julilili42/papers huggingface dataset:
Prediabetes and the risk of type 2 diabetes: Investigating the roles of depressive and anxiety symptoms in the Lifelines cohort study
2023-02-08

Abstract Aims Depression and anxiety may increase the risk of progressing from prediabetes to type 2 diabetes. The present study examined the interactions between prediabetes status and elevated depressive and anxiety symptoms with the risk of type 2 diabetes. Methods Participants ( N = 72,428) were adults aged 40 years and above without diabetes at baseline from the Lifelines Cohort Study (58% female; mean age = 51.4 years). The Mini‐International Neuropsychiatric Interview screened for elevated symptoms of major depressive disorder and generalized anxiety disorder. Glycated haemoglobin A1c (HbA 1c ) levels determined prediabetes status at baseline (2007–2013), and HbA 1c and self‐reported diabetes diagnoses determined diabetes status at follow‐up (2014–2017). Groups were formed for elevated depressive and anxiety symptoms, respectively, and prediabetes status at baseline (elevated depressive/anxiety symptoms with prediabetes, elevated depressive/anxiety symptoms alone, and prediabetes alone), and compared to a reference group (no prediabetes or anxiety/depression) on the likelihood of developing diabetes during the follow‐up period. Results N = 1300 (1.8%) participants developed diabetes. While prediabetes alone was associated with incident diabetes (OR = 5.94; 95% CI = 5.10–6.90, p &lt; 0.001), the group with combined prediabetes and depressive symptoms had the highest likelihood of developing diabetes over follow‐up (OR = 8.29; 95% CI = 5.58–12.32, p &lt; 0.001). Similar results were found for prediabetes and anxiety symptoms (OR = 6.57; 95% CI = 4.62–9.33, p &lt; 0.001), compared to prediabetes alone (OR = 6.09; 95% CI = 5.23–7.11, p &lt; 0.001), though with a smaller effect. The interaction between depressive symptoms and prediabetes was synergistic in age‐and‐sex adjusted analyses. Conclusions Individuals with elevated depressive, and to some extent anxiety, symptoms in combination with prediabetes may represent a high‐risk subgroup for type 2 diabetes.
Powerful stories of local climate action: Comparing the evolution of narratives using the “narrative rate” index
2023-02-08

Abstract The complex relationship between local climate action and reducing global emissions is often difficult to grasp and cities might scale back their ambitions if they realize that the way is hard and rocky. We analyze local climate change narratives through the lens of the narrative policy framework (NPF). Following the NPF, policy actors use narratives to communicate information to change an existing system in order to achieve a specific goal. For our study, this implies that local climate action can be improved by using narratives to communicate information to achieve climate neutrality. We focus on the position and interplay of the most important and dominant actors and concepts in the plot of the narratives. To better analyze the main actors and content of the NPF plot in a systematic and comparable way, we offer the “narrative rate index” to dynamically trace the narratives. To include the dynamics and effects of global significant developments in the plots of the NPF narratives, we selected three phases between January 2018 and June 2021. What are the main characters and dominant actors in the plot of the narratives in the two cases? Are the narratives different depending on the context of the city, and are there general observable patterns? Our findings identify the central actors in the narratives of both cities: the science institute in Karlsruhe and the City Administration in Mannheim. Karlsruhe, a climate change pioneer, has slowed down its climate change activities somewhat, while Mannheim is a latecomer with high ambitions.
The Usher syndrome 1C protein harmonin regulates canonical Wnt signaling
2023-02-08

