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Symbolic or incomplete trephinations are very common in Hungary in 9th-11thcentury AD skeletal series connected to early Hungarians, although they also occur in the preceding Avar Age (6th-9th c. AD) material. During the compilation of a database of regional cranial modification data, the authors found rare almond-shaped symbolic trephinations in both periods, while these had formerly only been reported in Early Hungarian series. In this study, the new almond-shaped lesions are described along with other symbolic trephinations of 14 newly found skulls from the 8th-11thcenturies AD in the Southern Great Plain of Hungary. The authors review the research of the phenomenon. The new findings may strengthen the theory of direct and very close cultural connections of these two ethnic groups, adding a new aspect to the debate over the origin and relationship of Late Avar (late 7th-early 9th c. AD) and Early Hungarian (9th-11th c. AD) populations. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

This paper presents the adaptation of a mechanical mini-lathing machine to a computerized numerical control (CNC) lathing machine. This machine is composed of a ASIST mini-lathe and a two-degrees-of-freedom XZ stage designed specifically for this application. The whole system is controlled from a PC using adequate CNC control software.

Three types of highly promising small RNA therapeutics, namely, small interfering RNAs (siRNAs), microRNAs (miRNAs) and the RNA subtype of antisense oligonucleotides (ASOs), offer advantages over small-molecule drugs. These small RNAs can target any gene product, opening up new avenues of effective and safe therapeutic approaches for a wide range of diseases. In preclinical research, synthetic small RNAs play an essential role in the investigation of physiological and pathological pathways as silencers of specific genes, facilitating discovery and validation of drug targets in different conditions. Off-target effects of small RNAs, however, could make it difficult to interpret experimental results in the preclinical phase and may contribute to adverse events of small RNA therapeutics. Out of the two major types of off-target effects we focused on the hybridization-dependent, especially on the miRNA-like off-target effects. Our main aim was to discuss several approaches, including sequence design, chemical modifications and target prediction, to reduce hybridization-dependent off-target effects that should be considered even at the early development phase of small RNA therapy. Because there is no standard way of predicting hybridization-dependent off-target effects, this review provides an overview of all major state-of-the-art computational methods and proposes new approaches, such as the possible inclusion of network theory and artificial intelligence (AI) in the prediction workflows. Case studies and a concise survey of experimental methods for validating in silico predictions are also presented. These methods could contribute to interpret experimental results, to minimize off-target effects and hopefully to avoid off-target-related adverse events of small RNA therapeutics. LINKED ARTICLES: This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background and Purpose: Cardioprotective miRNAs (protectomiRs) are promising therapeutic tools. Here, we aimed to identify protectomiRs in a translational porcine model of acute myocardial infarction (AMI) and to validate their cardiocytoprotective effect., Experimental Approach: ProtectomiR candidates were selected after systematic analysis of miRNA expression changes in cardiac tissue samples from a closed-chest AMI model in pigs subjected to sham operation, AMI and ischaemic preconditioning, postconditioning or remote preconditioning, respectively. Cross-species orthologue protectomiR candidates were validated in simulated ischaemia-reperfusion injury (sI/R) model of isolated rat ocardiomyocytes and in human AC16 cells as well. For miR-450a, we performed target prediction and analysed the potential mechanisms of action by GO enrichment and KEGG pathway analysis., Key Results: Out of the 220 detected miRNAs, four were up-regulated and 10 were down-regulated due to all three conditionings versus AMI. MiR-450a and miR-451 mimics at 25 nM were protective in rat cardiomyocytes, and miR-450a showed protection in human cardiomyocytes as well. MiR-450a has 3987 predicted mRNA targets in pigs, 4279 in rats and 8328 in humans. Of these, 607 genes are expressed in all three species. A total of 421 common enriched GO terms were identified in all three species, whereas KEGG pathway analysis revealed 13 common pathways., Conclusion and Implications: This is the first demonstration that miR-450a is associated with cardioprotection by ischaemic conditioning in a clinically relevant porcine model and shows cardiocytoprotective effect in human cardiomyocytes, making it a promising drug candidate. The mechanism of action of miR-450a involves multiple cardioprotective pathways., Linked Articles: This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The Subalyuk hominin remains were uncovered in 1932 in a cave of the same name in the Bükk Mountains, near the village of Cserépfalu in Borsod-Abaúj-Zemplén County, Northern Hungary. The remains represent two individuals, an adult and a young child who have been described in a few publications since their discovery, providing substantial anthropological data and general assessments of their Neanderthal affiliation. They were associated with Late Mousterian industry. Thus, the Bükk Mountains gain importance in the discussion concerning the contribution of East Central European sites to the debate on the peopling history of Europe during the Late Middle to Early Upper Palaeolithic transition. In this paper, we summarize the archaeological and chronological context of the two individuals, and publish the first direct dating results that place them among the Last Neanderthals of Central Europe.

