bluuebunny/crossref_metadata_2025 huggingface dataset:
Il-10 signaling reduces survival in mouse models of synucleinopathy
Authors: Cockey Samuel G. , McFarland Karen N. , Koller Emily J. , Brooks Mieu M. T. , Gonzalez De La Cruz Elsa , Cruz Pedro E. , Ceballos-Diaz Carolina , Rosario Awilda M. , Levites Yona R. , Borchelt David R. , Golde Todd E. , Giasson Benoit I. , Chakrabarty Paramita
Published: March 2021

Parkinson’s disease (PD) and related synucleinopathies are characterized by chronic neuroinflammation leading to the premise that anti-inflammatory therapies could ameliorate synucleinopathy and associated sequelae. To test this idea, we used recombinant adeno-associated viruses (AAV) to express the anti-inflammatory cytokine, Interleukin (Il)-10, in Line M83 transgenic mice that expresses the PD-associated A53T mutant human α-synuclein (αSyn). Contrary to our expectations, we observed that intraspinal Il-10 expression initiated at birth upregulated microgliosis and led to early death in homozygous M83+/+ mice. We further observed that Il-10 preconditioning led to reduced lifespan in the hemizygous M83+/− mice injected with preformed αSyn aggregates in hindlimb muscles. To determine the mechanistic basis for these adverse effects, we took advantage of the I87A variant Il-10 (vIl-10) that has predominantly immunosuppressive properties. Sustained intraspinal expression of vIl-10 in preformed αSyn-aggregate seeded M83+/− mice resulted in earlier death, accelerated αSyn pathology, pronounced microgliosis, and increased apoptosis compared to control mice. AAV-vIl-10 expression robustly induced p62 and neuronal LC3B accumulation in these mice, indicating that Il-10 signaling mediated preconditioning of the neuraxis can potentially exacerbate αSyn accumulation through autophagy dysfunction in the neurons. Together, our data demonstrate unexpected adverse effects of both Il-10 and its immunosuppressive variant, vIl-10, in a mouse model of PD, highlighting the pleiotropic functions of immune mediators and their complex role in non-cell autonomous signaling in neurodegenerative proteinopathies.
Peripheral decarboxylase inhibitors paradoxically induce aromatic L-amino acid decarboxylase
Authors: van Rumund Anouke , Pavelka Lukas , Esselink Rianne A. J. , Geurtz Ben P. M. , Wevers Ron A. , Mollenhauer Brit , Krüger Rejko , Bloem Bastiaan R. , Verbeek Marcel M.
Published: March 2021

Peripheral decarboxylase inhibitors (PDIs) prevent conversion of levodopa to dopamine in the blood by the enzyme aromatic L-amino acid decarboxylase (AADC). Alterations in enzyme activity may contribute to the required higher dosages of levodopa observed in many patients with Parkinson’s disease. We evaluated the effect of levodopa/PDI use on serum AADC enzyme activity. Serum AADC enzyme activity was evaluated in three independent cohorts of patients with Parkinson’s disease or parkinsonism (n = 301) and compared between patients on levodopa/PDI vs. patients not on this medication. AADC enzyme activity was elevated in 62% of patients on levodopa/PDI treatment, compared to 19% of patients not on levodopa/PDI (median 90 mU/L vs. 50 mU/L, p < 0.001). Patients with elevated AADC activity had longer disease duration and higher doses of levodopa/PDI. These findings may implicate that peripheral AADC induction could underlie a waning effect of levodopa, necessitating dose increases to maintain a sustained therapeutic effect.
Electronic reconstruction forming a C2-symmetric Dirac semimetal in Ca3Ru2O7
Authors: Horio M. , Wang Q. , Granata V. , Kramer K. P. , Sassa Y. , Jöhr S. , Sutter D. , Bold A. , Das L. , Xu Y. , Frison R. , Fittipaldi R. , Kim T. K. , Cacho C. , Rault J. E. , Fèvre P. Le , Bertran F. , Plumb N. C. , Shi M. , Vecchione A. , Fischer M. H. , Chang J.
Published: March 2021

Electronic band structures in solids stem from a periodic potential reflecting the structure of either the crystal lattice or electronic order. In the stoichiometric ruthenate Ca3Ru2O7, numerous Fermi surface-sensitive probes indicate a low-temperature electronic reconstruction. Yet, the causality and the reconstructed band structure remain unsolved. Here, we show by angle-resolved photoemission spectroscopy, how in Ca3Ru2O7 a C2-symmetric massive Dirac semimetal is realized through a Brillouin-zone preserving electronic reconstruction. This Dirac semimetal emerges in a two-stage transition upon cooling. The Dirac point and band velocities are consistent with constraints set by quantum oscillation, thermodynamic, and transport experiments, suggesting that the complete Fermi surface is resolved. The reconstructed structure—incompatible with translational-symmetry-breaking density waves—serves as an important test for band structure calculations of correlated electron systems.
Heterogeneity of mesenchymal stem cells in cartilage regeneration: from characterization to application
Authors: Zha Kangkang , Li Xu , Yang Zhen , Tian Guangzhao , Sun Zhiqiang , Sui Xiang , Dai Yongjing , Liu Shuyun , Guo Quanyi
Published: March 2021