Human Usher syndrome (USH) is the most common form of hereditary combined deaf-blindness. USH is a complex genetic disorder, and the pathomechanisms underlying the disease are far from being understood, especially in the eye and retina. The USH1C gene encodes the scaffold protein harmonin which organizes protein networks due to binary interactions with other proteins, such as all USH proteins. Interestingly, only the retina and inner ear show a disease-related phenotype, although USH1C /harmonin is almost ubiquitously expressed in the human body and upregulated in colorectal cancer. We show that harmonin binds to β -catenin, the key effector of the canonical Wnt (cWnt) signaling pathway. We also demonstrate the interaction of the scaffold protein USH1C /harmonin with the stabilized acetylated β -catenin, especially in nuclei. In HEK293T cells, overexpression of USH1C /harmonin significantly reduced cWnt signaling, but a USH1C -R31* mutated form did not. Concordantly, we observed an increase in cWnt signaling in dermal fibroblasts derived from an USH1C R31*/R80Pfs*69 patient compared with healthy donor cells. RNAseq analysis reveals that both the expression of genes related to the cWnt signaling pathway and cWnt target genes were significantly altered in USH1C patient-derived fibroblasts compared to healthy donor cells. Finally, we show that the altered cWnt signaling was reverted in USH1C patient fibroblast cells by the application of Ataluren, a small molecule suitable to induce translational read-through of nonsense mutations, hereby restoring some USH1C expression. Our results demonstrate a cWnt signaling phenotype in USH establishing USH1C /harmonin as a suppressor of the cWnt/ β -catenin pathway.
Design and performance simulation studies of a breast PET insert integrable into a clinical whole-body PET/MRI scanner
2023-02-08

Abstract Objective . Three different breast positron emission tomography (PET) insert geometries are proposed for integration into an existing magnetic resonance imaging (MRI) breast coil (Breast Biopsy Coil, NORAS MRI products) to be used inside a whole-body PET/MRI scanner (Biograph mMR, Siemens Healthineers) to enhance the sensitivity and spatial resolution of imaging inside the breast. Approach . Monte Carlo simulations were performed to predict and compare the performance characteristics of the three geometries in terms of the sensitivity, spatial resolution, scatter fraction, and noise equivalent count rate (NECR). In addition, the background single count rate due to organ uptake in a clinical scan scenario was predicted using a realistic anthropomorphic phantom. Main results . In the center of the field of view (cFOV), absolute sensitivities of 3.1%, 2.7%, and 2.2% were found for Geometry A (detectors arranged in two cylinders), Geometry B (detectors arranged in two partial cylinders), and Geometry C (detectors arranged in two half cylinders combined with two plates), respectively. The full width at half maximum spatial resolution was determined to be 1.7 mm (Geometry A), 1.8 mm (Geometry B) and 2.0 mm (Geometry C) at 5 mm from the cFOV. Designs with multiple scintillation-crystal layers capable of determining the depth of interaction (DOI) strongly improved the spatial resolution at larger distances from the transaxial cFOV. The system scatter fractions were 33.1% (Geometries A and B) and 32.3% (Geometry C). The peak NECRs occurred at source activities of 300 MBq (Geometry A), 310 MBq (Geometry B) and 340 MBq (Geometry C). The background single-event count rates were 17.1 × 10 6 cps (Geometry A), 15.3 × 10 6 cps (Geometry B) and 14.8 × 10 6 cps (Geometry C). Geometry A in the three-layer DOI variant exhibited the best PET performance characteristics but could be challenging to manufacture. Geometry C had the lowest impact on the spatial resolution and the lowest sensitivity among the investigated geometries. Significance . Geometry B in the two-layer DOI variant represented an effective compromise between the PET performance and manufacturing difficulty and was found to be a promising candidate for the future breast PET insert.
Transmission of Basic Psychological Need Satisfaction Between Parents and Adolescents: The Critical Role of Parental Perceptions
2023-02-08

Although studies have documented the importance of basic psychological need satisfaction in parent–child relationships, a gap remains in understanding how parent and adolescent need satisfaction are associated. Using two longitudinal intergenerational data sets (200 parent–adolescent dyads and 408 mother–adolescent dyads; two waves), we examined whether (a) parents’ need satisfaction predicts adolescents’ need satisfaction (parental needs effect), (b) adolescents’ need satisfaction predicts parents’ need satisfaction (child’s needs effect), and (c) parental perception of adolescent’s need satisfaction predicts adolescents’ need satisfaction (parental perception effect). Findings from cross-lagged path models analogous to actor–partner interdependence models only supported parental perception effects: Parents’ T1 perception of their adolescent’s need satisfaction predicted their adolescent’s T2 self-reported need satisfaction, especially for autonomy and competence needs. Findings highlight the importance of parents’ perceptions, which may benefit the design of new interventions for basic psychological needs.
Metabolization of α-D-carba-glucosamine in vivo generates antimetabolites of cell wall precursors
2023-02-08

