bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative electron microscopy of synapses in the vertebrate spinal cord
Authors: Charlton B. T. , Gray E. G.
Published: April 2021

Synapses with a cleft with ‘thickened’ membranes and presynaptic vesicles and mitochondria occur commonly throughout the grey matter of the spinal cord of goldfish, frog and various mammals studied. Such synapses are generally thought to have a chemical mode of transmission. The absence or rare occurrence of presynaptic neurofilaments in fish and frog accounts for the failure to detect boutons by silver methods, and there is no need to postulate morphologically unspecialized synaptic contacts in the lower vertebrates as some light microscopists did. Both fish and frog show axo-somatic or axo-dendritic tight junctions, which could be sites of electrical synaptic transmission. No neuronal tight junctions have yet been seen in the mammalian spinal cord. Axo-axo-dendritic synapses have been seen in the frog and mammalian cord, but not so far in the fish. Such serial synapses may be responsible for presynaptic inhibition. Neuroglia of fish, frog and mammals have tight junctions at their apposed surfaces. These differ structurally from neuronal tight junctions. Neuroglia in fish cord have, in addition, desmosomes at their apposed surfaces.
A note on the structure of spindle fibres
Authors: Barnicot N. A.
Published: April 2021

Single mitotic cells from cultures of newt heart tissue or from human fibroblast cultures were burst on a dilute calcium chloride solution and negatively stained on electron-microscope grids. The electron-microscopic appearance of spindle fibres negatively stained with uranyl acetate and with ammonium molybdate is described. As in the case of fibres from sperm tails, the spindle fibres were found to be tubular and the wall was seen to be composed of longitudinal fibrils about 35 Å in diameter.
The lobster optic lamina I. General organization
Authors: Hámori J. , Horridge G. A.
Published: April 2021

The lamina is 150–220 μ thick and has five layers: (a) ganglion cells (2nd-order neurons); (b) a thick-layered glial sheath; (c) more ganglion cells of the same kind; (d) columnar structures called optic cartridges, where retinula fibres terminate in inflated bags which are penetrated by numerous spines of the ganglion cell axons; and (e) a lower multilamellate layer of glial cells among which are neurosecretory cells with short centrifugal axons. Horizontal nerve fibres run along the lamina in the columnar region, where there is a 1:1 relation between ommatidia and cartridges. Retinula fibre terminals are recognized by numerous vesicles and by large pale mitochondria, ganglion cell spines by small dark mitochondria and lack of vesicles. Ganglion cell axons have neurotubules whereas transverse fibres do not. The latter have both synaptic and other vesicles. Some of the horizontal fibres are secretory in appearance.
The Effect of Different Species’ Lens Antisera on Pregnant Mice and Rats and their Progeny
Authors: Finlay G. F.
Published: April 2021

The passive immunisation of mice and rats to lens was undertaken to study the effects of the antibodies on embryos. Rat lens, sheep lens, ox lens, and ox vitreous humour were used as antigens and antisera prepared. Only lens antisera that gave precipitin reactions were employed for injection. These different sera all gave almost equally definite precipitin reactions with a normal saline extract of either mouse, rat, sheep, or ox lens. The antisera were injected chiefly into female mice, the majority of which could be expected to be pregnant. The results differed greatly. The anti-rat lens serum was very toxic and the mice which received injections of this gave an average litter of 1.1 within the expected time; the sheep and ox antiserum group averaged 2.9; while the control group injected with anti-vitreous humour produced an average of 5 per litter. It would therefore seem that, as antigens, these different species lens are not so organ specific as the precipitin test would indicate. The relation of the rat to the mouse could account for the toxicity of the anti-rat lens serum for embryonic mice. The eyes of the surviving F1 were normal. An F2 generation by brother x sister matings was also normal. The active immunisation of female rats and mice to sheep's lens was attempted, but the litters born under treatment were of fair average numbers and were normal in every respect. If antibodies against sheep lens had been generated in the bodies of the female rats, as one could expect, then these had no apparent effect on the embryo. Female rats were injected with rat lens at intervals for several weeks, until they became pregnant. The F1 were normal. From the breeding results there was nothing to indicate that antibodies toxic for embryos had been generated. In these experiments it is the injection of anti-rat serum into mice that has the most bearing on the work done by Guyer and Smith with rabbits. They found that anti-rabbit lens serum was very toxic for embryo rabbits. Fortunately they were enabled to rear a number of the affected young which had defective eyes due to the specific influence of the antiserum. But with mice it is difficult to rear defectives, hence it is quite possible that of the many embryos that died, some were effected in a specific manner by the anti-lens serum
Late Local Recurrence and Metastasis in Soft Tissue Sarcoma of the Extremities and Trunk Wall: Better Outcome After Treatment of Late Events Compared with Early
Authors: von Konow Arvid , Ghanei Iman , Styring Emelie , Vult von Steyern Fredrik
Published: April 2021

Background

Approximately 80% of soft tissue sarcoma (STS) recurrences, local and metastatic disease, are diagnosed within the first 3 years after primary diagnosis and treatment. Recurrences, however, can present after a longer period of remission. Our goal was to identify factors that may predict the risk of late recurrence.

Methods

We identified 677 patients with STS of the extremities and trunk wall from a population-based sarcoma register. Of these, 377 patients were alive and event-free at 3 years and were included for analysis of possible risk factors for late recurrence.