Articular cartilage is susceptible to damage but hard to self-repair due to its avascular nature. Traditional treatment methods are not able to produce satisfactory effects. Mesenchymal stem cells (MSCs) have shown great promise in cartilage repair. However, the therapeutic effect of MSCs is often unstable partly due to their heterogeneity. Understanding the heterogeneity of MSCs and the potential of different types of MSCs for cartilage regeneration will facilitate the selection of superior MSCs for treating cartilage damage. This review provides an overview of the heterogeneity of MSCs at the donor, tissue source and cell immunophenotype levels, including their cytological properties, such as their ability for proliferation, chondrogenic differentiation and immunoregulation, as well as their current applications in cartilage regeneration. This information will improve the precision of MSC-based therapeutic strategies, thus maximizing the efficiency of articular cartilage repair.
AS03-adjuvanted H7N9 inactivated split virion vaccines induce cross-reactive and protective responses in ferrets
Authors: Stadlbauer Daniel , Waal Leon de , Beaulieu Edith , Strohmeier Shirin , Kroeze Edwin J. B. Veldhuis , Boutet Philippe , Osterhaus Albert D. M. E. , Krammer Florian , Innis Bruce L. , Nachbagauer Raffael , Stittelaar Koert J. , Mallett Corey P.
Published: March 2021

Human infections with avian H7N9 subtype influenza viruses are a major public health concern and vaccines against H7N9 are urgently needed for pandemic preparedness. In early 2013, novel H7N9 influenza viruses emerged in China that caused about 1600 human cases of infection with a high associated case fatality rate. In this study, two H7N9 split virion vaccines with or without AS03 adjuvant were tested in the naive ferret model. Serological analyses demonstrated that homologous hemagglutination inhibition and microneutralization antibody titers were detectable in the ferrets after the first immunization with the AS03-adjuvanted vaccines that were further boosted by the second immunization. In addition, heterologous antibody titers against older H7 subtype viruses of the North American lineage (H7N7, H7N3) and newer H7 subtype viruses of the Eurasian lineage (H7N9) were detected in the animals receiving the AS03-adjuvanted vaccines. Animals receiving two immunizations of the AS03-adjuvanted vaccines were protected from weight loss and fever in the homologous challenge study and had no detectable virus in throat or lung samples. In addition, microscopic examination post-challenge showed animals immunized with the AS03-adjuvanted vaccines had the least signs of lung injury and inflammation, consistent with the greater relative efficacy of the adjuvanted vaccines. In conclusion, this study demonstrated that the AS03-adjuvanted H7N9 vaccines elicited high levels of homologous and heterologous antibodies and protected against H7N9 virus damage post-challenge.
Disulfide HMGB1 acts via TLR2/4 receptors to reduce the numbers of oligodendrocyte progenitor cells after traumatic injury in vitro
Authors: Ved R. , Sharouf F. , Harari B. , Muzaffar M. , Manivannan S. , Ormonde C. , Gray W. P. , Zaben M.
Published: March 2021

Traumatic brain injury (TBI) is associated with poor clinical outcomes; autopsy studies of TBI victims demonstrate significant oligodendrocyte progenitor cell (OPC) death post TBI; an observation, which may explain the lack of meaningful repair of injured axons. Whilst high-mobility group box-1 (HMGB1) and its key receptors TLR2/4 are identified as key initiators of neuroinflammation post-TBI, they have been identified as attractive targets for development of novel therapeutic approaches to improve post-TBI clinical outcomes. In this report we establish unequivocal evidence that HMGB1 released in vitro impairs OPC response to mechanical injury; an effect that is pharmacologically reversible. We show that needle scratch injury hyper-acutely induced microglial HMGB1 nucleus-to-cytoplasm translocation and subsequent release into culture medium. Application of injury-conditioned media resulted in significant decreases in OPC number through anti-proliferative effects. This effect was reversed by co-treatment with the TLR2/4 receptor antagonist BoxA. Furthermore, whilst injury conditioned medium drove OPCs towards an activated reactive morphology, this was also abolished after BoxA co-treatment. We conclude that HMGB1, through TLR2/4 dependant mechanisms, may be detrimental to OPC proliferation following injury in vitro, negatively affecting the potential for restoring a mature oligodendrocyte population, and subsequent axonal remyelination. Further study is required to assess how HMGB1-TLR signalling influences OPC maturation and myelination capacity.
The dear enemy effect drives conspecific aggressiveness in an Azteca-Cecropia system
Authors: Zorzal Gabriela , Camarota Flávio , Dias Marcondes , Vidal Diogo M. , Lima Eraldo , Fregonezi Aline , Campos Ricardo I.
Published: March 2021

Territoriality is costly, and the accurate identification of intruders and the decision to perform aggressive responses are key behavioral traits in social animals. We studied aggression among individuals belonging to close and distant nests of the plant-antAzteca muelleri, which lives in stems of the pioneer treeCecropia glaziovii. More specifically, we aim to investigate if the DE (dear-enemy effect—less aggression towards neighbors than strangers) or NN (nasty-neighbor effect—less aggression to strangers than neighbors) effects or even none of them apply for this iconic Azteca-Cecropia system. We further checked if ant aggression towards conspecifics is related to cuticular hydrocarbon profiles (CHCs), which provide chemical cues for nestmate recognition. Therefore, we sampled 46 nests ofA.muelleriin three Brazilian Atlantic forest fragments and performed behavioral trials within and between sites. Consistently with the DE effect, we found higher aggression levels in ‘between sites’ versus ‘within sites’ treatments as well as a positive effect of spatial distance on ant aggressiveness. We found no effect of the overall dissimilarities on CHC blend on ant aggressiveness, but of one CHC class, the methylated alkanes. Overall, we provide key insights on nest-mate recognition in obligatory ant-plant mutualisms.
Development of a rapid scabies immunodiagnostic assay based on transcriptomic analysis of Sarcoptes scabiei var. nyctereutis
Authors: Akuta Teruo , Minegishi Daisuke , Kido Nobuhide , Imaizumi Keitaro , Nakaoka Shinji , Tachibana Shin-Ichiro , Hikosaka Kenji , Hori Fumi , Masataka  , Nakagawa  , Sakuma Chiaki , Oouchi Yuki , Nakajima Yu , Tanaka Sohei , Omiya Tomoko , Morikaku Kouki , Kawahara Minori , Tada Yoshifumi , Tarui Hiroshi , Ueda Takafumi , Kikuchi-Ueda Takane , Ono Yasuo
Published: March 2021

