bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protective effects of a small-molecule inhibitor DDQ against tau-induced toxicities in a transgenic tau mouse model of Alzheimer’s disease
Authors: Vijayan Murali , George Mathew , Bunquin Lloyd E , Bose Chhanda , Reddy P Hemachandra 
Published: September 2021

Abstract
The purpose of our study is to determine DDQ (diethyl (3,4-dihydroxyphenethylamino) (quinolin-4-yl) methylphosphonate)—a newly discovered molecule that has been shown to protect against phosphorylated tau (p-tau) in Alzheimer’s disease (AD) pathogenesis. We used a well-studied tau (P301L) transgenic mouse model to achieve our goal. We administered DDQ into 12-month-old Tau mice, at 20 mg/kg body weight intraperitoneally two times per week for 2 months. We also assessed DDQ levels in the blood, skeletal muscle and brain using biochemical and molecular techniques. We investigated the mRNA and protein levels of mitochondrial dynamics, biogenesis, synaptic, p-tau and longevity genes sirtuins in DDQ-treated tau mice using real-time quantitative PCR (q-RT-PCR), immunoblotting and immunofluorescence techniques. Our extensive pharmacodynamics investigations revealed that skeletal muscle had the greatest peak levels of DDQ, followed by serum and brain. Interestingly, DDQ-treated tau mice had higher levels of mitochondrial fusion, biogenesis, synaptic genes and sirtuins than DDQ-untreated tau mice. In addition, DDQ-treated tau mice had lower levels of mitochondrial fission and p-tau than untreated tau mice. The current findings, combined with our prior findings, firmly show that DDQ possesses anti-aging, anti-amyloid-beta and anti-p-tau properties, making it a promising molecule for reducing age-related, amyloid-beta and p-tau-induced synaptic and mitochondrial toxicities in AD.
Mutations at a split codon in the GTPase-encoding domain of OPA1 cause dominant optic atrophy through different molecular mechanisms
Authors: Weisschuh Nicole , Marino Valerio , Schäferhoff Karin , Richter Paul , Park Joohyun , Haack Tobias B , Dell’Orco Daniele 
Published: September 2021

Abstract
Exonic (i.e. coding) variants in genes associated with disease can exert pathogenic effects both at the protein and mRNA level, either by altering the amino acid sequence or by affecting pre-mRNA splicing. The latter is often neglected due to the lack of RNA analyses in genetic diagnostic testing. In this study we considered both pathomechanisms and performed a comprehensive analysis of nine exonic nucleotide changes in OPA1, which is the major gene underlying autosomal dominant optic atrophy (DOA) and is characterized by pronounced allelic heterogeneity. We focused on the GTPase-encoding domain of OPA1, which harbors most of the missense variants associated with DOA. Given that the consensus splice sites extend into the exons, we chose a split codon, namely codon 438, for our analyses. Variants at this codon are the second most common cause of disease in our large cohort of DOA patients harboring disease-causing variants in OPA1. In silico splice predictions, heterologous splice assays, analysis of patient’s RNA when available, and protein modeling revealed different molecular outcomes for variants at codon 438. The wildtype aspartate residue at amino acid position 438 is directly involved in the dimerization of OPA1 monomers. We found that six amino acid substitutions at codon 438 (i.e. all substitutions of the first and second nucleotide of the codon) destabilized dimerization while only substitutions of the first nucleotide of the codon caused exon skipping. Our study highlights the value of combining RNA analysis and protein modeling approaches to accurately assign patients to future precision therapies.
Brain 5-HT1A Receptor PET Binding, Cortisol Responses to Stress, and the Familial Transmission of Suicidal Behavior
Authors: Melhem Nadine M , Zhong Yongqi , Miller Jeffrey M , Zanderigo Francesca , Ogden R Todd , Sublette M Elizabeth , Newell Madison , Burke Ainsley , Keilp John G , Lesanpezeshki Mohammad , Bartlett Elizabeth , Brent David A , Mann J John 
Published: September 2021

