bluuebunny/crossref_metadata_2025 huggingface dataset:
ORGAN DONATION IN THE CONTEXT OF HUMAN
TENDENCY TO BE CONSISTENT. CONSIDERATIONS
WITH REFERENCE TO LAW AND PSYCHOLOGY
Authors: Burdziak Konrad
Published: September 2021

The text verifies the hypotheses that exploiting the human tendency to be consistent and introducing appropriate legal solutions can increase organ donation. The considerations found that there are arguments for the status quo bias (the tendency to be consistent) exists and affects humans. Concurrently, there are multiple rational psychological justifications for this kind of occurrences. Thus, the status quo bias can be exploited for increasing the organ donation, imposing on a person the decision regarding being willing to become an organ donor after their death or not, and count on this person not changing their decision in the future due to the tendency to be consistent. In Poland, such a solution could be introduced by adding the 7th item to the Article 11 section 1 of the Act on Vehicle Operators with the following wording: “declared that they agree or not to the removal of cells, tissues or organs from their corpses for transplantation, or the removal of cells and tissues for transplanting them into another person. The declaration may be changed at any time.”
Molecular insights into the role of genetic determinants of congenital hypothyroidism
Authors: Kollati Yedukondalu , Akella Radha Rama Devi , Naushad Shaik Mohammad , Patel Rajesh K. , Reddy G. Bhanuprakash , Dirisala Vijaya R.
Published: September 2021

In our previous studies, we have demonstrated the association of certain variants of the thyroid-stimulating hormone receptor (TSHR), thyroid peroxidase (TPO), and thyroglobulin (TG) genes with congenital hypothyroidism. Herein, we explored the mechanistic basis for this association using different in silico tools. The mRNA 3'-untranslated region (3'-UTR) plays key roles in gene expression at the post-transcriptional level. In TSHR variants (rs2268477, rs7144481, and rs17630128), the binding affinity of microRNAs (miRs) (hsa-miR-154-5p, hsa-miR-376a-2-5p, hsa-miR-3935, hsa-miR-4280, and hsa-miR-6858-3p) to the 3'-UTR is disrupted, affecting post-transcriptional gene regulation. TPO and TG are the two key proteins necessary for the biosynthesis of thyroid hormones in the presence of iodide and H2O2. Reduced stability of these proteins leads to aberrant biosynthesis of thyroid hormones. Compared to the wild-type TPO protein, the p.S398T variant was found to exhibit less stability and significant rearrangements of intra-atomic bonds affecting the stoichiometry and substrate binding (binding energies, ΔG of wild-type vs. mutant: ‒15 vs. ‒13.8 kcal/mol; and dissociation constant, Kd of wild-type vs. mutant: 7.2E-12 vs. 7.0E-11 M). The missense mutations p.G653D and p.R1999W on the TG protein showed altered ΔG (0.24 kcal/mol and 0.79 kcal/mol, respectively). In conclusion, an in silico analysis of TSHR genetic variants in the 3'-UTR showed that they alter the binding affinities of different miRs. The TPO protein structure and mutant protein complex (p.S398T) are less stable, with potentially deleterious effects. A structural and energy analysis showed that TG mutations (p.G653D and p.R1999W) reduce the stability of the TG protein and affect its structure-functional relationship.
Reduction of Bisphenol A-induced Male Reproductive Toxicity by Bromelain in Mice
Authors: Khazaeel Kaveh , Atashfaraz Ammar , Davoudi Zhara , Jamshidian Javad , Erfani Majd Naeem , Mohammadi Ghodratollah
Published: September 2021

Background: Bisphenol A (BPA) is an endocrine-disrupting agent with a weak estrogenic effect. BPA causes testicular damage by reducing the activity of antioxidant enzymes. Bromelain (BROM) is a natural compound derived from pineapple, which is widely used as a dietary supplement with antioxidant properties. Objectives: The present study aimed to investigate the possible therapeutic effects of BROM on the testicular damage induced by BPA administration. Methods: This study was conducted on 40 adult male mice, which were divided into four groups of control (daily treatment with olive oil), BPA (600 mg/kg), BROM (70 mg/kg), and BPA + BROM. The treatments were administered orally for 35 consecutive days. Following that, the animals were euthanized by cervical dislocation, their testes were dissected, and morphometric evaluations (length, width, and thickness of testis) were performed. The epididymal tail was cut to release the sperms for sperm parameter assessment (count and motility). Afterwards, the testes were fixed in buffered formalin for histological examinations (number, diameter, and wall thickness of seminiferous tubules and the counts of spermatogenic, Sertoli, and Leydig cells). Results: All the indices of testicular morphology decreased significantly (P < 0.05) following BPA administration compared to the controls. In addition, the sperm parameters and Leydig and Sertoli cell counts indicated significant decremental effects on the animals administered with BPA compared to the controls (P < 0.05). After the administration of BROM in the BPA + BROM group, all the testicular morphometric indices increased significantly (P < 0.05) compared to the animals administered with BPA alone. These indices were the morphometric values of the testes, sperm parameters, cell counts, and seminiferous morphometric properties. Conclusions: According to the results, BROM could reduce the debilitative effects of BPA on the testes of the mice and protect the reproductive health of the animals against BPA-induced toxicity.
Dostoevsky’s Christ and Nietzsche’s Jesus as “Conceptual Characters”
Authors: Kuzubova Tamara S. ,   Bulgarian Academy of Sciences
Published: September 2021