Results

Fifty-five of 377 (15%) patients developed late recurrence: 23 local recurrence, 21 metastasis, and 11 both manifestations. With R0 wide surgical margin as reference, R0 marginal (hazard ratio [HR] 2.6; p = 0.02) and R1 (HR 5.0; p = 0.005) margins were risk factors for late local recurrence. Malignancy grade (HR 8.3; p = 0.04) and R0 marginal surgical margin (HR 2.3; p = 0.04) were risk factors for late metastasis. We could not find a statistically significant correlation of late recurrence with many of the generally known risk factors for local recurrence and metastasis in STS. Outcome after treatment of late recurrences was better compared with outcome after treatment of early events.

Conclusions

Late recurrences, albeit relatively rare, do occur. Outcome after treatment was good compared with outcome after early events. Long surveillance of all patients with high-grade STS, especially if R0 wide surgical margin is not achieved in the primary treatment, appear to be well justified.
Ensemble switching unveils a kinetic rheostat mechanism of the eukaryotic thiamine pyrophosphate riboswitch
Authors: Ma Junyan , Saikia Nabanita , Godar Subash , Hamilton George L. , Ding Feng , Alper Joshua , Sanabria Hugo
Published: April 2021

Thiamine pyrophosphate (TPP) riboswitches regulate thiamine metabolism by inhibiting the translation of enzymes essential to thiamine synthesis pathways upon binding to thiamine pyrophosphate in cells across all domains of life. Recent work on the Arabidopsis thaliana TPP riboswitch suggests a multistep TPP binding process involving multiple riboswitch configurational ensembles and Mg2+ dependence underlies the mechanism of TPP recognition and subsequent transition to the expression-inhibiting state of the aptamer domain followed by changes in the expression platform. However, details of the relationship between TPP riboswitch conformational changes and interactions with TPP and Mg2+ in the aptamer domain constituting this mechanism are unknown. Therefore, we integrated single-molecule multiparameter fluorescence and force spectroscopy with atomistic molecular dynamics simulations and found that conformational transitions within the aptamer domain's sensor helices associated with TPP and Mg2+ ligand binding occurred between at least five different ensembles on timescales ranging from µs to ms. These dynamics are orders of magnitude faster than the 10 sec-timescale folding kinetics associated with expression-state switching in the switch helix. Together, our results show that a TPP and Mg2+ dependent mechanism determines dynamic configurational state ensemble switching of the aptamer domain's sensor helices that regulate the switch helix's stability, which ultimately may lead to the expression-inhibiting state of the riboswitch. Additionally, we propose that two pathways exist for ligand recognition and that this mechanism underlies a kinetic rheostat-like behavior of the Arabidopsis thaliana TPP riboswitch.
Ο έλεγχος της χρηστής δημοσιονομικής διαχείρησης στο Ηνωμένο Βασίλειο και στην Ελλάδα
Authors: Νικητάκης Αντώνιος
Published: April 2021

Η ως άνω διατριβή πραγματεύεται το ακανθώδες ζήτημα του ελέγχου νομιμότητας των δημοσίων δαπανών ως διαμορφώνεται στις μέρες μας είτε μέσω ανεξάρτητων αρχών, ως συμβαίνει στις χώρες που έχουν υιοθετήσει το αγγλοσαξωνικό μοντέλο ελέγχου των δημοσίων δαπανών, είτε μέσω ανεξάρτητων ελεγκτικών θεσμών με δικαιοδοτική υπόσταση, όπως είναι το Ελληνικό Ελεγκτικό Συνέδριο, το οποίο κατά τη σύστασή του ακολούθησε το γαλλικό μοντέλο της Cour des Comptes. Η διαφορετική φύση των ως άνω θεσμών συνεπάγεται και διαφορετική μεθοδολογία στην προσέγγιση του ελέγχου των δημοσίων δαπανών και συνακόλουθα και διαφορετικότητα στη διαδικασία αντιμετώπισης της μη σύννομης δαπάνης. Ωστόσο η διεθνής πρακτική στα ως άνω ζητήματα καταδεικνύει ότι οι διαφορετικές νομικές και ελεγκτικές προσεγγίσεις μπορούν σε κάποιο βαθμό, να λειτουργήσουν συμπληρωματικά ανάλογα με τη φύση του ελεγχόμενου φορέα και τον επιδιωκόμενο σκοπό δημοσιονομικού ελέγχου.
CFM: a database of experimentally validated protocols for chemical compound-based direct reprogramming and transdifferentiation
Authors: Sizykh Alexey , Murtazalieva Khalimat , Vyshkvorkina Yulia , Stupnikov Alexey , Medvedeva Yulia A.
Published: April 2021

Cell fate engineering technologies are critically important for basic and applied science, yet many protocols for direct cell conversions are still unstable, have a low yield and require improvement. There is an increasing need for a data aggregator containing a structured collection of protocols -  preprocessed, verified, and represented in a standardized manner to facilitate their comparison, and providing a platform for the researchers to evaluate and improve the protocols.  