ABSTRACT α-D-Carba-glucosamine (CGlcN) is a carbocyclic analog of α-D-glucosamine that inhibits growth of Bacillus subtilis and Staphylococcus aureus . CGlcN is internalized and concomitantly phosphorylated via the phosphotransferase system yielding α-D-carba-glucosamine-6-phosphate (CGlcN6P), which interferes with expression of the glutamine-fructose-6-phosphate amidotransferase (GlmS; glucosamine synthase) by activating the glmS riboswitch. Herein, we report that CGlcN6P is efficiently metabolized to carbasugar nucleotides along the peptidoglycan biosynthetic route. Mass spectrometric analysis confirmed the occurrence of carbocyclic peptidoglycan nucleotides UDP-carba-D- N -acetyl-glucosamine (UDP-CGlcNAc) and UDP-carba-D- N -acetylmuramic acid-pentapeptide (UDP-CMurNAc-5P) in the presence of CGlcN and revealed accumulation of these carba-metabolites upon antibiotic treatment interfering with biosynthetic enzyme functions. Thus, carbocyclic carbohydrates and nucleotide analogs are generated by the promiscuous bacterial cell wall biosynthetic enzymes and act as antimetabolites, causing bacterial growth inhibition by interference with cell wall synthesis. Our findings reveal CGlcN not only as putative antibiotic molecule with previously unknown antimetabolite mode of action, but also as tool to study the bacterial cell wall metabolism, e.g., in synergy with other antibiotics.
Rapid Thermalization of Spin Chain Commuting Hamiltonians
2023-02-09

We prove that spin chains weakly coupled to a large heat bath thermalize rapidly at any temperature for finite-range, translation-invariant commuting Hamiltonians, reaching equilibrium in a time which scales logarithmically with the system size. This generalizes to the quantum regime a seminal result of Holley and Stroock from 1989 for classical spin chains and represents an exponential improvement over previous bounds based on the nonclosure of the spectral gap. We discuss the implications in the context of dissipative phase transitions and in the study of symmetry protected topological phases.
Fibroblast-expressed LRRC15 is a receptor for SARS-CoV-2 spike and controls antiviral and antifibrotic transcriptional programs
2023-02-09

Although ACE2 is the primary receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, a systematic assessment of host factors that regulate binding to SARS-CoV-2 spike protein has not been described. Here, we use whole-genome CRISPR activation to identify host factors controlling cellular interactions with SARS-CoV-2. Our top hit was a TLR -related cell surface receptor called leucine-rich repeat-containing protein 15 ( LRRC15 ). LRRC15 expression was sufficient to promote SARS-CoV-2 spike binding where they form a cell surface complex. LRRC15 mRNA is expressed in human collagen-producing lung myofibroblasts and LRRC15 protein is induced in severe Coronavirus Disease 2019 (COVID-19) infection where it can be found lining the airways. Mechanistically, LRRC15 does not itself support SARS-CoV-2 infection, but fibroblasts expressing LRRC15 can suppress both pseudotyped and authentic SARS-CoV-2 infection in trans . Moreover, LRRC15 expression in fibroblasts suppresses collagen production and promotes expression of IFIT, OAS, and MX-family antiviral factors. Overall, LRRC15 is a novel SARS-CoV-2 spike-binding receptor that can help control viral load and regulate antiviral and antifibrotic transcriptional programs in the context of COVID-19 infection.
Discovery of Novel Human Constitutive Androstane Receptor Agonists with the Imidazo[1,2-a]pyridine Structure
2023-02-09