In the present article, the author analyses the interpretation of the phenomenon of Christ by Dostoevsky and Nietzsche. The author uses comparative and hermeneutic methods of historical and philosophical research. Dostoevsky's Christ and Nietzsche's Jesus are interpreted as “conceptual characters” (G. Deleuze), occupying an important place in the philosophical constructions of both thinkers. Stating the epoch-making event of the “death of God” in European culture, they discover the origins of nihilism in Christianity itself and attempt (each in his own way) to recreate the original, pristine Christianity. Reconstruction of the original image of Christ makes it possible to comprehend not only the historical destiny of Christianity and the European portion of humanity, but also the prospects for overcoming the crisis of European and Russian (in the case of Dostoevsky) self-consciousness. It is argued that both interpretations, although far from orthodox Christianity, play the role of a central link in the development of the philosophic thinking of the Russian writer and German philosopher from the critical deposition of European humanism and metaphysics to new projects of human existence in the world. The conceptual images of Dostoevsky's Christ and Nietzsche's Jesus personally embody the spiritual attitudes and models of life that are timeless in nature, and at the same time serve as an expression of the “fundamental metaphysical positions” (M. Heidegger) of existential thinkers. The assertion of the absolute genuineness and beauty of the moral ideal of Christ allows Dostoevsky to return transcendence to the godless world – to substantiate the neo-Christian version of metaphysics, the religious-existential ontology. The “Glad Tidings” of Jesus, his life and death, appear in Nietzsche’s works as a practical elimination of transcendence, the Platonic dualism of the “true” and “visible” worlds. The spiritual attitude of Jesus reveals a direct affinity to Nietzsche's anti-metaphysical “philosophy of becoming”.
Struggling to Achieve High Creative Standards in Romanian Advertising Industry
Authors: Moraru Mădălina ,   Bulgarian Academy of Sciences
Published: September 2021

The creative industry daily faces genuine challenges in its work when it comes to advertising and meeting clients’ demands. Indeed, technology and the necessity of updating creativity resources urge on new approaches during campaigns, at least in the creative department. Extrinsic and intrinsic motivation stand for essential aspects in challenging new resources of creativity in a field where copywriters and art directors unfold incredibly sensitive messages based on strong and relevant insights. The present paper aims to point out the difficulties and opportunities of creative work in any advertising agency, by exploring the purpose, the barriers and the prospects of this activity in the context of a complex relationship between client and agency, brand and consumers. One could perhaps say that copywriters are just gifted people able to simply follow instructions given by the planning department. Actually, they have their own psychological and social barriers, which represent real challenges. Therefore, we have investigated these issues by conducting semi-structured interviews based on their creative experiences in both cases, as juniors and seniors, respectively. The data collected via semi-structured interviews are investigated by using content analysis.
Some Nomotechnical Weaknesses of the Regulation of Presidential Functions and Powers in the Serbian Constitution of 2006
Authors: Đorđević Miroslav
Published: September 2021

The present Constitution of the Republic of Serbia from 2006 cannot be unfortunately praised for the style it was written in and the quality of its systematics. In addition to the multitude of content-questionable solutions it envisages, nomotechnical omissions of various kinds often make it difficult to interpret or simply create various problems in practice. In this paper, the author presents and analyzes some of the errors and omissions of the Serbian Constitution in the domain of regulations of the President of the Republic, as well as those that stand in an indirect relationship with the head of state. From the lack of systematics of the norms regulating president’s constitutional position, which practically restricts systemic interpretation to evident mistakes ranging from terminological to those with significant concrete and practical consequences (such as inadvertent determination of the type of electoral system), the constitutional regulation of the function of the President of the Republic demands its revision, during which special care should be taken in order not to repeat the mistakes present in the present constitutional framework of the Republic of Serbia.
Tax on the Income of Natural Persons Republic of Srpska
Authors: Drljača Zorica , Muminović Elvir
Published: September 2021

Tax on the income of natural persons is one of the most important and complex forms of tax. It is considered a very generous form of tax, suitable for realization of both fiscal and numerous extra-fiscal taxation goals. Most authors classify this tax as a form of tax of developed capitalism, because it was only in capitalism that the preconditions for its introduction into the tax system were created.Among the assumptions that imposed the need for income tax and which enabled its inclusion in the tax system, are: the existence of several sources of income from which the taxpayer derives its economic strength, the existence of relevant data for tax assessment, the existence of adequately trained tax administration that has the necessary knowledge and skills to successfully control tax collection, definition of the content of the income (total income), as the most appropriate expression of the economic strength of the taxpayer, as well as the development of awareness that citizens integrated into society should contribute to the financing of increased state functions. The existing system of tax on the income of natural persons in the Republika Srpska is based on synthetic (global) income tax, so that the basic sources of income, except those exempted by law, are taxed at the source, while the annual income tax is the sum of all earned income reduced by the recognized tax credit. The aim of this paper is to examine the basic characteristics and elements of the tax on the income of natural persons in the Republika Srpska.
Tax Consulting as a Special Type of Service Activity
Authors: Drljača Zorica , Muminović Elvir
Published: September 2021