We developed CFM (cell fate mastering), a database of experimentally validated protocols for chemical compound-based direct reprogramming and direct cell conversion. The current version of CFM contains 169 distinct protocols, 113 types of cell conversions, and 158 small molecules capable of inducing cell conversion. CFM allows stem cell biologists to compare and choose the best protocol with high efficiency and reliability for their needs. The protocol representation contains PubChem CIDs and Mechanisms Of Action (MOA) for chemicals, protocol duration, media , and yield with a comment on a measurement strategy. Ratings of the protocols and feedback from the community will help to promote high-quality and reproducible protocols. We are committed to a long-term database maintenance strategy. The database is currently available at https://cfm.mipt.ru}{cfm.mipt.ru
A Large-Scale Comparative Study of Informal Social Networks in Firms
Authors: Jacobs Abigail Z. , Watts Duncan J.
Published: April 2021

Theories of organizations are sympathetic to long-standing ideas from network science that organizational networks should be regarded as multiscale and capable of displaying emergent properties. However, the historical difficulty of collecting individual-level network data for many (N ≫ 1) organizations, each of which comprises many (n ≫ 1) individuals, has hobbled efforts to develop specific, theoretically motivated hypotheses connecting micro- (i.e., individual-level) network structure with macro-organizational properties. In this paper we seek to stimulate such efforts with an exploratory analysis of a unique data set of aggregated, anonymized email data from an enterprise email system that includes 1.8 billion messages sent by 1.4 million users from 65 publicly traded U.S. firms spanning a wide range of sizes and 7 industrial sectors. We uncover wide heterogeneity among firms with respect to all measured network characteristics, and we find robust network and organizational variation as a result of size. Interestingly, we find no clear associations between organizational network structure and firm age, industry, or performance; however, we do find that centralization increases with geographical dispersion—a result that is not explained by network size. Although preliminary, these results raise new questions for organizational theory as well as new issues for collecting, processing, and interpreting digital network data.

This paper was accepted by David Simchi-Levi, Special Section of Management Science: 65th Anniversary.
Structure and refractive index of fibrin protofibril aggregates according to laser phase microscopy accompanied by DLS and AFM
Authors: Kirichenko M. N. , Shkirin A. V. , Chaikov L. L. , Simakin A. V. , Tcherniega N. V. , Gudkov S. V.
Published: April 2021

The structures, sizes, and refractive indices (RI) of protein aggregates formed in a fibrinogen-thrombin system are examined using laser phase microscopy (LPM) accompanied by dynamic light scattering (DLS) and atomic force microscopy (AFM) measurements. Fibrin aggregates found in pure fibrinogen and fibrinogen with thrombin solutions by the DLS method, after drying the sample, form complex structures of different shapes and sizes on a glass surface. The LPM reveals submicron-sized dimeric structures in the pure fibrinogen solution, elongated micron-length structures, and rectangular structures in the fibrinogen-thrombin sample. AFM measurements show that the elongated structures form branched fibers, which in turn assembly into rectangular structures. All sizes obtained by LPM and AFM are consistent with DLS measurements. The refractive indices of all the structures, estimated by optical thickness, vary from 1.53 to 1.62, which indicates that they are fibrinogen derivatives. Effective visualization of the structure and determination of the optical properties for fibrin gel indicate that laser phase microscopy is capable of tissue imaging and characterization.
Analytical method for the description of important obstructed optical beams and the Poisson–Arago spot
Authors: Carvalho Bento Juliano , Zamboni-Rached Michel , Recami Erasmo
Published: April 2021

In this work, we describe analytically the diffraction of some important beams due to a circular obstacle. In order to obtain the desired results, we deal with the wave equation in paraxial approximation together with the diffraction Fresnel integral and apply the analytical method proposed by Zamboni-Rached et al. [Appl. Opt. 51, 3370–3379 (2012)APOPAI0003-693510.1364/AO.51.003370]. As a byproduct of our method, we notice the formation of the Poisson–Arago spot for ordinary beams (plane wave and Gaussian beam) and a reconstruction of the beam for nondiffracting beams (Bessel beam). Then, we pass to a vectorial analysis for better describing the electromagnetic beams.
Lifetime-resolved photon-correlation Fourier spectroscopy
Authors: Utzat Hendrik , Bawendi Moungi G.
Published: April 2021

The excited state population of single solid-state emitters is subjected to energy fluctuations around the equilibrium driven by the bath and relaxation through the emission of phonons or photons. Simultaneous measurement of the associated spectral dynamics requires a technique with a high spectral and temporal resolution with an additionally high temporal dynamic range. We propose a pulsed excitation-laser analog of photon-correlation Fourier spectroscopy (PCFS), which extracts the linewidth and spectral diffusion dynamics along the emission lifetime trajectory of the emitter, effectively discriminating spectral dynamics from relaxation and bath fluctuations. This lifetime-resolved PCFS correlates photon-pairs at the output arm of a Michelson interferometer in both their time-delay between laser-excitation and photon-detection T and the time-delay between two photons τ. We propose the utility of the technique for systems with changing relative contributions to the emission from multiple states, for example, quantum emitters exhibiting phonon-mediated exchange between different fine-structure states.
Bridging the gap between measurement-based and simulation-based metamodels for deriving bulk optical properties from spatially-resolved reflectance profiles: effect of illumination and detection geometry
Authors: Sun Chanjun , Aernouts Ben , Saeys Wouter
Published: April 2021