AbstractBackgroundThe serotonin 1A (5-HT1A) receptor has been implicated in depression and suicidal behavior. Lower resting cortisol levels are associated with higher 5-HT1A receptor binding, and both differentiate suicide attempters with depression. However, it is not clear whether 5-HT1A receptor binding and cortisol responses to stress are related to familial risk and resilience for suicidal behavior.Methods[11C]CUMI-101 positron emission tomography imaging to quantify regional brain 5-HT1A receptor binding was conducted in individuals considered to be at high risk for mood disorder or suicidal behavior on the basis of having a first- or second-degree relative(s) with an early onset mood disorder and history of suicidal behavior. These high-risk individuals were subdivided into the following groups: high risk resilient having no mood disorder or suicidal behavior (n = 29); high risk with mood disorder and no suicidal behavior history (n = 31); and high risk with mood disorder and suicidal behavior (n = 25). Groups were compared with healthy volunteers without a family history of mood disorder or suicidal behavior (n = 34). Participants underwent the Trier Social Stress Task (TSST). All participants were free from psychotropic medications at the time of the TSST and PET scanning.ResultsWe observed no group differences in 5-HT1A receptor binding considering all regions simultaneously, nor did we observe heterogeneity of the effect of group across regions. These results were similar across outcome measures (BPND for all participants and BPp in a subset of the sample) and definitions of regions of interest (ROIs; standard or serotonin system-specific ROIs). We also found no group differences on TSST outcomes. Within the high risk with mood disorder and suicidal behavior group, lower BPp binding (β = −0.084, SE = 0.038, P = .048) and higher cortisol reactivity to stress (β = 9.25, 95% CI [3.27,15.23], P = .004) were associated with higher lethality attempts. There were no significant relationships between 5-HT1A binding and cortisol outcomes.Conclusions5-HT1A receptor binding in ROIs was not linked to familial risk or resilience protecting against suicidal behavior or mood disorder although it may be related to lethality of suicide attempt. Future studies are needed to better understand the biological mechanisms implicated in familial risk for suicidal behavior and how hypothalamic-pituitary-adrenal axis function influences such risk.
Role of Key Infectivity Parameters in the Transmission of Ebola Virus Makona in Macaques
Authors: de La Vega Marc Antoine , Wong Gary , Wei Haiyan , He Shihua , Bello Alexander , Fausther-Bovendo Hugues , Audet Jonathan , Tierney Kevin , Tran Kaylie , Soule Geoff , Racine Trina , Strong James E , Qiu Xiangguo , Kobinger Gary P 
Published: September 2021

AbstractMany characteristics associated with Ebola virus disease remain to be fully understood. It is known that direct contact with infected bodily fluids is an associated risk factor, but few studies have investigated parameters associated with transmission between individuals, such as the dose of virus required to facilitate spread and route of infection. Therefore, we sought to characterize the impact by route of infection, viremia, and viral shedding through various mucosae, with regards to intraspecies transmission of Ebola virus in a nonhuman primate model. Here, challenge via the esophagus or aerosol to the face did not result in clinical disease, although seroconversion of both challenged and contact animals was observed in the latter. Subsequent intramuscular or intratracheal challenges suggest that viral loads determine transmission likelihood to naive animals in an intramuscular-challenge model, which is greatly facilitated in an intratracheal-challenge model where transmission from challenged to direct contact animal was observed consistently.
Influences on the assessment of resource- and animal-based welfare indicators in unweaned dairy calves for usage by farmers
Authors: Hayer Jason J , Nysar Dorit , Heinemann Céline , Leubner Caroline D , Steinhoff-Wagner Julia 
Published: September 2021

