1,721,111 research outputs found
Neuro-Physiological Correlates of Voice Onset Time in Kannada and Tamil Speaking
No full textVoice Onset Time (VOT) refers to the time difference between two events—one articulatory and the other laryngeal. VOT is measured as the time difference between the onset of the burst (articulatory event) and the onset of vocal fold vibration (laryngeal event) Lisker [14]. The cross-linguistic variation with respect to voicing perception is more in multilingual countries like India. For example, in Tamil language, there is no good distinction between voiced and unvoiced stops; however, in Kannada, Telugu, and Hindi, there exists a difference. To verify the cross-linguistic difference, the behavioral response for VOT continuum in native Kannada and Tamil speakers, and the neuro-physiological changes for VOT continuum in native Kannada and Tamil speakers were taken as objective of the study. Two groups of subjects were participated in the study. Group I consisted of ten male Kannada speakers in the age range of 20–35 years. All the subjects were native speakers of Kannada language, and they belong to Mysore dialect and they are fluent speakers in Kannada only. All though they were exposed to English, they were not fluent speakers of English or Hindi. Group II consisted of ten male Tamil speakers in the age range of 20–35. All the subjects were native speakers of Tamil language, and they belong to Coimbatore/Chennai dialect and they are fluent speakers in Tamil only. Although they were exposed to English, they were not fluent speakers of English or Kannada or Hindi. From the naturally recorded speech sounds, /da-ta/ continuum was created using copy past synthesis method. This continuum had 10 tokens. Using this stimulus, behavioral identification curve was generated. Also electrophysiological, N100 potential was recorded using Neuro-Scan instrument (Compumedies, AUS) with five tokens, which covers the entire dynamic range of the /da-ta/ continuum. The recording was done with 16 channels. The behavioral result showed there was difference between Tamil and Kannada languages; however, electrophysiological results showed that there was a change with N100 latency with changing VOT but there was no language difference found. The author concluded that N100 may not be an effective measure to indicate to represent the voice /voiceless categorical perception. May be higher potential might give better information.</p
Neuartige Medikamente gegen Tuberkulose: pharmakologische und biochemische Charakterisierung in geeigneten Testsystemen
Get PDFTuberculosis remains one of the leading infectious causes of morbidity and mortality worldwide. Pyrazinamide (PZA) and rifampicin (RIF) are two frontline anti-TB drugs facing a huge obstacle of resistance. PZA is a prodrug which is activated into pyrazinoic acid (POA) by the pyrazinamidase (PZase) encoded by the PncA gene. It is important to find PZA analogues that can evade the mutations in pncA gene and RNAP inhibitors that can substitute RIF.
In order to characterize the role of PncA mutations in PZA-resistance, the kinetics of the mycobacterial PZase -wild type and 5 mutants from 5 resistant strains- were evaluated using the cell free PZase assay. Three POA amides were synthesized and evaluated as prodrugs using the same assay. The POA esters could be considered as a logic rationale to circumvent the mutations in PncA. Three POA esters were synthesized and evaluated with the regard of their in vitro efficacy/toxicity profiles.
Myxopyronin, corallopyronin and ripostatin are attractive RNAP inhibitors for anti-microbial drug researchers. Their mode of action is different than that of RIF representing a possible solution for widespread RIF-resistance. Their high binding to plasma proteins is considered as a hindrance to take them a head in the development pathway. The synergism of the three substances with ethambutol, the cell wall inhibitor, was evaluated. The efficacy/toxicity profiles and the binding to proteins of different combinations were determined.
LX079 was chosen by screening of a random library of compounds as it showed a favorable in vitro safety profile. It was evaluated for acute oral toxicity in mice, in vitro and in vivo pharmacokinetic profiles.Tuberkulose (TB) ist eine der führenden infektiöse Ursachen von Morbidität und Mortalität. Pyrazinamid (PZA) und Rifampicin (RIF) sind zwei Frontline Anti-TB-Medikamente. Leider ist die Resistenz gegenüber beiden Mitteln ein häufiges großes Hindernis bei der Behandlung von TB. PZA ist eine Prodrug, die erst durch die Pyrazinamidase (PZase) - kodiert durch das pncA-Gen - in die aktive Form, pyrazinoic Säure (POA), überführt wird.