Scabies is a highly contagious skin disease caused by the mite Sarcoptes scabiei that affects many mammals. However, the sensitivity of traditional tests for scabies diagnosis in humans is less than 50%. To simplify the diagnosis of scabies, methods that are simple, sensitive, specific, and cost-effective are required. We developed an immunodiagnostic test based on S. scabiei var. nyctereutis RNA-seq data collected from Japanese raccoon dogs with sarcoptic mange. Three candidate antigens—a highly expressed hypothetical protein “QR98_0091190,” another mite allergen known as “SMIPP-Cc,” and an abundant “vitellogenin-like protein”—were evaluated by western-blot analysis. A lateral flow immunoassay, using specific antibodies against the vitellogenin-like protein, successfully detected scabies in the skin flakes of S. scabiei-infected raccoon dogs. This assay can potentially diagnose scabies more accurately in wildlife, as well as in humans.
Discontinuous phase transitions in the multi-state noisy q-voter model: quenched vs. annealed disorder
Authors: Nowak Bartłomiej , Stoń Bartosz , Sznajd-Weron Katarzyna
Published: March 2021

We introduce a generalized version of the noisy q-voter model, one of the most popular opinion dynamics models, in which voters can be in one of $$s \ge 2$$

s
≥
2

states. As in the original binary q-voter model, which corresponds to $$s=2$$

s
=
2

, at each update randomly selected voter can conform to its q randomly chosen neighbors only if they are all in the same state. Additionally, a voter can act independently, taking a randomly chosen state, which introduces disorder to the system. We consider two types of disorder: (1) annealed, which means that each voter can act independently with probability p and with complementary probability $$1-p$$

1
-
p

conform to others, and (2) quenched, which means that there is a fraction p of all voters, which are permanently independent and the rest of them are conformists. We analyze the model on the complete graph analytically and via Monte Carlo simulations. We show that for the number of states $$s>2$$

s
>
2

the model displays discontinuous phase transitions for any $$q>1$$

q
>
1

, on contrary to the model with binary opinions, in which discontinuous phase transitions are observed only for $$q>5$$

q
>
5

. Moreover, unlike the case of $$s=2$$

s
=
2

, for $$s>2$$

s
>
2

discontinuous phase transitions survive under the quenched disorder, although they are less sharp than under the annealed one.
Vaginal microbiome and serum metabolite differences in late gestation commercial sows at risk for pelvic organ prolapse
Authors: Kiefer Zoë E. , Koester Lucas R. , Showman Lucas , Studer Jamie M. , Chipman Amanda L. , Keating Aileen F. , Schmitz-Esser Stephan , Ross Jason W.
Published: March 2021

Sow mortality attributable to pelvic organ prolapse (POP) has increased in the U.S. swine industry and continues to worsen. Two main objectives of this study were, (1) to develop a perineal scoring system that can be correlated with POP risk, and (2) identify POP risk-associated biological factors. To assess POP risk during late gestation, sows (n = 213) were scored using a newly developed perineal scoring (PS) system. Sows scored as PS1 (low), PS2 (moderate), or PS3 (high) based on POP risk. Subsequently, 1.5, 0.8, and 23.1% of sows scored PS1, PS2, or PS3, respectively, experienced POP. To identify biomarkers, serum and vaginal swabs were collected from late gestation sows differing in PS. Using GC–MS, 82 serum metabolite differences between PS1 and PS3 animals (P < 0.05) were identified. Vaginal swabs were utilized for 16S rRNA gene sequencing and differences in vaginal microbiomes between PS1 and PS3 animals were detected on a community level (P < 0.01) along with differences in abundances of 89 operational taxonomic units (P < 0.05). Collectively, these data demonstrate that sows with greater POP risk have differential serum metabolites and vaginal microflora. Additionally, an initial and novel characterization of the sow vaginal microbiome was determined.
Initial cell density encodes proliferative potential in cancer cell populations
Authors: Enrico Bena Chiara , Del Giudice Marco , Grob Alice , Gueudré Thomas , Miotto Mattia , Gialama Dimitra , Osella Matteo , Turco Emilia , Ceroni Francesca , De Martino Andrea , Bosia Carla
Published: March 2021

Individual cells exhibit specific proliferative responses to changes in microenvironmental conditions. Whether such potential is constrained by the cell density throughout the growth process is however unclear. Here, we identify a theoretical framework that captures how the information encoded in the initial density of cancer cell populations impacts their growth profile. By following the growth of hundreds of populations of cancer cells, we found that the time they need to adapt to the environment decreases as the initial cell density increases. Moreover, the population growth rate shows a maximum at intermediate initial densities. With the support of a mathematical model, we show that the observed interdependence of adaptation time and growth rate is significantly at odds both with standard logistic growth models and with the Monod-like function that governs the dependence of the growth rate on nutrient levels. Our results (i) uncover and quantify a previously unnoticed heterogeneity in the growth dynamics of cancer cell populations; (ii) unveil how population growth may be affected by single-cell adaptation times; (iii) contribute to our understanding of the clinically-observed dependence of the primary and metastatic tumor take rates on the initial density of implanted cancer cells.
Potential benefits of L. acidophilus in dyslipidemic rats
Authors: Reamtong Onrapak , Thiangtrongjit Tipparat , Kosoltanapiwat Nathamon , Panbangred Watanalai , Prangthip Pattaneeya
Published: March 2021