Tax consulting is a special type of service activity, with certain specifics related to some other activities. The name itself indicates that it involves providing advisory services, given by specially qualified and trained professionals, with respect to professional-ethical and professional principles, and above all the principles of legality, independence, autonomy, expertise, conscientiousness and professional secrecy as well as other principles that are mutually determined and supplemented. The main purpose of tax consulting is to help taxpayers in completing their tax obligations and to properly understand and apply tax laws. In a broader sense, it means representing the taxpayer in tax and court proceedings. On the other hand, observing the complexity of the tax-legal relationship, the inequality of the parties in this relationship, which stems from the very nature of taxes, it is indisputable that tax advice contributes to tax efficiency and overall tax policy, humanization of tax-legal relationship, development of taxpayers’ awareness on the importance of taxation and the development of tax morale. The goal of this paper is to investigate tax consulting in Bosnia and Herzegovina and the countries of the region, using research, historical, normative and comparative methods.
Traffic Demand Management Tools in Small and Medium-Sized Cities
Authors: Gladović Pavle , Drašković Danislav , Jakupović Esad
Published: September 2021

The function of the public urban and suburban passenger transport (PUPT) system as a transport activity is to provide transportation services in a certain urban area. By using new solutions in traffic demand management in small and medium-sized cities, which do not have an efficient PUPT system, in combination with paratransit systems, we can significantly increase the combined mobility of the population, reduce the use of passenger cars, reduce the need to build new roads, and take full advantage of the PUPT system. This paper presents the traffic demand management tools by which these effects can be achieved.
Models of Management of Railway Infrastructure of Montenegro
Authors: Kalač Safet , Jovanović Dragutin
Published: September 2021

In time of rapid economic and technological change and turmoil, no one can manage business successfully, just because they think they are ‘smart’. In order to successfully manage organizations in the era of dramatic change, in this case ŽICG (Railway infrastructure of Montenegro), it is no longer sufficient to master the classical management process, but also to master the overall quality of management process. In order to achieve the best possible business results in the Railway Infrastructure of Montenegro, the theoretical and practical knowledge on which the management process is based, starting from planning (goal setting, determining ways to achieve goals, allocating required resources), organizing (a division of labor, delegation of authority, coordination), leadership (supervision, motivation, remuneration and punishment, training), conflict resolution) and lastely control (choice of control parameters, monitoring of results, comparison of planned and realized, taking corrective actions). In order to improve the current situation, the models of management of railway infrastructure are considered, for which as a manager builds and invests in railway infrastructure, takes care of its modernization, current maintenance, provides access and allocates infrastructure capacities and organizes and regulates railway traffic. In the processing of the management model, the work relies on the Strategy for the Development of Transport of Montenegro in the period 2019-2035, which establishes the situation in the areas of transport, defines the infrastructure, organizational and operational goals of the development of the transport system, which are realized through time and long-term implementation plans.
Application of New Materials Technology With the Aim of Satisfying the Regulations
Authors: Vujinović Tomislav , Milovanović Milan , Drašković Danislav , Mihić Dragan
Published: September 2021

The reconstruction of the passenger car body is approached for several reasons: development of a new model, installation of a new unit, compliance with new regulations, weight reduction, introduction of new materials and technologies, etc. It can be realized through: constructive changes, introduction of new materials or combined. The paper analyses the effects of implemented changes in order to meet regulations as well as the need to change existing technologies on the example of a car body. The introduction of new materials can significantly improve the existing structure with minimal changes.
Update of the Egyptian mongoose (Herpestes ichneumon) distribution in Spain
Authors: Descalzo Esther , Díaz-Ruiz Francisco , Delibes-Mateos Miguel , Salgado Iván , Martínez-Jauregui María , Soliño Mario , Jiménez José , Linares Olmo , Ferreras Pablo
Published: September 2021

The Egyptian mongoose Herpestes ichneumon (Linnaeus, 1758) is the only species of family Herpestidae that occurs naturally in Europe. It was restricted to SW Iberian Peninsula from where it seems to be expanding in the last decades. However, information on mongoose distribution and recent trends in some areas, such as central Spain (e.g. Castilla - La Mancha region), is scarce. With the aim of updating the distribution of the species in Spain, and particularly in this central area, we 1) performed a systematic questionnaire survey to environmental rangers, 2) collected citations from experts, and 3) carried out specific field surveys in some particular areas. Overall, 1,305 citations of the Egyptian mongoose were collected, resulting in 193 new 10x10 km UTM grids with mongoose occurrence in Spain; this extended the Egyptian mongoose distribution to 28.34 % of the Iberian 10x10 km UTM grids. Our results show that the Egyptian mongoose occurs in most of Extremadura, western Castilla - La Mancha and centralwestern Andalucía, with some isolated records in northern areas of Spain. This suggests that the range of this mongoose may be expanding in Spain, although other possible explanations for the new records, such as the lack of previous systematic studies on the species in the allegedly expanding area, could not be fully discarded.
Initial assessment of the groundwater flow and budget using Geographic Information System, MODFLOW-2005 and the FREEWAT modeling tool in Bouteldja coastal aquifer (Northern East of Algeria)
Authors: Harizi Khaled , Menani Mohamed Reda , Chabour Nabil , Labar Sofiane
Published: September 2021