Non-invasive determination of the optical properties is essential for understanding the light propagation in biological tissues and developing optical techniques for quality detection. Simulation-based models provide flexibility in designing the search space, while measurement-based models can incorporate the unknown system responses. However, the interoperability between these two types of models is typically poor. In this research, the mismatches between measurements and simulations were explored by studying the influences from light source and the incident and detection angle on the diffuse reflectance profiles. After reducing the mismatches caused by the factors mentioned above, the simulated diffuse reflectance profiles matched well with the measurements, with R2 values above 0.99. Successively, metamodels linking the optical properties with the diffuse reflectance profiles were respectively built based on the measured and simulated profiles. The prediction performance of these metamodels was comparable, both obtaining R2 values above 0.96. Proper correction for these sources of mismatches between measurements and simulations thus allows to build a simulation-based metamodel with a wide range of desired optical properties that is applicable to different measurement configurations.
Broadband tunable orbital angular momentum mode converter based on a conventional single-mode all-fiber configuration
Authors: Zhou Min , Zhang Zhe , Shao Laipeng , Liu Shen , Liu Yu , Pang Yu , Bai Zhiyong , Fu Cailing , Cui Wei , Qi Lin , Wang Yiping
Published: April 2021

A broadband tunable orbital angular momentum (OAM) mode converter based on a helical long-period fiber grating (HLPFG) inscribed in a conventional single-mode fiber (SMF) is experimentally demonstrated. The proposed all-fiber OAM mode converter is based on the core-cladding mode dual resonance near the dispersion turning point (DTP). The converter can operate with a bandwidth of 303.9 nm @ −3 dB and 182.2 nm @ −10 dB, which is, as far as we know, the widest bandwidth for a conventional SMF. Furthermore, the bandwidth of the OAM mode can be dynamically tuned within a large dynamic range (>80 nm) by simply twisting the fiber clockwise (CW) or counterclockwise (CCW). The dynamic tunability of the bandwidth of the proposed OAM mode generator may find vital applications in large-capacity optical fiber communication systems.
Orbit-induced localized spin angular momentum of vector circular Airy vortex beam in the paraxial regime
Authors: Geng Tao , Li MIN , Guo Hanming
Published: April 2021

We theoretically study the propagation properties of the vector circular Airy vortex beam in detail. The results show that the orbital angular momentum can induce a localized spin angular momentum after autofocusing in the paraxial regime, which leads to an abrupt polarization transition just before the focal plane. However, there is no angular momentum conversion from orbital angular momentum to spin angular momentum during the whole propagation process. We provide an intuitive explanation for the appearance of such spin angular momentum localization. This investigation is expected to advance our understanding of the vector properties of circular Airy beam and optical spin-orbit coupling.
Thermal effects in molecular gas-filled hollow-core fibers
Authors: Beetar John E. , Nrisimhamurty M. , Truong Tran-Chau , Liu Yangyang , Chini Michael
Published: April 2021

Few-cycle sources with high average powers are required for applications to attosecond science. Raman-enhanced spectral broadening of Yb-doped laser amplifiers in molecular gases can yield few-cycle pulses, but thermal excitation of vibrational and rotational degrees of freedom may preclude high-power operation. Here we investigate changes in the spectral broadening associated with repetitive laser interactions in an

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-filled hollow-core fiber. By comparing experimental measurements of the spectrum associated with each laser pulse to simulations based on a density matrix model, we find that losses in a spectral bandwidth and transmission are largely dominated by thermal excitation of the gas.
Large-area optical metasurface fabrication using nanostencil lithography
Authors: Su Peter , Shalaginov Mikhail , Gu Tian , An Sensong , Li Duanhui , Li Lan , Jiang Helena , Joo Seoyoung , Kimerling Lionel , Zhang Hualiang , Hu Juejun , Agarwal Anuradha
Published: April 2021

We demonstrate a large-area fabrication process for optical metasurfaces utilizing reusable SiN on Si nanostencils. To improve the yield of the nanostencil fabrication, we partially etch the front-side SiN layer to transfer the metasurface pattern from the resist to the nanostencil membrane, preserving the integrity of the membrane during the subsequent potassium hydroxide etch. To enhance the reliability and resolution of metasurface fabrication using the nanostencil, we spin coat a sacrificial layer of resist to precisely determine the gap between the nanostencil and the metasurface substrate for the subsequent liftoff. 1.5 mm diameter PbTe meta-lenses on

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fabricated using nanostencils show diffraction-limited focusing and focusing efficiencies of 42% for a 2 mm focal length lens and 53% for a 4 mm focal length lens. The nanostencils can also be cleaned using chemical cleaning methods for reuse.
Optical nonlinearity and laser modulation performance of FeNi-LDH in the mid-infrared region
Authors: Liang Yangyang , Liu Yizhou , Qiao Wenchao , Zhao Yuefeng , Li Tao
Published: April 2021

In this Letter, we prepare FeNi–layered-double-hydroxide (LDH) nanoflakes and illustrate the corresponding microcosmic morphology. The optical response and laser modulation performance of the nanoflakes in the mid-infrared region were investigated for the first time, to the best of our knowledge. Employed as a saturable absorber in an

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laser system, pulses with 256-ns duration were yielded at a repetition of 129 kHz under 7.8-W pump power, which corresponds to a pulse energy of 4.98 µJ.
Accurate contact-based modelling of repeat proteins predicts the structure of new repeats protein families
Authors: Bassot Claudio , Elofsson Arne
Published: April 2021