Several studies have shown that probiotics and synbiotics ameliorate dyslipidemia. However, the molecular mechanisms mediating their effects remain to be determined. Therefore, we aimed to compare the effects of a probiotic, a prebiotic, and a synbiotic in dyslipidemic Sprague–Dawley rats, and explore the mechanisms involved using a proteomic approach. The rats were allocated to five groups: a control group that was fed normal chow, and four high-fat diet-fed groups, three of which were administered a probiotic (Lactobacillus acidophilus), a prebiotic (inulin), or a combination of the two (a synbiotic) for 30 days. We showed that the administration of inulin, and especially L. acidophilus, improved the lipid profile and reduced the serum concentrations of inflammatory markers in high-fat diet-fed rats. Proteomic analysis showed changes in lipid elongation, glycerolipid metabolism, activation of antioxidants, and a reduction in the activation of the mitogen-activated protein kinase signaling pathway in the livers of rats administered L. acidophilus, which likely mediate its beneficial effects on inflammation and dyslipidemia by reduced the levels of 18.56% CRP, 35.71% TNF-α 25.6% LDL-C and 28.57% LDL-C/HDL-C ratio when compared to HF group. L. acidophilus and inulin may represent effective natural means of maintaining inflammation and dyslipidemia.
Nitrocellulose-bound achromopeptidase for point-of-care nucleic acid tests
Authors: Chondrogiannis Georgios , Khaliliazar Shirin , Toldrà Anna , Réu Pedro , Hamedi Mahiar M.
Published: March 2021

Enzymes are the cornerstone of modern biotechnology. Achromopeptidase (ACP) is a well-known enzyme that hydrolyzes a number of proteins, notably proteins on the surface of Gram-positive bacteria. It is therefore used for sample preparation in nucleic acid tests. However, ACP inhibits DNA amplification which makes its integration difficult. Heat is commonly used to inactivate ACP, but it can be challenging to integrate heating into point-of-care devices. Here, we use recombinase polymerase amplification (RPA) together with ACP, and show that when ACP is immobilized on nitrocellulose paper, it retains its enzymatic function and can easily and rapidly be activated using agitation. The nitrocellulose-bound ACP does, however, not leak into the solution, preventing the need for deactivation through heat or by other means. Nitrocellulose-bound ACP thus opens new possibilities for paper-based Point-of-Care (POC) devices.
The medium-chain fatty acid decanoic acid reduces oxidative stress levels in neuroblastoma cells
Authors: Mett Janine , Müller Uli
Published: March 2021

Enhanced oxidative stress is a contributing factor in the pathogenesis of several neurodegenerative disorders such as Alzheimer´s disease. Beneficial effects have been demonstrated for medium-chain fatty acids (MCFAs) nutritionally administered as medium-chain triglycerides (MCTs) or coconut oil (CO). The observed effects on cognitive impairment are generally attributed to the hepatic metabolism of MCFAs, where resulting ketone bodies serve as an alternate energy source to compensate for the impaired glucose utilisation in the human brain. Here we show that the saturated MCFA decanoic acid (10:0) reduces the oxidative stress level in two different neuroblastoma cell lines. Phosphatidylcholine (PC) containing decanoic acid (10:0) (PC10:0/10:0) reduced the cellular H2O2 release in comparison to solvent, L-α-Glycerophosphorylcholine and PC containing the long-chain fatty acid (LCFA) arachidic acid (20:0). This effect seems to be at least partially based on an upregulation of catalase activity, independent of alterations in catalase gene expression. Further, PC10:0/10:0 decreased the intracellular oxidative stress level and attenuated the H2O2-induced cell death. It did not affect the level of the ketone body β-hydroxybutyrate (βHB). These results indicate that decanoic acid (10:0) and possibly MCFAs in general directly reduce oxidative stress levels independent of ketone levels and thus may promote neuronal health.
Population pharmacokinetics and dose optimization of vancomycin in neonates
Authors: Lee Soon Min , Yang Seungwon , Kang Soyoung , Chang Min Jung
Published: March 2021