The Bouteldja coastal aquifer is one of the most important groundwater resources in North eastern of Algeria. The region is under a sub-humid climate with an average rainfall of 600-880 mm/y. The unconfined aquifer is constituted of Quaternary sands formations. The hydrogeological characteristics were determined based on previous reports. A very important inflow recharges the sandy aquifer in the Southeastern boundary, in relation to a fault network system linking the aquifer and the Obeira Lake area. Another inflow is observed at the Southern boundary in relation to the exchanges with the alluvial aquifer of Bouteldja. The purpose of the present study is to provide an initial assessment of the groundwater flow and water budget of this aquifer. To achieve this goal, a one-layer groundwater flow numerical model was developed using the MODFLOW-2005 code and the FREEWAT software, using the available data. The model was run in steady state conditions. Calibration was achieved using the piezometric measurements of May 2018 as calibration target. After several trials of manual calibrations, the model successfully simulated the groundwater flows directions and heads. Calibration efforts lead to an acceptable concordance (for the purpose of this study) between the estimated and calculated hydraulic conductivity and piezometric heads, except at the Eastern border. The analyses of the simulated inflow budget shows that aside the rainfall infiltration, exchanges with surface water bodies, the adjoining alluvial aquifer and the fault system provide a relevant amount of water. This significant recharge needs additional investigations. This numerical modeling exercise using MODFLOW, the FREEWAT software and GIS reached the objective of a preliminary description of the groundwater flow and it represents an acceptable starting point for more thorough hydrodynamic characterization of the Bouteldja coastal aquifer.
Groundwater and climate change
Authors: Beretta Giovanni Pietro
Published: September 2021

In reconstructing the effects of climate change, the problem of water availability is of considerable importance. Globally, the quantity of water resources will not change, but its availability in time and space on the earth’s crust will undergo modifications that will have important social and economic consequences [...].
Experimental study on longitudinal aerodynamic characteristics of flying wing model with plasma flow control
Authors: 牛中国  , 许相辉  , 王建峰  , 蒋甲利  , 梁华
Published: September 2021

The horizontal tail is eliminated from the flying wing layout for improved the low observable and aerodynamic efficiency, resulting in poor longitudinal maneuverability and fight stability. The low speed wind tunnel test study on the improvement of longitudinal aerodynamic characteristics of large aspect ratio flying wing model was carried out by using plasma flow control technology. The flying wing model has a 34.5 degree leading-edge sweep angle and 5.79 aspect ratio. The reasons for the deterioration of the static maneuverability and stability of the flying wing model and the mechanism of plasma control on the flow field and longitudinal aerodynamic characteristics were studied by particle image velocimetry (PIV) flow visualization and static force measurement test. The control law of plasma control on the flight maneuverability and stability of the flying wing model was studied by virtual flight test. That the flow separation of the outer wing of the flying wing model occurs earlier than the inner wing and the wing is swept back result in the forward movement of the aerodynamic center and the deterioration of the longitudinal static stability. The shock disturbance induced by plasma can suppress the flow separation of the suction surface, thereby extending the linear section of the lift curve of the model, preventing the aerodynamic center from moving forward, and improving the longitudinal static stability. When the wind speed is 50m/s, the plasma control improves the horizontal rudder efficiency at the high angle of attack of the flying wing model, increases the maximum lift coefficient of the model by about 0.1 and postponed the stall angle of attack by more than 4 degrees at different rudder angles. Plasma control allows the flying model to follow the command movement better while flying, increases the flying pitch limit angle from 11.5 to 15.1, reduces the amplitude of longitudinal disturbance motion by 2 degrees, and reduce the oscillation attenuation time from 15 seconds to 8seconds, thereby improving the longitudinal flight maneuverability and stability of the flying wing model. It can be seen that plasma flow control technology has great application potential in improving the flight quality of flying wing layout.
Mutational analysis to explore long-range allosteric couplings involved in a pentameric channel receptor pre-activation and activation
Authors: Lefebvre Solène N , Taly Antoine , Menny Anaïs , Medjebeur Karima , Corringer Pierre-Jean
Published: September 2021

Pentameric ligand-gated ion channels (pLGICs) mediate chemical signaling through a succession of allosteric transitions that are yet not completely understood as intermediate states remain poorly characterized by structural approaches. In a previous study on the prototypic bacterial proton-gated channel GLIC, we generated several fluorescent sensors of the protein conformation that report a fast transition to a pre-active state, which precedes the slower process of activation with pore opening. Here, we explored the phenotype of a series of allosteric mutations, using simultaneous steady-state fluorescence and electrophysiological measurements over a broad pH range. Our data, fitted to a three-state Monod-Wyman-Changeux model, show that mutations at the subunit interface in the extracellular domain (ECD) principally alter pre-activation, while mutations in the lower ECD and in the transmembrane domain principally alter activation. We also show that propofol alters both transitions. Data are discussed in the framework of transition pathways generated by normal mode analysis (iModFit). It further supports that pre-activation involves major quaternary compaction of the ECD, and suggests that activation involves principally a reorganization of a ‘central gating region’ involving a contraction of the ECD β-sandwich and the tilt of the channel lining M2 helix.
Localization of KRAS downstream target ARL4C to invasive pseudopods accelerates pancreatic cancer cell invasion
Authors: Harada Akikazu , Matsumoto Shinji , Yasumizu Yoshiaki , Shojima Kensaku , Akama Toshiyuki , Eguchi Hidetoshi , Kikuchi Akira
Published: September 2021