The nuclear constitutive androstane receptor (CAR, NR1I3) plays significant roles in many hepatic functions, such as fatty acid oxidation, biotransformation, liver regeneration, as well as clearance of steroid hormones, cholesterol, and bilirubin. CAR has been proposed as a hypothetical target receptor for metabolic or liver disease therapy. Currently known prototype high-affinity human CAR agonists such as CITCO (6-(4-chlorophenyl)imidazo[2,1-<i>b</i>][1,3]thiazole-5-carbaldehyde-<i>O</i>-(3,4-dichlorobenzyl)oxime) have limited selectivity, activating the pregnane X receptor (PXR) receptor, a related receptor of the NR1I subfamily. We have discovered several derivatives of 3-(1<i>H</i>-1,2,3-triazol-4-yl)imidazo[1,2-<i>a</i>]pyridine that directly activate human CAR in nanomolar concentrations. While compound <b>39</b> regulates CAR target genes in humanized CAR mice as well as human hepatocytes, it does not activate other nuclear receptors and is nontoxic in cellular and genotoxic assays as well as in rodent toxicity studies. Our findings concerning potent human CAR agonists with in vivo activity reinforce the role of CAR as a possible therapeutic target.
The Chloroplast Envelope of Angiosperms Contains a Peptidoglycan Layer
2023-02-09

Plastids in plants are assumed to have evolved from cyanobacteria as they have maintained several bacterial features. Recently, peptidoglycans, as bacterial cell wall components, have been shown to exist in the envelopes of moss chloroplasts. Phylogenomic comparisons of bacterial and plant genomes have raised the question of whether such structures are also part of chloroplasts in angiosperms. To address this question, we visualized canonical amino acids of peptidoglycan around chloroplasts of Arabidopsis and Nicotiana via click chemistry and fluorescence microscopy. Additional detection by different peptidoglycan-binding proteins from bacteria and animals supported this observation. Further Arabidopsis experiments with D-cycloserine and AtMurE knock-out lines, both affecting putative peptidoglycan biosynthesis, revealed a central role of this pathway in plastid genesis and division. Taken together, these results indicate that peptidoglycans are integral parts of plastids in the whole plant lineage. Elucidating their biosynthesis and further roles in the function of these organelles is yet to be achieved.
P/Key: PUF based second factor authentication
2023-02-09

One-time password (OTP) mechanisms are widely used to strengthen authentication processes. In time-based one-time password (TOTP) mechanisms, the client and server store common secrets. However, once the server is compromised, the client’s secrets are easy to obtain. To solve this issue, hash-chain-based second-factor authentication protocols have been proposed. However, these protocols suffer from latency in the generation of OTPs on the client side because of the hash-chain traversal. Secondly, they can generate only a limited number of OTPs as it depends on the length of the hash-chain. In this paper, we propose a second-factor authentication protocol that utilizes Physically Unclonable Functions (PUFs) to overcome these problems. In the proposed protocol, PUFs are used to store the secrets of the clients securely on the server. In case of server compromise, the attacker cannot obtain the seeds of clients’ secrets and can not generate valid OTPs to impersonate the clients. In the case of physical attacks, including side-channel attacks on the server side, our protocol has a mechanism that prevents attackers from learning the secrets of a client interacting with the server. Furthermore, our protocol does not incur any client-side delay in OTP generation.
Genome sequencing identifies complex structural MLH1 variant in unsolved Lynch syndrome
2023-02-09

Abstract Background Lynch syndrome is one of the most common cancer predisposition syndromes. It is caused by inherited changes in the mismatch repair pathway. With current diagnostic approaches, a causative genetic variant can be found in less than 50% of cases. A correct diagnosis is important for ensuring that an appropriate surveillance program is used and that additional high‐risk family members are identified. Methods We used clinical genome sequencing on DNA from blood and subsequent transcriptome sequencing for confirmation. Data were analyzed using the megSAP pipeline and classified according to basic criteria in diagnostic laboratories. Segregation analyses in family members were conducted via breakpoint PCR. Results We present a family with the clinical diagnosis of Lynch syndrome in which standard diagnostic tests, such as panel or exome sequencing, were unable to detect the underlying genetic variant. Genome sequencing in the index patient confirmed the previous diagnostic results and identified an additional complex rearrangement with intronic breakpoints involving MLH1 and its neighboring gene LRRFIP2. The previously undetected structural variant was classified as medically relevant. Segregation analysis in the family identified additional at‐risk individuals which were offered intensified cancer screening. Discussion and Conclusions This case illustrates the advantages of clinical genome sequencing in detecting structural variants compared with current diagnostic approaches. Although structural variants are rare in Lynch syndrome families, they seem to be underreported, in part because of technical challenges. Clinical genome sequencing offers a comprehensive genetic characterization detecting a wide range of genetic variants.
Influence of Excited-State Delocalization on Singlet Fission: Tuning Triplet-Pair-State Emission in Thin Films
2023-02-09