The pharmacokinetics of vancomycin vary among neonates, and we aimed to conduct population pharmacokinetic analysis to determine the optimal dosage of vancomycin in Korean neonates. From a retrospective chart review, neonates treated with vancomycin from 2008 to 2017 in a neonatal intensive care unit (NICU) were included. Vancomycin concentrations were collected based on therapeutic drug monitoring, and other patient characteristics were gathered through electronic medical records. We applied nonlinear mixed-effect modeling to build the population pharmacokinetic model. One- and two-compartment models with first-order elimination were evaluated as potential structural pharmacokinetic models. Allometric and isometric scaling was applied to standardize pharmacokinetic parameters for clearance and volume of distribution, respectively, using fixed powers (0.75 and 1, respectively, for clearance and volume). The predictive performance of the final model was developed, and dosing strategies were explored using Monte Carlo simulations with AUC0–24 targets 400–600. The patient cohort included 207 neonates, and 900 vancomycin concentrations were analyzed. Only 37.4% of the analyzed concentrations were within trough concentrations 5–15 µg/mL. A one-compartment model with first-order elimination best described the vancomycin pharmacokinetics in neonates. Postmenstrual age (PMA) and creatinine clearance (CLcr) affected the clearance of vancomycin, and model evaluation confirmed the robustness of the final model. Population pharmacokinetic modeling and dose optimization of vancomycin in Korean neonates showed that vancomycin clearance was related to PMA and CLcr, as well as body weight. A higher dosage regimen than the typical recommendation is suggested.
Histopathological lesions of congenital Zika syndrome in newborn squirrel monkeys
Authors: de Alcantara Bianca Nascimento , Imbeloni Aline Amaral , de Brito Simith Durans Darlene , de Araújo Marialva Tereza Ferreira , do Rosário Moutinho da Cruz Ermelinda , de Carvalho Carlos Alberto Marques , de Mendonça Maria Helena Rodrigues , de Sousa Jorge Rodrigues , Moraes Adriana Freitas , Filho Arnaldo Jorge Martins , de Lourdes Gomes Lima Maria , Neto Orlando Pereira Amador , Chiang Jannifer Oliveira , de Azevedo Scalercio Sarah Raphaella Rocha , Carneiro Liliane Almeida , Quaresma Juarez Antônio Simões , da Costa Vasconcelos Pedro Fernando , de Almeida Medeiros Daniele Barbosa
Published: March 2021

The absence of an adequate animal model for studies has limited the understanding of congenital Zika syndrome (CZS) in humans during the outbreak in America. In this study, we used squirrel monkeys (Saimiri collinsi), a neotropical primate (which mimics the stages of human pregnancy), as a model of Zika virus (ZIKV) infection. Seven pregnant female squirrel monkeys were experimentally infected at three different gestational stages, and we were able reproduce a broad range of clinical manifestations of ZIKV lesions observed in newborn humans. Histopathological and immunohistochemical analyses of early-infected newborns (2/4) revealed damage to various areas of the brain and ZIKV antigens in the cytoplasm of neurons and glial cells, indicative of CZS. The changes caused by ZIKV infection were intrauterine developmental delay, ventriculomegaly, simplified brain gyri, vascular impairment and neuroprogenitor cell dysfunction. Our data show that the ZIKV infection outcome in squirrel monkeys is similar to that in humans, indicating that this model can be used to help answer questions about the effect of ZIKV infection on neuroembryonic development and the morphological changes induced by CZS.
Difference of binding modes among three ligands to a receptor mSin3B corresponding to their inhibitory activities
Authors: Hayami Tomonori , Kamiya Narutoshi , Kasahara Kota , Kawabata Takeshi , Kurita Jun-ichi , Fukunishi Yoshifumi , Nishimura Yoshifumi , Nakamura Haruki , Higo Junichi
Published: March 2021

A preceding experiment suggested that a compound, which inhibits binding of the REST/NRSF segment to the cleft of a receptor protein mSin3B, can be a potential drug candidate to ameliorate many neuropathies. We have recently developed an enhanced conformational sampling method, genetic-algorithm-guided multi-dimensional virtual-system-coupled canonical molecular dynamics, and in the present study, applied it to three systems consisting of mSin3B and one of three compounds, sertraline, YN3, and acitretin. Other preceding experiments showed that only sertraline inhibits the binding of REST/NRSF to mSin3B. The current simulation study produced the spatial distribution of the compounds around mSin3B, and showed that sertraline and YN3 bound to the cleft of mSin3B with a high propensity, although acitretin did not. Further analyses of the simulation data indicated that only the sertraline–mSin3B complex produced a hydrophobic core similar to that observed in the molecular interface of the REST/NRSF-mSin3B complex: An aromatic ring of sertraline sunk deeply in the mSin3B’s cleft forming a hydrophobic core contacting to hydrophobic amino-acid residues located at the bottom of the cleft. The present study proposes a step to design a compound that inhibits competitively the binding of a ligand to its receptor.
Enhancing the compost maturation of swine manure and rice straw by applying bioaugmentation
Authors: Wang Wei-Kuang , Liang Chih-Ming
Published: March 2021

Microorganisms capable of decomposing cellulose, xylan, starch and protein were individually isolated from swine manure compost and soil in this study. The correlations with pH, carbon source concentration, C/N ratio and enzyme activity among these isolated microorganisms were also investigated. Furthermore, the effect of additional inoculation in the compost was studied by measuring variations in the C/N ratio, enzyme activity and compost maturation rate. The inoculated microorganisms used in this study included four bacterial isolates and one commercial microorganism Phanerochaete chrysosporium. The results indicated that the isolated Kitasatospora phosalacinea strain C1, which is a cellulose-degraded microorganism, presented the highest enzyme activity at 31 ℃ and pH 5.5, while the C/N ratio was 0.8%. The isolated xylan-degraded microorganism Paenibacillus glycanilyticus X1 had the highest enzyme activity at 45 ℃ and pH 7.5, while the C/N ratio was 0.5%. The starch-degraded microorganism was identified as Bacillus licheniformis S3, and its highest enzyme activities were estimated to be 31 ℃ and pH 7.5 while the C/N ratio was 0.8%. The highest enzyme activity of the protein-degraded microorganism Brevinacillus agri E4 was obtained at 45 ℃ and pH 8.5, while the C/N ratio was 1.0%. The rate of temperature increase in the compost inoculated with P. chrysosporium was only higher than that of the compost without inoculation, and its compost maturation level was also lower than that of other composts with additional inoculation. The optimal initial C/N ratio of the compost was 27.5 and the final C/N ratio was 18.9. The composting results also indicated that the secondary inoculation would benefit compost maturation, and the lowest final C/N ratio of 17.0 was obtained.
Antibodies against EGF-like domains in Ixodes scapularis BM86 orthologs impact tick feeding and survival of Borrelia burgdorferi
Authors: Koči Juraj , Bista Sandhya , Chirania Payal , Yang Xiuli , Kitsou Chrysoula , Rana Vipin Singh , Yas Ozlem Buyuktanir , Sonenshine Daniel E. , Pal Utpal
Published: March 2021