Repeat proteins are abundant in eukaryotic proteomes. They are involved in many eukaryotic specific functions, including signalling. For many of these proteins, the structure is not known, as they are difficult to crystallise. Today, using direct coupling analysis and deep learning it is often possible to predict a protein’s structure. However, the unique sequence features present in repeat proteins have been a challenge to use direct coupling analysis for predicting contacts. Here, we show that deep learning-based methods (trRosetta, DeepMetaPsicov (DMP) and PconsC4) overcomes this problem and can predict intra- and inter-unit contacts in repeat proteins. In a benchmark dataset of 815 repeat proteins, about 90% can be correctly modelled. Further, among 48 PFAM families lacking a protein structure, we produce models of forty-one families with estimated high accuracy.
Identification of long regulatory elements in the genome of Plasmodium falciparum and other eukaryotes
Authors: Menichelli Christophe , Guitard Vincent , Martins Rafael M. , Lèbre Sophie , Lopez-Rubio Jose-Juan , Lecellier Charles-Henri , Bréhélin Laurent
Published: April 2021

Long regulatory elements (LREs), such as CpG islands, polydA:dT tracts or AU-rich elements, are thought to play key roles in gene regulation but, as opposed to conventional binding sites of transcription factors, few methods have been proposed to formally and automatically characterize them. We present here a computational approach named DExTER (Domain Exploration To Explain gene Regulation) dedicated to the identification of candidate LREs (cLREs) and apply it to the analysis of the genomes of P. falciparum and other eukaryotes. Our analyses show that all tested genomes contain several cLREs that are somewhat conserved along evolution, and that gene expression can be predicted with surprising accuracy on the basis of these long regions only. Regulation by cLREs exhibits very different behaviours depending on species and conditions. In P. falciparum and other Apicomplexan organisms as well as in Dictyostelium discoideum, the process appears highly dynamic, with different cLREs involved at different phases of the life cycle. For multicellular organisms, the same cLREs are involved in all tissues, but a dynamic behavior is observed along embryonic development stages. In P. falciparum, whose genome is known to be strongly depleted of transcription factors, cLREs are predictive of expression with an accuracy above 70%, and our analyses show that they are associated with both transcriptional and post-transcriptional regulation signals. Moreover, we assessed the biological relevance of one LRE discovered by DExTER in P. falciparum using an in vivo reporter assay.

The source code (python) of DExTER is available at https://gite.lirmm.fr/menichelli/DExTER.
The metastable brain associated with autistic-like traits of typically developing individuals
Authors: Sase Takumi , Kitajo Keiichi
Published: April 2021

Metastability in the brain is thought to be a mechanism involved in the dynamic organization of cognitive and behavioral functions across multiple spatiotemporal scales. However, it is not clear how such organization is realized in underlying neural oscillations in a high-dimensional state space. It was shown that macroscopic oscillations often form phase-phase coupling (PPC) and phase-amplitude coupling (PAC), which result in synchronization and amplitude modulation, respectively, even without external stimuli. These oscillations can also make spontaneous transitions across synchronous states at rest. Using resting-state electroencephalographic signals and the autism-spectrum quotient scores acquired from healthy humans, we show experimental evidence that the PAC combined with PPC allows amplitude modulation to be transient, and that the metastable dynamics with this transient modulation is associated with autistic-like traits. In individuals with a longer attention span, such dynamics tended to show fewer transitions between states by forming delta-alpha PAC. We identified these states as two-dimensional metastable states that could share consistent patterns across individuals. Our findings suggest that the human brain dynamically organizes inter-individual differences in a hierarchy of macroscopic oscillations with multiple timescales by utilizing metastability.
Preventive chemotherapy for the control of strongyloidiasis in school-age children: Estimating the ivermectin need
Authors: Bisanzio Donal , Montresor Antonio , French Michael , Reithinger Richard , Rodari Paola , Bisoffi Zeno , Buonfrate Dora
Published: April 2021

Background

Strongyloides stercoralis is a soil-transmitted helminth (STH) that affects approximately 600 million people worldwide. Interventions targeting S. stercoralis have not been implemented yet. Specific treatment (ivermectin) could be included in already ongoing preventive chemotherapy (PC) campaigns targeting other STHs. The aim of this study was to estimate the quantity of ivermectin needed for an integrated STH/S. stercoralis control program.

Methododology/Principal findings

Our study estimates the number of school- age children (SAC) (the main focus of STH deworming campaigns) in need of PC with ivermectin. The normal approximation of the binomial distribution was adopted to calculate the hypothetical prevalence distribution in each endemic country. Considering prevalence thresholds for PC equal to 10%, 15%, and 20%, we estimated the number of SAC in need of treatment. We adjusted the estimates accounting for ivermectin distributed in lymphatic filariasis and onchocerciasis elimination programs and excluded from our calculation areas where Loa loa is endemic.

The global number of SAC that should be targeted in PC campaigns was estimated at 283.9 M (95% CI: 163.4–368.8), 207.2 M (95% CI: 160.9–380.7), and 160.7 M (95% CI: 86.6–225.7) when the threshold for intervention was set to 10%, 15%, and 20%, respectively. India, China, Indonesia, Bangladesh, and Nigeria accounted for about 50% of the global SAC would have to be covered by PC intervention.