Abstract
Consumers, industrial stakeholders, and the legislature demand a stronger focus on animal welfare of all livestock at the farm level by using suitable indicators in self-assessments. In order to deduce farms’ animal welfare status reliably, factors that influence indicators’ results need to be identified. Hence, this study aimed to apply possible animal welfare indicators for unweaned dairy calves on conventional dairy farms with early cow–calf separation and evaluate influencing factors such as age and sex of calves or climatic conditions on the applied indicators’ results. An animal welfare assessment using 7 resource-based and 14 animal-based indicators was conducted at 42 typical Western German dairy farms (844 calves) in 2018 and 2019 by two observers. The effect of influencing factors was calculated by binary and ordinal logistic regressions and expressed as odds ratios. Although every unweaned calf was assessed during the farm visits, most farms had relatively few unweaned calves (average number of calves ± standard deviation = 20.1 ± 6.7 calves), with six farms having not more than 10 calves. The small sample sizes question the usage of those indicators to compare between farms and to set thresholds at the farm level. Only one assessed indicator (cleanliness core body) was not statistically affected by the evaluated influencing factors. Calf age was identified as the most decisive factor, as it affected 16 of 21 evaluated indicators, and calf age distribution on-farm varied greatly. Climatic conditions (ambient temperature and rainfall) influenced resource-based indicators such as access to concentrate and water or the cleanliness of feeding implements and bedding as well as animal-based cleanliness indicators and the occurrence of health-related impairments such as coughing and diarrhea. The authors found differences between calves on farms assessed by the different observers not only in resource-based hygiene indicators but also in animal-based indicators such as hyperthermia or hypothermia, highlighting the need for further evaluation of quality criteria in dairy calf welfare assessments. Nevertheless, animal welfare assessments by farmers themselves could be useful tools to sensitize farmers to animal welfare and thereby improve calves’ welfare.
Inactivation of the Wnt/β-catenin signaling contributes to the epithelial barrier dysfunction induced by sodium oxalate in canine renal epithelial cells
Authors: Ji Yun , Fang Shuting , Yang Ying , Wu Zhenlong 
Published: September 2021

Abstract
High oxalate consumption has been recognized as a risk factor for renal calcium oxalate stones in companion animals (dogs and cats). However, the cellular signaling involved in oxalate-induced dysfunction in renal tubular epithelial cells remains not fully elucidated. In this study, Mardin–Darby canine kidney (MDCK) cells, an epithelial cell line derived from canine kidney tubule, were tested for cell proliferation activity and barrier function after being exposed to sodium oxalate (NaOx). Further, the involvement of Wnt/β-catenin in NaOx-induced renal epithelial barrier dysfunction was evaluated. MDCK cells treated with NaOx exhibited reduction in cell proliferation and migration. Besides, NaOx exposure led to a decrease in transepithelial electrical resistance and an increase in paracellular permeability. The deleterious effects of NaOx on epithelial barrier function were related to the suppressed abundance of tight junction proteins including zonula occludens, occludin, and claudin-1. Of note, protein levels of β-catenin and phosphorylated (p)-β-catenin (Ser552) in MDCK cells were repressed by NaOx, indicating inhibitory effects on Wnt/β-catenin signaling. An inhibition of glycogen synthase kinase-3β (GSK-3β) by SB216763 enhanced the abundance of β-catenin and p-β-catenin (Ser552), and protected against epithelial barrier dysfunction in NaOx-treated MDCK cells. The results revealed a critical role of Wnt/β-catenin signaling in the epithelial barrier function of MDCK cells. Activation of Wnt/β-catenin signaling might be a potential therapeutic target for the treatment of oxalate-linked renal stones.
Endogenous Circulating Sex Hormone Concentrations and Colon Cancer Risk in Postmenopausal Women: A Prospective Study and Meta-Analysis
Authors: Mori Nagisa , Keski-Rahkonen Pekka , Gicquiau Audrey , Rinaldi Sabina , Dimou Niki , Harlid Sophia , Harbs Justin , Van Guelpen Bethany , Aune Dagfinn , Cross Amanda J , Tsilidis Konstantinos K , Severi Gianluca , Kvaskoff Marina , Fournier Agnès , Kaaks Rudolf , Fortner Renée Turzanski , Schulze Matthias B , Jakszyn Paula , Sánchez Maria-Jose , Colorado-Yohar Sandra M , Ardanaz Eva , Travis Ruth , Watts Eleanor L , Masala Giovanna , Krogh Vittorio , Tumino Rosario , Sacerdote Carlotta , Panico Salvatore , Bueno-de-Mesquita Bas , Gram Inger Torhild , Waaseth Marit , Gunter Marc J , Murphy Neil 
Published: September 2021