Ixodes scapularisticks transmit multiple pathogens, includingBorrelia burgdorferisensu stricto, and encode many proteins harboring epidermal growth factor (EGF)-like domains. We show thatI. scapularisproduces multiple orthologs for Bm86, a widely studied tick gut protein considered as a target of an anti-tick vaccine, herein termed as Is86. We show that Is86 antigens feature at least three identifiable regions harboring EGF-like domains (termed as EGF-1, EGF-2, and EGF-3) and are differentially upregulated duringB. burgdorferiinfection. Although the RNA interference-mediated knockdown ofIs86genes did not show any influences on tick engorgement orB. burgdorferisensu stricto persistence, the immunization of murine hosts with specific recombinant EGF antigens marginally reduced spirochete loads in the skin, in addition to affecting tick blood meal engorgement and molting. However, given the borderline impact of EGF immunization on tick engorgement and pathogen survival in the vector, it is unlikely that these antigens, at least in their current forms, could be developed as potential vaccines. Further investigations of the biological significance of Is86 (and other tick antigens) would enrich our knowledge of the intricate biology of ticks, including their interactions with resident pathogens, and contribute to the development of anti-tick measures to combat tick-borne illnesses.
Cryogenic cave carbonate and implications for thawing permafrost at Winter Wonderland Cave, Utah, USA
Authors: Munroe Jeffrey , Kimble Kristin , Spötl Christoph , Marks Gabriela Serrato , McGee David , Herron David
Published: March 2021

Winter Wonderland Cave contains perennial ice associated with two types of cryogenic cave carbonate (CCC) formed during the freezing of water. CCCfine is characterized by relatively high δ13C values, whereas CCCcoarse exhibits notably low δ18O values indicating precipitation under (semi)closed-system conditions in a pool of residual water beneath an ice lid. Previous work has concluded that CCCcoarse forms during permafrost thaw, making the presence of this precipitate a valuable indicator of past cryospheric change. Available geochronologic evidence indicates that CCC formation in this cave is a Late Holocene or contemporary process, and field observations suggest that the cave thermal regime recently changed in a manner that permits the ingress of liquid water. This is the first documented occurence of CCCcoarse in the Western Hemisphere and one of only a few locations where these minerals have been found in association with ice. Winter Wonderland Cave is a natural laboratory for studying CCC genesis.
Practical lineshape of a laser operating near an exceptional point
Authors: Kim Jinuk , Kim Juman , Seo Jisung , Park Kyu-Won , Moon Songky , An Kyungwon
Published: March 2021

We present a practical laser linewidth broadening phenomenon in the viewpoint of high sensitivity of an exceptional point (EP). A stochastic simulation model is implemented to describe the fluctuations in the cavity resonance frequencies. The linewidth originated from external noises are maximized at the EP. The linewidth enhancement factor behaves similarly to the Petermann factor although the Petermann effect is not considered. In the long coherence time limit, the power spectral density of the laser exhibits a splitting in the vicinity of the EP although the cavity eigenfrequencies coalesce at the EP.
Self-rated health in individuals with and without disease is associated with multiple biomarkers representing multiple biological domains
Authors: Kananen L. , Enroth L. , Raitanen J. , Jylhävä J. , Bürkle A. , Moreno-Villanueva M. , Bernhardt J. , Toussaint O. , Grubeck-Loebenstein B. , Malavolta M. , Basso A. , Piacenza F. , Collino S. , Gonos E. S. , Sikora E. , Gradinaru D. , Jansen E. H. J. M. , Dollé M. E. T. , Salmon M. , Stuetz W. , Weber D. , Grune T. , Breusing N. , Simm A. , Capri M. , Franceschi C. , Slagboom P. E. , Talbot D. C. S. , Libert C. , Koskinen S. , Bruunsgaard H. , Hansen ÅM. , Lund R. , Hurme M. , Jylhä M.
Published: March 2021

Self-rated health (SRH) is one of the most frequently used indicators in health and social research. Its robust association with mortality in very different populations implies that it is a comprehensive measure of health status and may even reflect the condition of the human organism beyond clinical diagnoses. Yet the biological basis of SRH is poorly understood. We used data from three independent European population samples (N approx. 15,000) to investigate the associations of SRH with 150 biomolecules in blood or urine (biomarkers). Altogether 57 biomarkers representing different organ systems were associated with SRH. In almost half of the cases the association was independent of disease and physical functioning. Biomarkers weakened but did not remove the association between SRH and mortality. We propose three potential pathways through which biomarkers may be incorporated into an individual’s subjective health assessment, including (1) their role in clinical diseases; (2) their association with health-related lifestyles; and (3) their potential to stimulate physical sensations through interoceptive mechanisms. Our findings indicate that SRH has a solid biological basis and it is a valid but non-specific indicator of the biological condition of the human organism.
Distant metastasis time to event analysis with CNNs in independent head and neck cancer cohorts
Authors: Lombardo Elia , Kurz Christopher , Marschner Sebastian , Avanzo Michele , Gagliardi Vito , Fanetti Giuseppe , Franchin Giovanni , Stancanello Joseph , Corradini Stefanie , Niyazi Maximilian , Belka Claus , Parodi Katia , Riboldi Marco , Landry Guillaume
Published: March 2021