Conclusions/Significance

Our analysis may support endemic countries to evaluate the ivermectin quantity needed for integrating strongyloidiasis in the existing STH programs. These estimates might also show to generic drug manufacturers the size of the potential market for ivermectin and encourage its production.
Trichomonas vaginalis infection impairs anion secretion in vaginal epithelium
Authors: Xu Jian-Bang , Lu Shen-Jiao , Ke Li-Jiao , Qiu Zhuo-Er , Chen Lei , Zhang Hao-Li , Wang Xi-Yuan , Wei Xiao-Fan , He Shuming , Zhu Yun-Xin , Lun Zhao-Rong , Zhou Wen-Liang , Zhang Yi-Lin
Published: April 2021

Trichomonas vaginalis is a common protozoan parasite, which causes trichomoniasis associated with severe adverse reproductive outcomes. However, the underlying pathogenesis has not been fully understood. As the first line of defense against invading pathogens, the vaginal epithelial cells are highly responsive to environmental stimuli and contribute to the formation of the optimal luminal fluid microenvironment. The cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel widely distributed at the apical membrane of epithelial cells, plays a crucial role in mediating the secretion of Cl− and HCO3−. In this study, we investigated the effect of T. vaginalis on vaginal epithelial ion transport elicited by prostaglandin E2 (PGE2), a major prostaglandin in the semen. Luminal administration of PGE2 triggered a remarkable and sustained increase of short-circuit current (ISC) in rat vaginal epithelium, which was mainly due to Cl− and HCO3− secretion mediated by the cAMP-activated CFTR. However, T. vaginalis infection significantly abrogated the ISC response evoked by PGE2, indicating impaired transepithelial anion transport via CFTR. Using a primary cell culture system of rat vaginal epithelium and a human vaginal epithelial cell line, we demonstrated that the expression of CFTR was significantly down-regulated after T. vaginalis infection. In addition, defective Cl− transport function of CFTR was observed in T. vaginalis-infected cells by measuring intracellular Cl− signals. Conclusively, T. vaginalis restrained exogenous PGE2-induced anion secretion through down-regulation of CFTR in vaginal epithelium. These results provide novel insights into the intervention of reproductive complications associated with T. vaginalis infection such as infertility and disequilibrium in vaginal fluid microenvironment.
An investigation of conventional microbial culture for the Naja atra bite wound, and the comparison between culture-based 16S Sanger sequencing and 16S metagenomics of the snake oropharyngeal bacterial microbiota
Authors: Mao Yan-Chiao , Chuang Han-Ni , Shih Chien-Hung , Hsieh Han-Hsueh , Jiang Yu-Han , Chiang Liao-Chun , Lin Wen-Loung , Hsiao Tzu-Hung , Liu Po-Yu
Published: April 2021

Naja atra is a major venomous snake found in Taiwan. The bite of this snake causes extensive wound necrosis or necrotizing soft tissue infection. Conventional microbial culture-based techniques may fail to identify potential human pathogens and render antibiotics ineffective in the management of wound infection. Therefore, we evaluated 16S Sanger sequencing and next-generation sequencing (NGS) to identify bacterial species in the oropharynx of N. atra. Using conventional microbial culture methods and the VITEK 2 system, we isolated nine species from snakebite wounds. On the basis of the 16S Sanger sequencing of bacterial clones from agar plates, we identified 18 bacterial species in the oropharynx of N. atra, including Morganella morganii, Proteus vulgaris, and Proteus mirabilis, which were also present in the infected bite wound. Using NGS of 16S metagenomics, we uncovered more than 286 bacterial species in the oropharynx of N. atra. In addition, the bacterial species identified using 16S Sanger sequencing accounted for only 2% of those identified through NGS of 16S metagenomics. The bacterial microbiota of the oropharynx of N. atra were modeled better using NGS of 16S metagenomics compared to microbial culture-based techniques. Stenotrophomonas maltophilia, Acinetobacter baumannii, and Proteus penneri were also identified in the NGS of 16S metagenomics. Understanding the bacterial microbiota that are native to the oropharynx of N. atra, in addition to the bite wound, may have additional therapeutic implications regarding empiric antibiotic selection for managing N. atra bites.
Orientia tsutsugamushi modulates cellular levels of NF-κB inhibitor p105
Authors: Wangsanut Tanaporn , Brann Katelynn R. , Adcox Haley E. , Carlyon Jason A.
Published: April 2021

Background

Scrub typhus is a neglected tropical disease that threatens more than one billion people. If antibiotic therapy is delayed, often due to mis- or late diagnosis, the case fatality rate can increase considerably. Scrub typhus is caused by the obligate intracellular bacterium, Orientia tsutsugamushi, which invades phagocytes and endothelial cells in vivo and diverse tissue culture cell types in vitro. The ability of O. tsutsugamushi to replicate in the cytoplasm indicates that it has evolved to counter eukaryotic host cell immune defense mechanisms. The transcription factor, NF-κB, is a tightly regulated initiator of proinflammatory and antimicrobial responses. Typically, the inhibitory proteins p105 and IκBα sequester the NF-κB p50:p65 heterodimer in the cytoplasm. Canonical activation of NF-κB via TNFα involves IKKβ-mediated serine phosphorylation of IκBα and p105, which leads to their degradation and enables NF-κB nuclear translocation. A portion of p105 is also processed into p50. O. tsutsugamushi impairs NF-κB translocation into the nucleus, but how it does so is incompletely defined.

Principal findings

Western blot, densitometry, and quantitative RT-PCR analyses of O. tsutsugamushi infected host cells were used to determine if the pathogen’s ability to inhibit NF-κB is linked to modulation of p105. Results demonstrate that p105 levels are elevated several-fold in O. tsutsugamushi infected HeLa and RF/6A cells with only a nominal increase in p50. The O. tsutsugamushi-stimulated increase in p105 is bacterial dose- and protein synthesis-dependent, but does not occur at the level of host cell transcription. While TNFα-induced phosphorylation of p105 serine 932 proceeds unhindered in infected cells, p105 levels remain elevated and NF-κB p65 is retained in the cytoplasm.