Die weit verbreitete Resistenz gegen diese Frontline Medikamente unterstreicht die Notwendigkeit der Entwicklung alternativer Wirkstoffe. Diese Fakten unterstreichen die Bedeutung der Suche nach PZA-Analoga, die die Wirkung der Mutationen im pncA Gen sowie RNAP-Inhibitoren, die RIF ersetzen können.
Um die Rolle von Mutationen in pncA bei der PZA-Resistenz zu charakterisieren, wurde die Kinetik der mykobakteriellen PZase von Wildtyp und 5 resistenten Mutanten unter Verwendung des zellfreien PZase Assays evaluiert. Drei POA Amide wurden synthetisiert und als Prodrugs ausgewertet unter Verwendung des gleichen Assays. Die POA Ester können als eine logische Umgehung der Mutationen in PncA angesehen werden. Drei POA Ester wurden synthetisiert und mit dem Bezug ihrer in vitro Wirksamkeit/Toxizität Profile ausgewertet.
Myxopyronin, Corallopyronin und Ripostatin sind attraktive RNAP Inhibitoren für anti-mikrobiellen Wirkstoff Forscher. Der Synergismus der drei Substanzen mit Ethambutolwurde ausgewertet. Die Wirksamkeit/Toxizitätsprofile und die Bindung an Proteinen von unterschiedlichen Kombinationen wurde bestimmt.
LX079 wurde durch Screening einer zufälligen Bibliothek von Verbindungen ausgewählt, da sie eine günstiges in vitro Sicherheitsprofil zeigte. Die akute orale Toxizität wurde in Mäusen untersucht. Weiterhin, wurde pharmakokinetische Profil der Substanz in vitro und in vivo untersucht
Structural insights into assembly and regulation of HigBA toxin-antitoxin system from Escherichia coli
No full textIn the last few decades, bacterial Toxin-antitoxin (TA) systems have been identified to play crucial roles in bacterial survival under stressful conditions and virulence. TA systems are pair of genetic elements where one of the genes codes for a protein (toxin), which is toxic to the host cell, and the other gene code for its antidote (antitoxin), which can be an RNA or a protein. Under favourable growth conditions, the antitoxin inhibits the toxin activity; however, when the bacterial cell encounters stressful conditions such as antibiotic exposure, starvation, phage infection, etc., the toxin is released from antitoxin inhibition resulting in cell growth arrest or cell death. The TA systems have been mainly implicated in plasmid maintenance, inhibition of bacteriophage propagation (abortive infection), and survival against antibiotic exposure (persister cell formation). The current thesis work is focused on understanding the structural basis of toxin inhibition and autoregulation of operon expression in the HigBA type II TA system from E. coli. This study reports a high-resolution 2.09 Å crystal structure of the HigBA complex from E. coli K-12. This structure reveals the overall organization and mechanism of antitoxin HigA binding to toxin HigB. We also report a 2.3 Å resolution crystal structure of a truncated heterodimeric HigBA complex. This structure signifies the role of helices 1 and 2 in the dimerization of HigA. Also, we propose that the dimeric structure may indicate the possible proteolytic cleavage sites in toxin HigB and antitoxin HigA, which may have implications in HigBA complex disassembly and regulation in bacteria under proteolytic stress. Further using CD spectroscopy, NMR spectroscopy, and MD simulation studies, we suggest that E. coli HigA antitoxin is well-folded and stable in solution; however, it shows an intrinsic dynamic behavior.