Pancreatic cancer has a high mortality rate due to metastasis. Whereas KRAS is mutated in most pancreatic cancer patients, controlling KRAS or its downstream effectors has not been succeeded clinically. ARL4C is a small G protein whose expression is induced by the Wnt and EGF–RAS pathways. In the present study, we found that ARL4C is frequently overexpressed in pancreatic cancer patients and showed that its localization to invasive pseudopods is required for cancer cell invasion. IQGAP1 was identified as a novel interacting protein for ARL4C. ARL4C recruited IQGAP1 and its downstream effector, MMP14, to invasive pseudopods. Specific localization of ARL4C, IQGAP1, and MMP14 was the active site of invasion, which induced degradation of the extracellular matrix. Moreover, subcutaneously injected antisense oligonucleotide against ARL4C into tumor-bearing mice suppressed metastasis of pancreatic cancer. These results suggest that ARL4C–IQGAP1–MMP14 signaling is activated at invasive pseudopods of pancreatic cancer cells.
Neural excitability and sensory input determine intensity perception with opposing directions in initial cortical responses
Authors: Stephani Tilman , Hodapp Alice , Jamshidi Idaji Mina , Villringer Arno , Nikulin Vadim V
Published: September 2021

Perception of sensory information is determined by stimulus features (e.g., intensity) and instantaneous neural states (e.g., excitability). Commonly, it is assumed that both are reflected similarly in evoked brain potentials, that is, larger amplitudes are associated with a stronger percept of a stimulus. We tested this assumption in a somatosensory discrimination task in humans, simultaneously assessing (i) single-trial excitatory post-synaptic currents inferred from short-latency somatosensory evoked potentials (SEPs), (ii) pre-stimulus alpha oscillations (8–13 Hz), and (iii) peripheral nerve measures. Fluctuations of neural excitability shaped the perceived stimulus intensity already during the very first cortical response (at ~20 ms) yet demonstrating opposite neural signatures as compared to the effect of presented stimulus intensity. We reconcile this discrepancy via a common framework based on the modulation of electro-chemical membrane gradients linking neural states and responses, which calls for reconsidering conventional interpretations of brain potential magnitudes in stimulus intensity encoding.
A MET-PTPRK kinase-phosphatase rheostat controls ZNRF3 and Wnt signaling
Authors: Kim Minseong , Reinhard Carmen , Niehrs Christof
Published: September 2021

Zinc and ring finger 3 (ZNRF3) is a transmembrane E3 ubiquitin ligase that targets Wnt receptors for ubiquitination and lysosomal degradation. Previously, we showed that dephosphorylation of an endocytic tyrosine motif (4Y motif) in ZNRF3 by protein tyrosine phosphatase receptor-type kappa (PTPRK) promotes ZNRF3 internalization and Wnt receptor degradation (Chang et al 2020). However, a responsible protein tyrosine kinase(s) (PTK) phosphorylating the 4Y motif remained elusive. Here we identify the proto-oncogene MET (mesenchymal-epithelial transition factor) as a 4Y kinase. MET binds to ZNRF3 and induces 4Y phosphorylation, stimulated by the MET ligand HGF (hepatocyte growth factor, scatter factor). HGF-MET signaling reduces ZNRF3-dependent Wnt receptor degradation thereby enhancing Wnt/β-catenin signaling. Conversely, depletion or pharmacological inhibition of MET promotes the internalization of ZNRF3 and Wnt receptor degradation. We conclude that HGF-MET signaling phosphorylates- and PTPRK dephosphorylates ZNRF3 to regulate ZNRF3 internalization, functioning as a rheostat for Wnt signaling that may offer novel opportunities for therapeutic intervention.
Adaptation and compensation in a bacterial gene regulatory network evolving under antibiotic selection
Authors: Patel Vishwa , Matange Nishad
Published: September 2021

Gene regulatory networks allow organisms to generate coordinated responses to environmental challenges. In bacteria, regulatory networks are re-wired and re-purposed during evolution, though the relationship between selection pressures and evolutionary change is poorly understood. In this study, we discover that the early evolutionary response of Escherichia coli to the antibiotic trimethoprim involves derepression of PhoPQ signaling, an Mg2+-sensitive two-component system, by inactivation of the MgrB feedback-regulatory protein. We report that derepression of PhoPQ confers trimethoprim-tolerance to E. coli by hitherto unrecognized transcriptional upregulation of dihydrofolate reductase (DHFR), target of trimethoprim. As a result, mutations in mgrB precede and facilitate the evolution of drug resistance. Using laboratory evolution, genome sequencing, and mutation re-construction, we show that populations of E. coli challenged with trimethoprim are faced with the evolutionary ‘choice’ of transitioning from tolerant to resistant by mutations in DHFR, or compensating for the fitness costs of PhoPQ derepression by inactivating the RpoS sigma factor, itself a PhoPQ-target. Outcomes at this evolutionary branch-point are determined by the strength of antibiotic selection, such that high pressures favor resistance, while low pressures favor cost compensation. Our results relate evolutionary changes in bacterial gene regulatory networks to strength of selection and provide mechanistic evidence to substantiate this link.
Inhibition of SARS-CoV-2 polymerase by nucleotide analogs from a single-molecule perspective
Authors: Seifert Mona , Bera Subhas C , van Nies Pauline , Kirchdoerfer Robert N , Shannon Ashleigh , Le Thi-Tuyet-Nhung , Meng Xiangzhi , Xia Hongjie , Wood James M , Harris Lawrence D , Papini Flavia S , Arnold Jamie J , Almo Steven , Grove Tyler L , Shi Pei-Yong , Xiang Yan , Canard Bruno , Depken Martin , Cameron Craig E , Dulin David
Published: September 2021