Conclusions

O. tsutsugamushi specifically stabilizes p105 to inhibit the canonical NF-κB pathway, which advances understanding of how it counters host immunity to establish infection.
Serology, infection, and clinical trachoma as tools in prevalence surveys for re-emergence of trachoma in a formerly hyperendemic district
Authors: Odonkor Michelle , Naufal Fahd , Munoz Beatriz , Mkocha Harran , Kasubi Mabula , Wolle Meraf , West Sheila
Published: April 2021

Background

To eliminate trachoma as a public health problem, countries must achieve a district-level prevalence of trachomatous inflammation—follicular (TF) <5% in children ages 1–9 years. Re-emergence of TF could trigger additional rounds of mass drug/antibiotic administration (MDA), so accurate tools for use in surveys assessing trachoma prevalence are essential.

Methodology & principal findings

We surveyed 2401 children ages 1–9 years from 50 villages in Kongwa, Tanzania, 2 years post-MDA and 1.5 years after an impact survey found TF <5% in the same villages. Our survey included multiple tools: clinical determination of TF, Cepheid testing for Chlamydia trachomatis infection, and testing for anti-pgp3 antibodies via multiplex bead array. Photographs of the upper tarsal conjunctiva were taken in a subset of children to corroborate the field grades.

Overall TF prevalence in 1–9 year olds was 7.1% (95% CI: 5.6%-8.9%), which decreased with age (p = <0.0001). TF prevalence by village was heterogeneous, with 19 villages having TF <5% and 16 villages having TF >10%. There was a strong correlation between field and photo grading of TF (kappa = 0.69; 95% CI: 0.60–0.78) and between TF and infection, with 21.5% of TF-positive children also testing positive for infection, as compared to only 1.6% of TF-negative children (p = 0.0010). Overall seroprevalence was 18.2% (95% CI: 14.8%-22.1%), which increased with age (p = <0.0001). Notably, 1–2 year olds, who were born after the cessation of MDA and theoretically should not have had exposure to C. trachomatis in the absence of transmission, had an average seroprevalence of 6.7%.

Conclusions & significance

Field TF prevalence, supported by photographic review and infection data, suggested re-emergence of trachoma in Kongwa. Moreover, seropositivity in the children born after cessation of MDA indicated exposure to C. trachomatis despite a previous survey finding of TF <5%. Examining seropositivity in specific age groups expected to have limited exposure to C. trachomatis can be used to detect re-emergence.
CSNK1G2 differently sensitizes tamoxifen-induced decrease in PI3K/AKT/mTOR/S6K and ERK signaling according to the estrogen receptor existence in breast cancer cells
Authors: Nguyen Hoang Anh Thu , Hoe Kwang-Lae , Lee Sook-Jeong
Published: April 2021

Tamoxifen (TAM) is a selective estrogen receptor modulator used for breast cancer patients. Prolonged use of tamoxifen is not recommended for some patients. In this study, we aimed to identify molecular targets sensitive to TAM using a genome-wide gene deletion library screening of fission yeast heterozygous mutants. From the screening, casein kinase 1 gamma 2 (CSNK1G2), a serine-/threonine protein kinase, was the most sensitive target to TAM with a significant cytotoxicity in estrogen receptor-positive (ER+) breast cancer cells but with only a slight toxicity in the case of ER- cells. In addition, tumor sphere formation and expression of breast stem cell marker genes such as CD44/CD2 were greatly inhibited by CSNK1G2 knockdown in ER+ breast cancer cells. Consistently, CSNK1G2 altered ERα activity via phosphorylation, specifically at serine (Ser)167, as well as the regulation of estrogen-responsive element (ERE) of estrogen-responsive genes such as CTSD and GREB1. However, ERα silencing almost completely blocked CSNK1G2-induced TAM sensitivity. In ER+ breast cancer cells, combined treatment with TAM and CSNK1G2 knockdown further enhanced the TAM-mediated decrease in phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase (S6K) signaling but not extracellular signal-regulated kinase (ERK) signaling. Inversely, in ER- cells treated with TAM, only ERK and PI3K signaling was altered by CSNK1G2 knockdown. The CK1 inhibitor, D4476, partly mimicked the CSNK1G2 knockdown effect in ER+ breast cancer cells, but with a broader repression ranging from PI3K/AKT/mTOR/S6K to ERK signaling. Collectively, these results suggest that CSNK1G2 plays a key role in sensitizing TAM toxicity in ER+ and ER- breast cancer cells via differently regulating PI3K/AKT/mTOR/S6K and ERK signaling.
Impact of variant-level batch effects on identification of genetic risk factors in large sequencing studies
Authors: Wickland Daniel P. , Ren Yingxue , Sinnwell Jason P. , Reddy Joseph S. , Pottier Cyril , Sarangi Vivekananda , Carrasquillo Minerva M. , Ross Owen A. , Younkin Steven G. , Ertekin-Taner Nilüfer , Rademakers Rosa , Hudson Matthew E. , Mainzer Liudmila Sergeevna , Biernacka Joanna M. , Asmann Yan W.
Published: April 2021