Using EMSA, SEC-MALS, and ITC experiments we establish that HigBA binds to its 33bp promoter DNA (Pal-1 DNA) in a 2:1 (HigA: Pal-1) ratio, and through ITC experiments we report that both the HigBA complex and HigA have comparable high binding affinity towards 33bp Pal-1 DNA. Therefore, we suggest that the toxin HigB has little or no effect on the antitoxin’s DNA binding activity. Further, the C-terminal DBD of HigA (HigA_DBD) was cloned and purified for the NMR-based titration experiments to identify the DNA binding residues. The sequential backbone assignments of HigA_DBD were achieved and using NMR CSP data from the titration experiments with different Pal-1 DNA sequences, we reveal that residues from helix 7, 8, loop L1 and loop L2 of the DNA binding domain of HigA interact with Pal-1 promoter DNA sequence. Further, we report the NMR CSP data-driven HADDOCK model of Pal-1 DNA bound HigBA complex. Finally, we report a low-resolution cryoEM structure of the HigBA and 27bp Pal-1 DNA complexes, confirming that two HigBA complexes bind the Pal-1 DNA sequence
Identification, characterization, structure, and assembly of type III toxin-antitoxin systems from Escherichia coli
No full textBacteria adopt several defense strategies to enable their survival against the environmental threats they encounter from time to time. Toxin-antitoxin (TA) systems are being understood as a key bacterial defense mechanism against invading viruses, antibiotics, and other environmental stress. TA systems consist of a pair of genes, usually under a common promoter, that code for a toxin and its cognate antitoxin . The toxin is usually a protein, that arrests cellular growth during stress, whereas the antitoxin can be a protein or a non-coding RNA, that inhibits the toxin. The TA systems are classified into six different types based on the mechanism of inhibition of toxin by antitoxin. In type III TA systems, the toxin is an endoribonuclease (RNase) that cleaves cellular RNAs when free, whereas antitoxin is a non-coding RNA. The toxin also processes its own precursor antitoxin RNA into smaller repeats and subsequently assembles with them to form an inactive TA complex. During normal growth conditions, the antitoxin RNA inhibits the toxin protein by forming the RNA-protein TA complex. However, when the bacteria encounter stress such as phage infection, the active toxin gets released from the complex and prevents phage replication.
Type III TA systems have been identified in several bacteria and classified into three different families - toxIN, cptIN, and tenpIN. However, type III systems have not been identified and well characterized in Escherichia coli. The identification and characterization of these systems in E. coli, which is the most commonly studied model organism with robust genetic manipulation tools available, would help in understanding them in detail for their functions and mechanism of action. In this thesis, by using protein sequence-based homology searches, we report the identification of ToxIN type III TA systems from several strains in E. coli. Multiple sequence alignment of the toxin protein sequences revealed that these systems could be further grouped in five different clusters and there are several conserved residue positions that could be vital for the toxin structure and function. Secondary structure analysis of representative sequences of antitoxin RNA repeats from five different clusters suggested that these RNAs have the propensity to form pseudoknot structure. Toxin-antitoxin functional assays performed using one of the identified TA systems from E. coli (strain 680) showed that the identified system indeed functions as a type III TA system.
Though type III TA systems are known to be found in several organisms, very few of them have been characterized structurally and biophysically. This is mainly due to the challenges in cloning the toxin proteins in expression vectors and the lack of standard protocols to express and purify the type III TA components. Hence, we decided to establish protocols for cloning and purification of type III TA components. Here, we report the large-scale expression and purification of the toxin, antitoxin and complex components from four different type III TA systems (three from toxIN and one from tenpIN families) in E. coli. This strategy involves cloning the toxin and antitoxin coding DNA sequences in two different co-expression compatible, commercially available expression vectors. Co-transformation and co-expression of toxin and antitoxin genes in laboratory strains of E. coli led to the expression and purification of type III TA complex. Using anion exchange chromatography, we could obtain separate fractions of toxin protein, antitoxin RNA, and complex components in significant quantities suitable for biophysical experiments.
Further, we were able to crystallize the type III TA complex from E. coli (strain 680) and solve the X-ray crystal structure at a resolution of 2.097 Å. This is the first reported structure of a type III TA complex from E. coli. The E. coli type III toxin and antitoxin were arranged in a cyclic heterohexameric assembly in the complex structure. This assembly was also verified in solution using SEC-MALS analysis. The toxin protein, which is an endoribonuclease, adopts a β-sheet containing core structure surrounded by α-alpha helices. The antitoxin RNA forms a pseudoknot structure with two stems and two loops and the 5′ and 3′ single-stranded regions interact with the toxin protein. The structure also uncovered the presence of several key interactions between the toxin and antitoxin and provided molecular basis for the substrate sequence specificity of the toxin. Mapping the amino acid residues which were conserved in all five clusters of E. coli toxIN, onto the structure of the E. coli type III TA complex showed that most of these residues were crucial for toxin folding and endoribonuclease activity. The multiple sequence alignment of antitoxin RNA sequences revealed that the core pseudoknot region was conserved for both sequence and structure across the five different clusters and the 5′ and 3′ single-stranded overhangs were variable, that could lead to specificity of the antitoxins to their cognate toxins.