The absence of ‘shovel-ready’ anti-coronavirus drugs during vaccine development has exceedingly worsened the SARS-CoV-2 pandemic. Furthermore, new vaccine-resistant variants and coronavirus outbreaks may occur in the near future, and we must be ready to face this possibility. However, efficient antiviral drugs are still lacking to this day, due to our poor understanding of the mode of incorporation and mechanism of action of nucleotides analogs that target the coronavirus polymerase to impair its essential activity. Here, we characterize the impact of remdesivir (RDV, the only FDA-approved anti-coronavirus drug) and other nucleotide analogs (NAs) on RNA synthesis by the coronavirus polymerase using a high-throughput, single-molecule, magnetic-tweezers platform. We reveal that the location of the modification in the ribose or in the base dictates the catalytic pathway(s) used for its incorporation. We show that RDV incorporation does not terminate viral RNA synthesis, but leads the polymerase into backtrack as far as 30 nt, which may appear as termination in traditional ensemble assays. SARS-CoV-2 is able to evade the endogenously synthesized product of the viperin antiviral protein, ddhCTP, though the polymerase incorporates this NA well. This experimental paradigm is essential to the discovery and development of therapeutics targeting viral polymerases.
Structure of mycobacterial CIII2CIV2 respiratory supercomplex bound to the tuberculosis drug candidate telacebec (Q203)
Authors: Yanofsky David J , Di Trani Justin M , Król Sylwia , Abdelaziz Rana , Bueler Stephanie A , Imming Peter , Brzezinski Peter , Rubinstein John L
Published: September 2021

The imidazopyridine telacebec, also known as Q203, is one of only a few new classes of compounds in more than 50 years with demonstrated antituberculosis activity in humans. Telacebec inhibits the mycobacterial respiratory supercomplex composed of complexes III and IV (CIII2CIV2). In mycobacterial electron transport chains, CIII2CIV2 replaces canonical CIII and CIV, transferring electrons from the intermediate carrier menaquinol to the final acceptor, molecular oxygen, while simultaneously transferring protons across the inner membrane to power ATP synthesis. We show that telacebec inhibits the menaquinol:oxygen oxidoreductase activity of purified Mycobacterium smegmatis CIII2CIV2 at concentrations similar to those needed to inhibit electron transfer in mycobacterial membranes and Mycobacterium tuberculosis growth in culture. We then used electron cryomicroscopy (cryoEM) to determine structures of CIII2CIV2 both in the presence and absence of telacebec. The structures suggest that telacebec prevents menaquinol oxidation by blocking two different menaquinol binding modes to prevent CIII2CIV2 activity.
Principles of mRNA targeting via the Arabidopsis m6A-binding protein ECT2
Authors: Arribas-Hernández Laura , Rennie Sarah , Köster Tino , Porcelli Carlotta , Lewinski Martin , Staiger Dorothee , Andersson Robin , Brodersen Peter
Published: September 2021

Specific recognition of N6-methyladenosine (m6A) in mRNA by RNA-binding proteins containing a YT521-B homology (YTH) domain is important in eukaryotic gene regulation. The Arabidopsis YTH domain protein ECT2 is thought to bind to mRNA at URU(m6A)Y sites, yet RR(m6A)CH is the canonical m6A consensus site in all eukaryotes and ECT2 functions require m6A-binding activity. Here, we apply iCLIP (individual nucleotide resolution crosslinking and immunoprecipitation) and HyperTRIBE (targets of RNA-binding proteins identified by editing) to define high-quality target sets of ECT2 and analyze the patterns of enriched sequence motifs around ECT2 crosslink sites. Our analyses show that ECT2 does in fact bind to RR(m6A)CH. Pyrimidine-rich motifs are enriched around, but not at m6A sites, reflecting a preference for N6-adenosine methylation of RRACH/GGAU islands in pyrimidine-rich regions. Such motifs, particularly oligo-U and UNUNU upstream of m6A sites, are also implicated in ECT2 binding via its intrinsically disordered region (IDR). Finally, URUAY-type motifs are enriched at ECT2 crosslink sites, but their distinct properties suggest function as sites of competition between binding of ECT2 and as yet unidentified RNA-binding proteins. Our study provides coherence between genetic and molecular studies of m6A-YTH function in plants and reveals new insight into the mode of RNA recognition by YTH domain-containing proteins.
The YTHDF proteins ECT2 and ECT3 bind largely overlapping target sets and influence target mRNA abundance, not alternative polyadenylation
Authors: Arribas-Hernández Laura , Rennie Sarah , Schon Michael , Porcelli Carlotta , Enugutti Balaji , Andersson Robin , Nodine Michael D , Brodersen Peter
Published: September 2021