Genetic studies have shifted to sequencing-based rare variants discovery after decades of success in identifying common disease variants by Genome-Wide Association Studies using Single Nucleotide Polymorphism chips. Sequencing-based studies require large sample sizes for statistical power and therefore often inadvertently introduce batch effects because samples are typically collected, processed, and sequenced at multiple centers. Conventionally, batch effects are first detected and visualized using Principal Components Analysis and then controlled by including batch covariates in the disease association models. For sequencing-based genetic studies, because all variants included in the association analyses have passed sequencing-related quality control measures, this conventional approach treats every variant as equal and ignores the substantial differences still remaining in variant qualities and characteristics such as genotype quality scores, alternative allele fractions (fraction of reads supporting alternative allele at a variant position) and sequencing depths. In the Alzheimer’s Disease Sequencing Project (ADSP) exome dataset of 9,904 cases and controls, we discovered hidden variant-level differences between sample batches of three sequencing centers and two exome capture kits. Although sequencing centers were included as a covariate in our association models, we observed differences at the variant level in genotype quality and alternative allele fraction between samples processed by different exome capture kits that significantly impacted both the confidence of variant detection and the identification of disease-associated variants. Furthermore, we found that a subset of top disease-risk variants came exclusively from samples processed by one exome capture kit that was more effective at capturing the alternative alleles compared to the other kit. Our findings highlight the importance of additional variant-level quality control for large sequencing-based genetic studies. More importantly, we demonstrate that automatically filtering out variants with batch differences may lead to false negatives if the batch discordances come largely from quality differences and if the batch-specific variants have better quality.
Clinical characteristics of Egyptian male patients with COVID‐19 acute respiratory distress syndrome
Authors: Doghish Ahmed S. , Elkhatib Walid F. , Hassan Essam A. , Elkhateeb Ahmed F. , Mahmoud Eman E. , Ahmed Mona I. , Khalil Mahmoud A. F.
Published: April 2021

Background

Coronavirus disease 2019 (COVID-19) is a serious illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and in severe cases associated with acute respiratory distress syndrome (ARDS).

Objective

To describe the clinical characteristics of patients with ARDS-COVID-19.

Materials and methods

This study involved 197 male Egyptian participants, among them111 COVID-19 patients presented with ARDS, 60 COVID-19 patients presented with non-ARDS, and 26 Non-COVID-19 patients. We reported the analysis results of clinical and laboratory information, including blood routine tests, blood biochemistry parameters [aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine and C‐reactive protein (CRP)], thrombotic activity (D‐dimer) and serum ferritin and lactate dehydrogenase (LDH).

Results

The levels of hemoglobin, AST, creatinine, monocyte count, monocyte %, RBC count, TLC, and platelet count were not significantly different among the groups. The lymphopenia and increased CRP, ALT, D-dimer, ferritin, and LDH were observed in patients with ARDS-COVID-19.

Conclusion

COVID-19 patients with ARDS presented with lymphopenia, increased thrombotic activity, increased CRP, LDH, and ferritin levels. The results revealed that CRP, D-dimer, LDH levels, and lymphopenia have a significant association with the COVID-19 severity and can be used as biomarkers to predict the disease severity.
Diagnostic performance of artificial intelligence model for pneumonia from chest radiography
Authors: Kwon TaeWoo , Lee Sang Pyo , Kim Dongmin , Jang Jinseong , Lee Myungjae , Kang Shin Uk , Kim Heejin , Oh Keunyoung , On Jinhee , Kim Young Jae , Yun So Jeong , Jin Kwang Nam , Kim Eun Young , Kim Kwang Gi
Published: April 2021

Objective

The chest X-ray (CXR) is the most readily available and common imaging modality for the assessment of pneumonia. However, detecting pneumonia from chest radiography is a challenging task, even for experienced radiologists. An artificial intelligence (AI) model might help to diagnose pneumonia from CXR more quickly and accurately. We aim to develop an AI model for pneumonia from CXR images and to evaluate diagnostic performance with external dataset.

Methods

To train the pneumonia model, a total of 157,016 CXR images from the National Institutes of Health (NIH) and the Korean National Tuberculosis Association (KNTA) were used (normal vs. pneumonia = 120,722 vs.36,294). An ensemble model of two neural networks with DenseNet classifies each CXR image into pneumonia or not. To test the accuracy of the models, a separate external dataset of pneumonia CXR images (n = 212) from a tertiary university hospital (Gachon University Gil Medical Center GUGMC, Incheon, South Korea) was used; the diagnosis of pneumonia was based on both the chest CT findings and clinical information, and the performance evaluated using the area under the receiver operating characteristic curve (AUC). Moreover, we tested the change of the AI probability score for pneumonia using the follow-up CXR images (7 days after the diagnosis of pneumonia, n = 100).

Results

When the probability scores of the models that have a threshold of 0.5 for pneumonia, two models (models 1 and 4) having different pre-processing parameters on the histogram equalization distribution showed best AUC performances of 0.973 and 0.960, respectively. As expected, the ensemble model of these two models performed better than each of the classification models with 0.983 AUC. Furthermore, the AI probability score change for pneumonia showed a significant difference between improved cases and aggravated cases (Δ = -0.06 ± 0.14 vs. 0.06 ± 0.09, for 85 improved cases and 15 aggravated cases, respectively, P = 0.001) for CXR taken as a 7-day follow-up.

Conclusions

The ensemble model combined two different classification models for pneumonia that performed at 0.983 AUC for an external test dataset from a completely different data source. Furthermore, AI probability scores showed significant changes between cases of different clinical prognosis, which suggest the possibility of increased efficiency and performance of the CXR reading at the diagnosis and follow-up evaluation for pneumonia.