Deep learning models based on medical images play an increasingly important role for cancer outcome prediction. The standard approach involves usage of convolutional neural networks (CNNs) to automatically extract relevant features from the patient’s image and perform a binary classification of the occurrence of a given clinical endpoint. In this work, a 2D-CNN and a 3D-CNN for the binary classification of distant metastasis (DM) occurrence in head and neck cancer patients were extended to perform time-to-event analysis. The newly built CNNs incorporate censoring information and output DM-free probability curves as a function of time for every patient. In total, 1037 patients were used to build and assess the performance of the time-to-event model. Training and validation was based on 294 patients also used in a previous benchmark classification study while for testing 743 patients from three independent cohorts were used. The best network could reproduce the good results from 3-fold cross validation [Harrell’s concordance indices (HCIs) of 0.78, 0.74 and 0.80] in two out of three testing cohorts (HCIs of 0.88, 0.67 and 0.77). Additionally, the capability of the models for patient stratification into high and low-risk groups was investigated, the CNNs being able to significantly stratify all three testing cohorts. Results suggest that image-based deep learning models show good reliability for DM time-to-event analysis and could be used for treatment personalisation.
Author Correction: Episiotomy practices in France: epidemiology and risk factors in non-operative vaginal deliveries
Authors: Clesse Christophe , Cottenet Jonathan , Lighezzolo-Alnot Joelle , Goueslard Karine , Scheffler Michele , Sagot Paul , Quantin Catherine
Published: March 2021

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Social signaling via bioluminescent blinks determines nearest neighbor distance in schools of flashlight fish Anomalops katoptron
Authors: Jägers Peter , Wagner Louisa , Schütz Robin , Mucke Maximilian , Senen Budiono , Limmon Gino V. , Herlitze Stefan , Hellinger Jens
Published: March 2021

The schooling flashlight fish Anomalops katoptron can be found at dark nights at the water surface in the Indo-Pacific. Schools are characterized by bioluminescent blink patterns of sub-ocular light organs densely-packed with bioluminescent, symbiotic bacteria. Here we analyzed how blink patterns of A. katoptron are used in social interactions. We demonstrate that isolated specimen of A. katoptron showed a high motivation to align with fixed or moving artificial light organs in an experimental tank. This intraspecific recognition of A. katoptron is mediated by blinking light and not the body shape. In addition, A. katoptron adjusts its blinking frequencies according to the light intensities. LED pulse frequencies determine the swimming speed and the blink frequency response of A. katoptron, which is modified by light organ occlusion and not exposure. In the natural environment A. katoptron is changing its blink frequencies and nearest neighbor distance in a context specific manner. Blink frequencies are also modified by changes in the occlusion time and are increased from day to night and during avoidance behavior, while group cohesion is higher with increasing blink frequencies. Our results suggest that specific blink patterns in schooling flashlight fish A. katoptron define nearest neighbor distance and determine intraspecific communication.
Malaria transmission in landscapes with varying deforestation levels and timelines in the Amazon: a longitudinal spatiotemporal study
Authors: Laporta Gabriel Z. , Ilacqua Roberto C. , Bergo Eduardo S. , Chaves Leonardo S. M. , Rodovalho Sheila R. , Moresco Gilberto G. , Figueira Elder A. G. , Massad Eduardo , de Oliveira Tatiane M. P. , Bickersmith Sara A. , Conn Jan E. , Sallum Maria Anice M.
Published: March 2021

The relationship between deforestation and malaria is a spatiotemporal process of variation in Plasmodium incidence in human-dominated Amazonian rural environments. The present study aimed to assess the underlying mechanisms of malarial exposure risk at a fine scale in 5-km2 sites across the Brazilian Amazon, using field-collected data with a longitudinal spatiotemporally structured approach. Anopheline mosquitoes were sampled from 80 sites to investigate the Plasmodium infection rate in mosquito communities and to estimate the malaria exposure risk in rural landscapes. The remaining amount of forest cover (accumulated deforestation) and the deforestation timeline were estimated in each site to represent the main parameters of both the frontier malaria hypothesis and an alternate scenario, the deforestation-malaria hypothesis, proposed herein. The maximum frequency of pathogenic sites occurred at the intermediate forest cover level (50% of accumulated deforestation) at two temporal deforestation peaks, e.g., 10 and 35 years after the beginning of the organization of a settlement. The incidence density of infected anophelines in sites where the original forest cover decreased by more than 50% in the first 25 years of settlement development was at least twice as high as the incidence density calculated for the other sites studied (adjusted incidence density ratio = 2.25; 95% CI, 1.38–3.68; p = 0.001). The results of this study support the frontier malaria as a unifying hypothesis for explaining malaria emergence and for designing specific control interventions in the Brazilian Amazon.
Syringeal vocal folds do not have a voice in zebra finch vocal development
Authors: Maxwell Alyssa , Adam Iris , Larsen Pernille S. , Sørensen Peter G. , Elemans Coen P. H.
Published: March 2021