The assembly of the type III TA complex has not been studied so far in terms of toxin-antitoxin binding affinity and free energy change of the complex formation. Hence, we characterized the binding of toxin protein and antitoxin RNA using isothermal titration calorimetry (ITC) experiments. The ITC experiments reveled that the toxin and antitoxin interact with each other with a very high binding affinity in a two-step binding event. The structure of the complex showed that toxin and antitoxin possess two non-identical binding sites for each other which leads to a two-step binding process. Using truncated antitoxin RNA mutants, we could simplify the two-step binding into two one-step binding events and estimate the binding contribution from each individual site. Based on our ITC experiments on the full-length antitoxin repeat and the truncated repeats, we have proposed a model for the assembly of toxin and antitoxin into a cyclic heterohexameric complex.
Using nuclear magnetic resonance (NMR) spectroscopy, we characterized the structure of the free antitoxin RNA repeat for its foldedness. The 1D 1H and the 2D 1H-1H NOESY NMR spectra showed that the free antitoxin RNA adopts a folded structure in solution. This was further confirmed by recording a 2D 1H-15N HSQC spectrum of the free antitoxin. The NMR spectra of only the core pseudoknot forming region of the antitoxin suggested that the antitoxin RNA could fold into a pseudoknot structure even in the absence of toxin protein. Perturbation of a noncanonical U-U base pair, which is part of a U:U:G triplet, in the antitoxin RNA significantly altered its structure indicating that noncanonical and tertiary interactions are crucial for antitoxin folding.
The thesis has been organized as follows: Chapter-1 provides a brief review on toxin-antitoxin (TA) systems and their classification with a special focus on type III TA systems, that have been studied in this work. Chapter-2 describes the identification and functional characterization of type III TA systems in Escherichia coli. Chapter-3 details the expression and purification of toxin, antitoxin, and complex components from four different type III TA systems in E. coli. In this chapter, we also propose a standard protocol for cloning, expression, and purification of type III TA components for biophysical experiments. In Chapter-4, we report the structure of the first type III TA complex in E. coli. Our studies on toxin and antitoxin binding using isothermal titration calorimetry (ITC) are also described in this chapter. Chapter-5 details the characterization of free antitoxin RNA by solution NMR spectroscopy
Entwicklung neuartiger Wirkstoff Screening Assays und molekulare Charakterisierung von Rifampicin und Pyrazinamid Resistenz in Mycobacterium tuberculosis
Get PDFThere is an urgent need for a better understanding of the mechanisms of resistance to antibiotics in M. tuberculosis and for the development of rapid assays suitable for high-throughput screening for the development of new drugs not only against drug resistant tuberculosis (TB) but also for the treatment of persistent and latent tuberculosis infection.
Rifampicin is one of the most potent and most effective drug against TB. However resistance to rifampicin in M. tuberculosis strain is caused due to mutation in rpoB gene, a subunit of RNA polymerase (RNAP). The enzyme complex as a whole is a well known target for new drug development. RNAP assay for the screening of drug was devised in the work. The method established was cost effective, suitable for high-throughput use and utilized natural nucleotides. With the devised assay several drug candidates were tested.
Pyrazinamide (PZA) is a nicotinamide analog which is also used as a frontline drug to treat TB. The exact mechanism of action of PZA, one of the most important antimycobacterial drug is still elusive. Mutations in pncA gene of M. tuberculosis are mostly responsible for the resistance developed by M. tuberculosis against PZA. In other to further understand the molecular basis of PZA resistance in M. tuberculosis, DNA sequence of pncA from PZA resistant and susceptible clinical isolates of M. tuberculosis were analysed. The analysis identified several different as yet unreported mutations. Further the pncA gene of M. tuberculosis H37Rv was cloned in E. coli BL21 (DE3), purified and characterized. A high throughput pyrazinamidase assay was developed in 96 well plate, which can be further used for the exploration of novel therapy for TB.Es gibt einen dringenden Bedarf für ein besseres Verständnis der Mechanismen, die zu Antibiotikaresistenzen bei M. tuberculosis führen. Darüberhinaus ist die Entwicklung schneller Verfahren notwendig, die ein High-throughput screening für die Entwicklung neuer Wirkstoffe möglich machen, die nicht nur gegen arzneimittelresistente Tuberkulose (TB), sondern auch für die Behandlung persistenter und latenter Tuberkuloseinfektionen verwendbar sind.