Gene regulation via N6-methyladenosine (m6A) in mRNA involves RNA-binding proteins that recognize m6A via a YT521-B homology (YTH) domain. The plant YTH domain proteins ECT2 and ECT3 act genetically redundantly in stimulating cell proliferation during organogenesis, but several fundamental questions regarding their mode of action remain unclear. Here, we use HyperTRIBE (targets of RNA-binding proteins identified by editing) to show that most ECT2 and ECT3 targets overlap, with only a few examples of preferential targeting by either of the two proteins. HyperTRIBE in different mutant backgrounds also provides direct views of redundant, ectopic, and specific target interactions of the two proteins. We also show that contrary to conclusions of previous reports, ECT2 does not accumulate in the nucleus. Accordingly, inactivation of ECT2, ECT3, and their surrogate ECT4 does not change patterns of polyadenylation site choice in ECT2/3 target mRNAs, but does lead to lower steady-state accumulation of target mRNAs. In addition, mRNA and microRNA expression profiles show indications of stress response activation in ect2/ect3/ect4 mutants, likely via indirect effects. Thus, previous suggestions of control of alternative polyadenylation by ECT2 are not supported by evidence, and ECT2 and ECT3 act largely redundantly to regulate target mRNA, including its abundance, in the cytoplasm.
Polyvinyl Butyral Synthesis Process Based on Deep Eutectic Solvent as a Catalyst
Authors: Li Po , Xue Weilan , Zeng Zuoxiang , Sun Li , Bai Yu
Published: September 2021

Polyvinyl butyral (PVB) was prepared by the condensation reaction of polyvinyl alcohol (PVA) with n-butyraldehyde using a catalyst which is a kind of deep eutectic solvent (DES) made of dodecyltrimethylammonium chloride and p-toluenesulfonic acid. The raw materials and products were characterized by Fourier transform infrared spectroscopy (FT-IR). The effects of the following reaction conditions on the degree of PVB acetal, yield and agglomeration of the products were investigated: the mass ratio of n-butyraldehyde to PVA (mBA/mPVA) of 0.48-0.96, the mass ratio of catalyst to PVA (mcat/mPVA) of 0.16-0.64, the low temperature reaction temperature (5-20℃), and the low temperature reaction time (1-3h). The results showed that at mBA/mPVA =0.8, mcat/mPVA =0.32, low temperature reaction temperature of 15°C and low temperature reaction time of 2 hours, the obtained PVB was a homogeneous powder with the highest acetal degree of 73.85%.
Impact of Rainwater Recharging on the Yield of Borewells at the GKVK Campus, Bengaluru
Authors: Soundarya N. , Ashoka H. G. , Devaraja K. , Rajashekarappa K. S. , Thimmegowda M. N.
Published: September 2021

The study was conducted to analyze the effect of recharging the borewells through rooftop rainwater and runoff water harvesting from open fields during the year 2020-21. Nine borewells were chosen for the study, with seven borewells using various recharge strategies and two borewells serving as controls. The yield from these borewells is measured at 15-day intervals on a regular basis. During the Kharif season of 2020-21, three borewells (BW1, BW3, and BW5) measured a constant discharge of 0.3 lps, 0.4 lps and 3.2 lps respectively, four borewells (BW2, BW4, BW6, and BW7) measured a rise in discharge from 2.4-2.8 lps, 2.3-2.4 lps, 2.2-2.6 lps, and 1.6-2 lps, respectively, and two borewells (BW 8 and BW9) without any recharge technique measured a drop in discharge from 3-2lps and 2.4-2lps, respectively. During the subsequent Rabi season five borewells (BW1, BW2, BW3, BW4 and BW6) showed a constant discharge of 0.3lps, 2.8lps, 0.4lps, 2.4lps and 2.6lps respectively, two borewells (BW5 and BW7) continued to have an increased discharge 3.2-3.4lps and 1.8-2 lps, respectively and the two control borewells (BW 8 and BW9) continued to show a decrease in the discharge from 2-1.8lps and 1.9-1.8lps, respectively. As a result, the procedure of recharging of borewells through rainwater had a significant impact on borewell yield. The yield of recharged borewell had shown an increase in discharge or had a constant discharge during the Rabi season.
Radiographic Proximal Caries Detection and Multiple Intelligences
Authors: Khan Emad A.
Published: September 2021

Introduction: The accuracy of radiographic caries detection is a multifactorial diagnostic task. One the important factors are the Inter-observer variability. One of the suggested procedures to estimate the variations is the Multiple Intelligence (MI) theory of Howard Gardner.

Aim: The current research aims to study the relation among radiographic proximal caries detection accuracy and MI for dental undergraduate and new graduates (trainees)

Patients and Methods: Twenty dental students who have just terminated caries detection training and 19 interns were employed. The sample composed of seventeen men and twenty two women. Caries detection precision was estimated as the region under Receiver Operating Characteristic (ROC) curve (Az) scores, and MI scores were estimated by sing a modified, bilingual MIS self-recorded questionnaire. MS Excel software was applied to calculate means, percentages and correlation.