Vocal behavior can be dramatically changed by both neural circuit development and postnatal maturation of the body. During song learning in songbirds, both the song system and syringeal muscles are functionally changing, but it is unknown if maturation of sound generators within the syrinx contributes to vocal development. Here we densely sample the respiratory pressure control space of the zebra finch syrinx in vitro. We show that the syrinx produces sound very efficiently and that key acoustic parameters, minimal fundamental frequency, entropy and source level, do not change over development in both sexes. Thus, our data suggest that the observed acoustic changes in vocal development must be attributed to changes in the motor control pathway, from song system circuitry to muscle force, and not by material property changes in the avian analog of the vocal folds. We propose that in songbirds, muscle use and training driven by the sexually dimorphic song system are the crucial drivers that lead to sexual dimorphism of the syringeal skeleton and musculature. The size and properties of the instrument are thus not changing, while its player is.
Regional environmental controllers influence continental scale soil carbon stocks and future carbon dynamics
Authors: Gonçalves Daniel Ruiz Potma , Mishra Umakant , Wills Skye , Gautam Sagar
Published: March 2021

Understanding the influence of environmental factors on soil organic carbon (SOC) is critical for quantifying and reducing the uncertainty in carbon climate feedback projections under changing environmental conditions. We explored the effect of climatic variables, land cover types, topographic attributes, soil types and bedrock geology on SOC stocks of top 1 m depth across conterminous United States (US) ecoregions. Using 4559 soil profile observations and high-resolution data of environmental factors, we identified dominant environmental controllers of SOC stocks in 21 US ecoregions using geographically weighted regression. We used projected climatic data of SSP126 and SSP585 scenarios from GFDL-ESM 4 Earth System Model of Coupled Model Intercomparison Project phase 6 to predict SOC stock changes across continental US between 2030 and 2100. Both baseline and predicted changes in SOC stocks were compared with SOC stocks represented in GFDL-ESM4 projections. Among 56 environmental predictors, we found 12 as dominant controllers across all ecoregions. The adjusted geospatial model with the 12 environmental controllers showed an R2 of 0.48 in testing dataset. Higher precipitation and lower temperatures were associated with higher levels of SOC stocks in majority of ecoregions. Changes in land cover types (vegetation properties) was important in drier ecosystem as North American deserts, whereas soil types and topography were more important in American prairies. Wetlands of the Everglades was highly sensitive to projected temperature changes. The SOC stocks did not change under SSP126 until 2100, however SOC stocks decreased up to 21% under SSP585. Our results, based on environmental controllers of SOC stocks, help to predict impacts of changing environmental conditions on SOC stocks more reliably and may reduce uncertainties found in both, geospatial and Earth System Models. In addition, the description of different environmental controllers for US ecoregions can help to describe the scope and importance of global and local models.
Association between smoking status and outcomes in myocardial infarction patients undergoing percutaneous coronary intervention
Authors: Sia Ching-Hui , Ko Junsuk , Zheng Huili , Ho Andrew Fu-Wah , Foo David , Foo Ling-Li , Lim Patrick Zhan-Yun , Liew Boon Wah , Chai Ping , Yeo Tiong-Cheng , Tan Huay-Cheem , Chua Terrance , Chan Mark Yan-Yee , Tan Jack Wei Chieh , Bulluck Heerajnarain , Hausenloy Derek J.
Published: March 2021

Smoking is one of the leading risk factors for cardiovascular diseases, including ischemic heart disease and hypertension. However, in acute myocardial infarction (AMI) patients, smoking has been associated with better clinical outcomes, a phenomenon termed the “smoker’s paradox.” Given the known detrimental effects of smoking on the cardiovascular system, it has been proposed that the beneficial effect of smoking on outcomes is due to age differences between smokers and non-smokers and is therefore a smoker’s pseudoparadox. The aim of this study was to evaluate the association between smoking status and clinical outcomes in ST-segment elevation (STEMI) and non-STEMI (NSTEMI) patients treated by percutaneous coronary intervention (PCI), using a national multi-ethnic Asian registry. In unadjusted analyses, current smokers had better clinical outcomes following STEMI and NSTEMI. However, after adjusting for age, the protective effect of smoking was lost, confirming a smoker’s pseudoparadox. Interestingly, although current smokers had increased risk for recurrent MI within 1 year after PCI in both STEMI and NSTEMI patients, there was no increase in mortality. In summary, we confirm the existence of a smoker’s pseudoparadox in a multi-ethnic Asian cohort of STEMI and NSTEMI patients and report increased risk of recurrent MI, but not mortality, in smokers.
Complete response to PD-1 blockade following EBV-specific T-cell therapy in metastatic nasopharyngeal carcinoma
Authors: Smith Corey , McGrath Margaret , Neller Michelle A. , Matthews Katherine K. , Crooks Pauline , Le Texier Laetitia , Panizza Benedict , Porceddu Sandro , Khanna Rajiv
Published: March 2021

Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV)-associated heterogeneous disease and is characterized by peritumoral immune infiltrate. Adoptive T-cell therapy (ACT) has emerged as a potential therapeutic strategy for NPC. However, the tumor microenvironment remains a major roadblock for the successful implementation of ACT in clinical settings. Expression of checkpoint molecules by malignant cells can inhibit the effector function of adoptively transferred EBV-specific T cells. Here we present a novel case report of a patient with metastatic NPC who was successfully treated with a combination of EBV-specific ACT and programmed cell death-1 blockade therapy. Following combination immunotherapy, the patient showed complete resolution of metastatic disease with no evidence of disease relapse for 22 months. Follow-up immunological analysis revealed dramatic restructuring of the global T-cell repertoire that was coincident with the clinical response. This case report provides an important platform for translating these findings to a larger cohort of NPC patients.