Rifampicin ist eines der stärksten und wirkungsvollsten Medikamente gegen TB. Dennoch wird eine Resistenz gegen Rifampicin bei M. tuberculosis durch eine Mutation im rpoB Gen, einer Untereinheit der RNA-Polymerase (RNAP), verursacht. Der Enzymkomplex als Ganzes ist ein weithin bekanntes Ziel für neue Wirkstoffentwicklungen, daher wurde in der (vorliegenden) Arbeit ein RNAP assay für das Drug screening (erfolgreich) realisiert . Die hierzu etablierteMethode, ist für den Hochdurchsatz geeignet ,kosteneffektiv und verwendet natürliche Nukleotide. Mittels dieses Tests wurden einige Wirkstoffkanditaten geprüft.
Pyrazinamide (PZA) ist eine Nikotinamid ähnlich Substanz, die auch als Frontliniedroge verwendet wird, um TB zu behandeln. Der genaue Wirkmechanismus von PZA, eines der wichtigsten antimykobakteriellen Medikamente, ist jedoch noch nicht geklärt. Für eine Resistenz gegen PZA sind meistens Veränderungen im pncA Gen von M. tuberculosis verantwortlich. Um zum weiteren Verständnis der molekularen Grundlagen der PZA-Resistenzs in M. tuberculosis beizutragen, wurden pncA DNS Sequenzen von PZA-resistenten und -resistenzanfälligen klinischen Isolaten von M. tuberculosis analysiert. Die Analyse identifizierte einige bis jetzt nicht berichtete Veränderungen. Weiterhin wurde das pncA Gen von M. tuberculosis H37Rv in Escherichia coli BL21 (DE3) kloniert, gereinigt und charakterisiert. Es konnte ein Hochdurchsatz–Pyrazinamidase-Test in 96-Well-Platten entwickelt werden, der für die Erforschung neuer Therapien bei TB weiter genutzt werden kann
Functional and structural studies of proteins involved in telomere maintenance
No full textThe linear ends of the eukaryotic chromosomes are protected by a specialized nucleoprotein complex known as telomere. Telomeres consist of telomere DNA and telomere DNA binding proteins (known as shelterin complex). The telomere DNA repeats consist of a 3’ G-rich overhang which folds into a lariat-like structure called the t/D-loops. The C-rich strand of telomere DNA is transcribed into a long non-coding RNA known as the telomere repeat containing RNA (TERRA) and comprises of repeats of UUAGGG in humans. Both TERRA RNA and telomere DNA, being G-rich, form higher order G-quadruplex structures both in vitro and in vivo. Thus, the higher order structures formed by telomere DNA along with TERRA RNA impart protection and stability to the telomere ends. However, these higher order structures have also been found to inhibit the telomere DNA elongation by the telomerase holoenzyme. Therefore, remodeling of the telomere DNA during its replication by DNA polymerase and elongation by the telomerase is important to prevent arrest of the replication. Several proteins are involved in t/D-loop disassembly and G-quadruplex unfolding in a non-enzymatic manner as well as using ATP dependent helicase activities.
In this thesis, we have studied two proteins, namely hnRNPA1 and RTEL1, involved in telomere DNA maintenance. hnRNPA1 is involved in unwinding of the G-quadruplex structures in a non-enzymatic fashion, whereas RTEL1 is involved in t/D-loop disassembly and G-quadruplex unfolding using its helicase activity. hnRNPA1 is a modular protein containing an N-terminal UP1 domain (comprising of two RNA Recognition Motifs, RRM1 and RRM2) followed by an RGG-box containing C-terminal region. The precise role of the RGG-box of hnRNPA1 in telomere DNA recognition and G-quadruplex DNA unfolding had remained unexplored. In this study, we showed that the RGG-box of hnRNPA1 is intrinsically disordered in solution and it specifically recognizes the TERRA RNA and telomere DNA G-quadruplex structures that have loops in their topology, whereas it shows no interaction with the single-stranded RNA/ DNA. Furthermore, the UP1 domain in the presence of the RGG-box destabilizes the loop containing TERRA RNA and telomere DNA G-quadruplexes efficiently compared to UP1 domain alone.