Results: There was little and mild positive correlation among Az and Spatial/Visual (0.29) and Intrapersonal (0.31) domains of MI respectively. The current correlation was mild for students (0.38) and (0.40), and it was lowered for interns (0.28) and (0.26) respectively.

Conclusions: There is positive weak relationship between Az and the domains of Spatial/Visual and Intrapersonal of MI. This relationship might be diminished by education and training.
A Pharmacological Review of Siddha Classical Preparations for the Management of COVID-19 at TPEC COVID Care Centre, Vellore
Authors: Thillaivanan S. , Samraj K. , Susikannamma S. , Parthiban P.
Published: September 2021

Despite the threat of coronavirus infection, the Siddha system of medicine, India's traditional medicine, plays an important role in southern India, particularly in Tamilnadu. It contributed considerably not only in the first wave of Covid-19, but also in the second wave. The Government of Tamilnadu developed Siddha COVID-19 treatment centers for asymptomatic, mild, and moderate COVID-19 positive patients in 2020. The TPEC COVID Care Centre initiated at Vellore also one of the Centers that can be managed by Siddha medicines and Siddhar’s Yogam. As of July 14, 2021, about 4525 COVID positive patients had been treated with Siddha integrated treatment at Vellore alone in the first and second waves. Kaba Sura Kudineer, Thalisathy Vadagam, Amukkara Chooranam Mathirai, Bramanandha Bairavam Mathirai, and Adathodai Manapagu are indeed the five Siddha classical preparations used to manage the symptoms of COVID-19 positive patients at TPEC COVID Care Centre in Vellore. This Siddha medical practice is effective in conditions of symptoms and helps in the reduction of clinical outcomes. A pilot study at the same site confirmed the Siddha classical preparation's safety and effectiveness. A feedback analysis study performed at the same center also revealed that the above-mentioned Siddha classical preparations are beneficial in symptomatic treatment without causing any side effects. The medicines utilized in this study are typically proposed in other COVID care centers also in Tamilnadu. This review attempted to analyze the preclinical and clinical efficacy of Siddha Classical medicines used at that Centre for the management of COVID-19.
Effects of Proprioceptive Neuromuscular Facilitation (PNF) Techniques on Bed Mobility, Transfer and Early Trunk Control in Acute Stroke Patients
Authors: Afzal Binash , Mukhtar Tehreem , Butt Ghazal Awais , Bashir Asifa , Manzoor Sadiaa , Abbas Syed Naeem
Published: September 2021

Aims: The aim of this study was to observe the effects of Proprioceptive neuromuscular facilitation (PNF) Techniques to improve bed mobility, transfer and early trunk control in Stroke patients.

Study Design: Assessor blinded Randomized Control Trail.

Place and Duration of the Study: Physiotherapy department of Shalamar hospital Lahore, Pakistan from March 2019 to September 2020.

Methodology: A total of 50 acute stroke patients with severity level NIHSS>21 were recruited and randomly allocated into 2 groups (males: 29, females: 21; age range: 50 to 65) after obtaining written informed consent. Patients were assessed at baseline 0 week and after 6 week of post treatment on Trunk impairment scale (TIS) and ICU mobility scale.

Results: It showed that PNF base trunk control exercises exhibited significant improvement in Trunk impairment scale(TIS) in Group A as compared with Group B at post-test, 18.44±3.176 vs 16.12±2.35 (p=0.004) respectively. ICU Mobility scale significantly improves at post-test in Group A as compared to Group B, 7.52 ±2.583 vs 5.84±1.434 (p=0.007) respectively.

Conclusion: This study concluded that PNF based trunk exercise showed more improvement in Group A (Trunk stability exercises using PNF techniques) when compared with conventional training.
Assessment of Teachers and Students Experiences on Online Teaching during COVID-19 Pandemic: A Case-Study at a University Dental Teaching Hospital
Authors: Bawane Shilpa , Bhate Kalyani , Kale Luke , Shetty Lakshmi , Raut Shreya
Published: September 2021

Background: COVID-19 disease is a global phenomenon that is exerting its influence on a lot more than just health sector. Colleges, Institutes, and Schools were also part of the lockdown that followed the outbreak. Educational institutes have shifted from classroom teaching to online teaching-learning platforms.

Aim: The study aimed to assess teachers' and students' experiences on online teaching during the COVID-19 pandemic at university dental teaching hospital Pune, India.

Methodology: The study design was a cross-sectional questionnaire-based study. The research setting was online. Eligibility Criteria of the study were the teaching staff of the College who had taken to online teaching and undergraduate students who had attended online classes. Custom-made questionnaire link using 'Google form' was sent to teachers and students through WhatsApp and E-mail.

Results: 63% of students and 90% of staff responded with the questionnaires. During COVID-19, 96.7% of teachers and 98.4% of students had used Zoom as an online teaching platform. 25.6% of teachers had experienced network issues as the main problem. 90% of staff did not prefer online teaching over classroom teaching. 10% of teachers did prefer online teaching during the COVID-19 pandemic.  82.4% of students didn't prefer an online learning method. The most common difficulties faced by students were network issues.

Conclusion: Knowledge of teachers' and students' experiences on online teaching is important to overcome the issues faced by them. Teachers' opinions are vital for improvising and dealing with issues with online teaching. The result of this study can be used as a guide for improving effective online teaching.