , and an IRF4 translocation in 1 case each. The mutational profile was similar in patients with and without evidence of hemophagocytic syndrome and in cases with or without dissemination of tumor cells outside the vessels. Our results confirm the relevance of mutations in B-cell receptor/nuclear factor-κB signaling and immune escape pathways in IVLBCL and identify novel driver alterations. The similar mutational profile in tumors with extravascular dissemination suggests that these cases may also be considered in the spectrum of IVLBCL.
Single-Cell Transcriptomic Profiling in Inherited Retinal Degeneration Reveals Distinct Metabolic Pathways in Rod and Cone Photoreceptors
2022-10-12

The cellular mechanisms underlying hereditary photoreceptor degeneration are still poorly understood. The aim of this study was to systematically map the transcriptional changes that occur in the degenerating mouse retina at the single cell level. To this end, we employed single-cell RNA-sequencing (scRNA-seq) and retinal degeneration-1 (rd1) mice to profile the impact of the disease mutation on the diverse retinal cell types during early post-natal development. The transcriptome data allowed to annotate 43,979 individual cells grouped into 20 distinct clusters. We further characterized cluster-specific metabolic and biological changes in individual cell types. Our results highlight Ca2+-signaling as relevant to hereditary photoreceptor degeneration. Although metabolic reprogramming in retina, known as the ‘Warburg effect’, has been documented, further metabolic changes were noticed in rd1 mice. Such metabolic changes in rd1 mutation was likely regulated through mitogen-activated protein kinase (MAPK) pathway. By combining single-cell transcriptomes and immunofluorescence staining, our study revealed cell type-specific changes in gene expression, as well as interplay between Ca2+-induced cell death and metabolic pathways.
Functional autoantibodies in systemic sclerosis: influence of autologous stem cell transplantation and correlation with clinical outcome
2022-10-12

Abstract Objectives To evaluate the effect of autologous stem cell transplantation (aSCT) on functional antibodies (abs) to the angiotensin II type-1-receptor (AT1R) and topoisomerase-I (topo-I) in SSc-patients and to analyse their prognostic relevance. Material and methods Forty-three SSc-patients in whom aSCT was performed were analysed. Thirty-one patients had a favourable outcome after aSCT (group 1), 12 patients showed no response or relapse (group 2). Patients’ sera were tested for anti-AT1R and anti-topo-I antibodies by ELISA and in a luminometric assay (LA) using AT1R-expressing Huh7-cells for inhibitory or stimulatory anti-AT1R antibodies before and after aSCT (4–217 months, median 28 months). Anti-topo-I antibodies were also analysed for their capacity to inhibit enzyme function. Results A total of 70% of the SSc patients had anti-topo-I- and 51% anti-AT1R antibodies in the ELISA before aSCT. In all instances, anti-topo-I antibodies inhibited topo-I-enzyme function. In the LA, 40% had stimulatory and 12% inhibitory anti-AT1R antibodies. Anti-topo-I- and anti-AT1R-reactivity (ELISA) significantly decreased after aSCT. Before aSCT, anti-topo-I-reactivity was significantly higher in group 2 patients than in group 1 patients (P &amp;lt; 0.001), while there was no difference between both groups for anti-AT1R antibodies detected by ELISA. Stimulatory anti-AT1R antibodies detected by LA were confined to group 1-patients. Conclusions Reactivity of functionally active anti-AT1R antibodies was not influenced by aSCT, while anti-topo-I antibodies decreased after aSCT. The fact that anti-topo-I antibodies inhibited enzyme function in all instances supports the hypothesis of a pathogenetic role of the topo-I antigen/antibody-system in SSc. High anti-topo-I reactivity before aSCT was associated with an unfavourable, presence of stimulatory anti-AT1R antibodies with a favourable course after aSCT.
An approach for quantification of the heterogeneity of DNAPL source zone geometries
2022-10-12

Many studies have investigated the migration and entrapment processes of source zones from dense non-aqueous phase liquid (DNAPL) contamination under different conditions. However, the characterization of occupying area by source zone (or source shape) in water-saturated aquifers is still rudimentarily considered. In this study, we demonstrated this issue (1) by providing a brief review of existing approaches for source shape consideration, (2) by proposing an approach with simple shape parameters based on the non-uniformity of source widths, and (3) by providing exemplary applications of our proposed approach on shapes already published in previous research works. Our literature review suggested that the source zone in mathematical approaches is generally characterized as simple geometrical shapes (arbitrary lines or rectangles) or system-defined parameters that contrast to complex and discontinuous shapes observed in the real world. But the characterization of such complex shapes is still not possible with acceptable efforts. Therefore, we proposed an approach to parameterize the source shape by considering the variation of width and midpoints over the depth of the entire source zone and formulate four parameters based on population statistics (mean, standard deviation). To illustrate the suitability of our approach, we applied it to the results of lab experiments, and by analyzing these complex shapes, we highlighted the potential for improving the characterization techniques of non-uniformity of the source zones.
Probabilistic modeling of rational communication with conditionals
2022-10-12

While a large body of work has scrutinized the meaning of conditional sentences, considerably less attention has been paid to formal models of their pragmatic use and interpretation. Here, we take a probabilistic approach to pragmatic reasoning about indicative conditionals which flexibly integrates gradient beliefs about richly structured world states. We model listeners' update of their prior beliefs about the causal structure of the world and the joint probabilities of the consequent and antecedent based on assumptions about the speaker's utterance production protocol. We show that, when supplied with natural contextual assumptions, our model uniformly explains a number of inferences attested in the literature, including epistemic inferences, conditional perfection and the dependency between antecedent and consequent of a conditional. We argue that this approach also helps explain three puzzles introduced by Douven (2012) about updating with conditionals: depending on the utterance context, the listener's belief in the antecedent may increase, decrease or remain unchanged.