RTEL1 is a modular protein with four identified domains: N terminal Fe-S cluster containing DNA helicase domain, two harmonin-N-like domains (HNL1 and HNL2), a PCNA interacting protein motif box (PIP box), and a C terminal zinc binding C4C4 type RING finger domain. In this thesis, the sequential resonance assignment of the HNL1 and HNL2 domains has been achieved using triple resonance NMR methods and the initial structural characterization of these domains has been achieved with the help of CS-ROSETTA. . In addition, the interacting protein partners of Harmonin-N-like domains (tandem HNL1 and HNL2 domains) have been identified by pull down assays followed by mass-spectrometry analysi
Structural and DNA binding properties of ARID domains present in hSWI/SNF chromatin remodeling complex subunits
No full textThe SWI/SNF complexes are multisubunit-containing protein complexes that are involved in chromatin-remodeling processes in the eukaryotic cells. In higher eukaryotes, SWI/SNF complexes contain one or more mutually exclusive AT-rich interaction domain (ARID)-containing proteins as one of the subunit. The SWI/SNF complexes can be further classified into sub complexes. Association of ARID-containing proteins BAF250a (also known as ARID1a) and BAF250b (also known as ARID1b) with the SWI/SNF complex results in BAF-A and BAF-B complexes respectively, whereas the association of ARID-containing BAF200 (also known as ARID2) results in PBAF complex. BAF250a, BAF250b and BAF200 subunits have an AT-rich interaction domain named as ARID. It has been proposed that BAF250a/b and BAF200 subunits likely recruit SWI/SNF complex through ARID domain to heterochromatin that allows transcriptional activation of normally silenced chromatin, thereby regulating the specific gene expression. The ARID is a conserved, all helical DNA binding domain found in several eukaryotic proteins. ARIDs in proteins such as human modulator recognition factor 2 (Mrf2), Drosophila Dead Ringer (Dri), and murine protein Bright were shown to recognize specific AT-rich DNA sequences. The evidences so far suggest that ARIDs of human SWI/SNF complexes interact with DNA without any sequence preference, therefore questioning the recruitment of SWI/SNF complexes by BAF250a to the target genes via its interaction with specific DNA sequences. The structure and functional annotation of BAF250a/b (> 2200 residues long proteins) remains poorly understood. The folded regions and domain boundaries of these lengthy proteins have not been clearly defined. Likewise, their DNA-binding specificities have not been studied systematically. With this background, we proposed to study the structure and DNA binding specificities of ARID domains in BAF250a, BAF250b, and BAF200 in this thesis. First, we have defined the domain architecture of BAF250a/ reveals the ARID and ARM-repeat domains with implication in function and assembly of the BAF remodeling complex. Next, systematically we have defined the domain boundary and DNA binding specificities of BAF250a ARID. Using NMR spectroscopy and ITC methods, our results showed that BAF250a ARID binds to AT rich DNA in a ‘specific’ manner with thermodynamic signatures for a specific DNA binding. NMR CSP driven model of BAF250a ARID – DNA complexes were generated and validated using mutagenesis approach. We have also completed the NMR chemical shift assignment of ARID domains of BAF250b and BAF200. We have generated a CS-Rosetta model structure of BAF200 ARID and currently we are in the process of refining the structure. DNA binding properties of BAF250b ARID have been studied using NMR and ITC methods. NMR CSP driven HADDOCK models of BAF250b ARID/DNA complexes suggest plausible mode of specific complex formation via DNA major groove recognition by helix H5 and minor groove interactions by loop L1. A temperature independent DNA binding thermodynamics was observed for BAF250b ARID unlike BAF250a ARID though these two proteins share > than 80% identity in their sequences. The reason of such differences may be due to the small and subtle deviations in loop L1 region. In case of BAF200 ARID, we have some preliminary results on its DNA binding properties obtained from NMR and SPR studies using AT-12 and GC-12 DNA
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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