The coherent distribution of an electronic excitation over multiple organic molecules in the solid state, namely excited-state delocalization, plays an important role in photophysical processes such as singlet fission. However, experimental studies of the influence of excited-state delocalization on singlet fission have been challenging mainly for two reasons. First, there is no easy way of measuring the excited-state delocalization, and second, tracking the resulting changes for singlet fission is demanding due to the triplet-pair state, which is a crucial intermediate in singlet fission, being an optically dark state and hence hard to access experimentally. Binary systems offer a way to adapt the growth conditions of a singlet fission material, which enables tuning of the excited-state delocalization, possibly due to the impact of structural disorder on exciton localization. By varying the growth conditions, we demonstrate that emission from the triplet-pair state via Herzberg–Teller coupling is detectable in films with low growth rates of the singlet fission material, while the triplet-pair state shows no luminescence in the other cases due to triplet dissociation outcompeting the luminescent decay. With this we find that triplet-pair state luminescence correlates with higher excited-state delocalization.
Novel Variants of SOX4 in Patients with Intellectual Disability
2023-02-09

SOX4 is a transcription factor with pleiotropic functions required for different developmental processes, such as corticogenesis. As with all SOX proteins, it contains a conserved high mobility group (HMG) and exerts its function via interaction with other transcription factors, such as POU3F2. Recently, pathogenic SOX4 variants have been identified in several patients who had clinical features overlapping with Coffin–Siris syndrome. In this study, we identified three novel variants in unrelated patients with intellectual disability, two of which were de novo (c.79G&gt;T, p.Glu27*; c.182G&gt;A p.Arg61Gln) and one inherited (c.355C&gt;T, p.His119Tyr). All three variants affected the HMG box and were suspected to influence SOX4 function. We investigated the effects of these variants on transcriptional activation by co-expressing either wildtype (wt) or mutant SOX4 with its co-activator POU3F2 and measuring their activity in reporter assays. All variants abolished SOX4 activity. While our experiments provide further support for the pathogenicity of SOX4 loss-of-function (LOF) variants as a cause of syndromic intellectual disability (ID), our results also indicate incomplete penetrance associated with one variant. These findings will improve classification of novel, putatively pathogenic SOX4 variants.
Mesenchymal Stromal Cell-Based Therapy
2023-02-09

The use of mesenchymal stromal cells (MSCs) for clinical application is intensively investigated for a variety of areas, such as bone repair, haematological and autoimmune diseases, and solid organ transplantation [...]
Processing spatial configurations in visuospatial working memory is influenced by shifts of overt visual attention
2023-02-09

When memorizing multiple objects, humans process them in relation to each other, proposing a configuration benefit. Shifts in overt visual attention through eye movements might influence the processing of spatial configurations. Whereas some research suggests that overt visual attention aids the processing of spatial representations, other research suggests a snapshot-like processing of spatial configurations, thus likely not relying on eye movements. In the first experiment, we focused on the comparison between an enforced fixation and a free view condition regarding configurational effects. Participants encoded objects’ locations and were asked for changes at retrieval. One object was displaced in half of the trials and was either accompanied by a configuration or was displayed alone. In the second experiment, we expanded this idea by enforcing fixation during different task phases, namely encoding, maintenance and retrieval. We investigated if a fixed gaze during one specific phase drives the influence of eye movements when processing spatial configurations. We observed reliable configuration benefits for the free view conditions. Whereas a fixed gaze throughout the whole trial reduced the effect, enforced fixations during the task phases did not break the configuration benefit. Our findings suggest that whereas the processing of spatial configurations in memory is supported by the ability of performing shifts of overt visual attention, configurational processing does not rely on these shifts occurring throughout the task. Our results indicate a reciprocal relationship of visuospatial working memory and eye movements.