AbstractBackgroundObservational studies have consistently reported that postmenopausal hormone therapy use is associated with lower colon cancer risk, but epidemiologic studies examining the associations between circulating concentrations of endogenous estrogens and colorectal cancer have reported inconsistent results.MethodsWe investigated the associations between circulating concentrations of estrone, estradiol, free estradiol, testosterone, free testosterone, androstenedione, dehydroepiandrosterone (DHEA), progesterone, and sex hormone–binding globulin (SHBG) with colon cancer risk in a nested case-control study of 1028 postmenopausal European women (512 colon cancer cases, 516 matched controls) who were noncurrent users of exogenous hormones at blood collection. Multivariable conditional logistic regression models were used to compute odds ratios and 95% confidence intervals to evaluate the association between circulating sex hormones and colon cancer risk. We also conducted a dose-response meta-analysis of prospective studies of circulating estrone and estradiol with colorectal, colon, and rectal cancer risk in postmenopausal women. All statistical tests were 2-sided.ResultsIn the multivariable model, a nonstatistically significantly positive relationship was found between circulating estrone and colon cancer risk (odds ratio per log2 1-unit increment = 1.17 [95% confidence interval = 1.00 to 1.38]; odds ratioquartile4-quartile1 = 1.33 [95% confidence interval = 0.89 to 1.97], Ptrend = .20). Circulating concentrations of estradiol, free estradiol, testosterone, free testosterone, androstenedione, DHEA, progesterone, and SHBG were not associated with colon cancer risk. In the dose-response meta-analysis, no clear evidence of associations were found between circulating estradiol and estrone concentrations with colorectal, colon, and rectal cancer risk.ConclusionOur observational and meta-analysis results do not support an association between circulating concentrations of endogenous sex hormones and colon or rectal cancer in postmenopausal women.
Prospective Welfare Analysis—Extending Willingness-To-Pay Assessment to Embrace Sustainability
Authors: Inderst Roman , Thomas Stefan 
Published: September 2021

Abstract
In this paper, we outline how a future change in consumers’ willingness-to-pay can be accounted for in a consumer welfare effects analysis in antitrust. Key to our solution is the prediction of preferences of new consumers and changing preferences of existing consumers in the future. The dimension of time is inextricably linked with that of sustainability. Taking into account the welfare of future cohorts of consumers, concerns for sustainability can therefore be integrated into the consumer welfare paradigm to a greater extent. As we argue in this paper, it is expedient to consider changes in consumers’ willingness-to-pay, in particular if society undergoes profound changes in such preferences, for example, caused by an increase in generally available information on environmental effects of consumption, and a rising societal awareness about how consumption can have irreversible impacts on the environment. We offer suggestions on how to conceptionalize and operationalize the projection of such consumers’ changing preferences in a “prospective welfare analysis.” This increases the scope of the consumer welfare paradigm and can help to solve conceptual issues regarding the integration of sustainability into antitrust enforcement while keeping consumer surplus as a quantitative gauge.
Structure, stability, and optical absorption spectra of small TinCx clusters: a first-principles approach
Authors: Gámez-Valenzuela Sergio , Alonso Julio A , Santoro Gonzalo , Martínez José I 
Published: September 2021

ABSTRACT
Titanium carbide molecular clusters are thought to form in the circumstellar envelopes of carbon-rich asymptotic giant branch (AGB) stars but, to date, their detection has remained elusive. To facilitate the astrophysical identification of those clusters in AGB and post-AGB environments, the molecular structures and optical absorption spectra of small TinCx clusters, with n = 1–4 and x = 1–4, and some selected larger clusters, Ti3C8, Ti4C8, Ti6C13, Ti7C13, Ti8C12, Ti9C15, and Ti13C22, have been calculated. The density functional formalism, within the B3LYP approximation for electronic exchange and correlation, was used to find the lowest energy structures. Except the clusters having a single Ti atom, the rest exhibit three-dimensional structures. Those are formed by a Ti fragment surrounded in general by carbon dimers. The optical spectra of TinCx, computed by time-dependent density functional theory, using the corrected CAM-B3LYP functional, show absorption features in the visible and near-infrared regions which may help in the identification of these clusters in space. In addition, most of the clusters have sizable electric dipole moments, allowing their detection by radioastronomical observations.
Single-molecule conformational dynamics of a transcription factor reveals a continuum of binding modes controlling association and dissociation
Authors: Chen Wei , Lu Wei , Wolynes Peter G , Komives Elizabeth A 
Published: September 2021

AbstractBinding and unbinding of transcription factors to DNA are kinetically controlled to regulate the transcriptional outcome. Control of the release of the transcription factor NF-κB from DNA is achieved through accelerated dissociation by the inhibitor protein IκBα. Using single-molecule FRET, we observed a continuum of conformations of NF-κB in free and DNA-bound states interconverting on the subseconds to minutes timescale, comparable to in vivo binding on the seconds timescale, suggesting that structural dynamics directly control binding kinetics. Much of the DNA-bound NF-κB is partially bound, allowing IκBα invasion to facilitate DNA dissociation. IκBα induces a locked conformation where the DNA-binding domains of NF-κB are too far apart to bind DNA, whereas a loss-of-function IκBα mutant retains the NF-κB conformational ensemble. Overall, our results suggest a novel mechanism with a continuum of binding modes for controlling association and dissociation of transcription factors.
Large-scale movement of eIF3 domains during translation initiation modulate start codon selection
Authors: Llácer Jose L , Hussain Tanweer , Dong Jinsheng , Villamayor Laura , Gordiyenko Yuliya , Hinnebusch Alan G 
Published: September 2021

Abstract
The eukaryotic initiation factor 3 (eIF3) complex is involved in every step of translation initiation, but there is limited understanding of its molecular functions. Here, we present a single particle electron cryomicroscopy (cryo-EM) reconstruction of yeast 48S ribosomal preinitiation complex (PIC) in an open conformation conducive to scanning, with core subunit eIF3b bound on the 40S interface near the decoding center in contact with the ternary complex eIF2·GTP·initiator tRNA. eIF3b is relocated together with eIF3i from their solvent interface locations observed in other PIC structures, with eIF3i lacking 40S contacts. Re-processing of micrographs of our previous 48S PIC in a closed state also suggests relocation of the entire eIF3b-3i-3g-3a-Cter module during the course of initiation. Genetic analysis indicates that high fidelity initiation depends on eIF3b interactions at the 40S subunit interface that promote the closed PIC conformation, or facilitate the relocation of eIF3b/eIF3i to the solvent interface, on start codon selection.
Vaptans or voluntary increased hydration to protect the kidney: how do they compare?
Authors: Bankir Lise , Guerrot Dominique , Bichet Daniel G 
Published: September 2021

ABSTRACTThe adverse effects of vasopressin (AVP) in diverse forms of chronic kidney disease have been well described. They depend on the antidiuretic action of AVP mediated by V2 receptors (V2R). Tolvaptan, a selective V2R antagonist, is now largely used for the treatment of patients with autosomal dominant polycystic kidney disease. Another way to reduce the adverse effects of AVP is to reduce endogenous AVP secretion by a voluntary increase in fluid intake. These two approaches differ in several ways, including the level of thirst and AVP. With voluntary increased drinking, plasma osmolality will decline and so will AVP secretion. Thus, not only will V2R-mediated effects be reduced, but also those mediated by V1a and V1b receptors (V1aR and V1bR). In contrast, selective V2R antagonism will induce a loss of fluid that will stimulate AVP secretion and thus increase AVP's influence on V1a and V1b receptors. V1aR is expressed in the luminal side of the collecting duct (CD) and in inner medullary interstitial cells, and their activation induces the production of prostaglandins, mostly prostaglandin E2 (PGE2). Intrarenal PGE2 has been shown to reduce sodium and water reabsorption in the CD and increase blood flow in the renal medulla, both effects contributing to increase sodium and water excretion and reduce urine-concentrating activity. Conversely, non-steroidal anti-inflammatory drugs have been shown to induce significant water and sodium retention and potentiate the antidiuretic effects of AVP. Thus, during V2R antagonism, V1aR-mediated actions may be responsible for part of the diuresis observed with this drug. These V1aR-dependent effects do not take place with a voluntary increase in fluid intake. In summary, while both strategies may have beneficial effects, the information reviewed here leads us to assume that pharmacological V2R antagonism, with resulting stimulation of V1aR and increased PGE2 production, may provide greater benefit than voluntary high water intake. The influence of tolvaptan on the PGE2 excretion rate and the possibility to use somewhat lower tolvaptan doses than presently prescribed remain to be evaluated.