Skeletal remains of two Neanderthal individuals, a 25-35 year-old woman and a 3-4 year-old child, were discovered in a Subalyuk Cave in North-Eastern Hungary. Radiocarbon dating of the female and child remains revealed an age of 39,732-39,076 and 36,117-35,387 cal BP, respectively. Paleopathological studies of these Neanderthal remains revealed probable evidence of skeletal mycobacterial infection, including in the sacrum of the adult specimen and the endocranial surface of the child's skull. Application of PCR amplification to the juvenile cranium and a vertebra gave a positive result (IS6110) for tuberculosis, backed up by spoligotyping. Lipid biomarker analyses of the same two specimens revealed definitive signals for C 32 mycoserosates, a very characteristic component of the Mycobacterium tuberculosis complex (MTBC). A vertebra from the adult provided weak evidence for mycocerosate biomarkers. The correlation of probable skeletal lesions with characteristic amplified DNA fragments and a proven lipid biomarker points to the presence of tuberculosis in these Neanderthals. In particular, the closely similar biomarker profiles, for two distinct juvenile cranial and vertebral bones, strengthen this diagnosis., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In 1932, skeletal remains of two Neanderthal individuals, a young adult female and a 3-4-year-old child, were discovered in Subalyuk Cave in Northern Hungary [1,2]. Results of the anthropological examination were published some years after this important discovery. Methodological progress encouraged re-examination of the material during the last few years. Radiocarbon dating revealed a chronological age of 39,732-39,076 cal. BP for the adult female and 36,117-35,387 cal. BP for the child [3]. Morphological paleopathological studies of these Neanderthal remains uncovered distinct evidence of skeletal infections. Alterations of the adult individual's sacrum suggest probable early-stage sacroiliitis, while several vertebral bodies indicate superficial osseous remodelling of infectious origin. Traces of pathological lesions were observed on the endocranial surface of the child's skull, reflecting a reaction of meningeal tissues, a consequence of a probable TB-related meningeal infectious process. Results of recent paleomicrobiological examinations - lipid biomarker and aDNA studies - support the morphological diagnosis of probable TB infections [4]., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The origins of horseback riding remain elusive. Scientific studies show that horses were kept for their milk ~3500 to 3000 BCE, widely accepted as indicating domestication. However, this does not confirm them to be ridden. Equipment used by early riders is rarely preserved, and the reliability of equine dental and mandibular pathologies remains contested. However, horsemanship has two interacting components: the horse as mount and the human as rider. Alterations associated with riding in human skeletons therefore possibly provide the best source of information. Here, we report five Yamnaya individuals well-dated to 3021 to 2501 calibrated BCE from kurgans in Romania, Bulgaria, and Hungary, displaying changes in bone morphology and distinct pathologies associated with horseback riding. These are the oldest humans identified as riders so far.

The aim of our paper is to present and discuss in detail the bony changes indicative of tuberculosis (TB) that were identified in a skeleton (KB67), unearthed from grave 67 of the 8th-century-CE cemetery of Kaba-Bitózug (Hungary). Furthermore, to provide the differential diagnoses of the observed alterations, with special attention to the cranial osteolytic lesions. During the macro- and micromorphological examinations of KB67, the skull revealed three small, well-circumscribed, punched-out osteolytic lesions accompanied by endocranial granular impressions, abnormal blood vessel impressions, periosteal appositions, and cortical erosion. The postcranial skeleton exhibited osteolytic lesions, cortical remodelling and erosion, and signs of hypervascularisation in the spine. Based on the differential diagnosis of the cranial osteolytic lesions and their co-occurrence with endocranial and vertebral bony changes indicative of TB, they most likely resulted from tuberculous involvement of the frontal and left parietal bones. The morphologically established diagnosis was confirmed by a PCR analysis that provided evidence for the presence of Mycobacterium tuberculosis DNA in KB67. KB67, the first reported archaeological case with calvarial TB from the present-day territory of Hungary, gives us a unique insight into the occurrence of a rare manifestation of TB in the Avar Age of the Great Plain., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The use of SU-8 material in the production of neural sensors has grown recently. Despite its widespread application, a detailed systematic quantitative analysis concerning its biocompatibility in the central nervous system is lacking. In this immunohistochemical study, we quantified the neuronal preservation and the severity of astrogliosis around SU-8 devices implanted in the neocortex of rats, after a 2 months survival. We found that the density of neurons significantly decreased up to a distance of 20 μm from the implant, with an averaged density decrease to 24 ± 28% of the control. At 20 to 40 μm distance from the implant, the majority of the neurons was preserved (74 ± 39% of the control) and starting from 40 μm distance from the implant, the neuron density was control-like. The density of synaptic contacts - examined at the electron microscopic level - decreased in the close vicinity of the implant, but it recovered to the control level as close as 24 μm from the implant track. The intensity of the astroglial staining significantly increased compared to the control region, up to 560 μm and 480 μm distance from the track in the superficial and deep layers of the neocortex, respectively. Electron microscopic examination revealed that the thickness of the glial scar was around 5-10 μm thin, and the ratio of glial processes in the neuropil was not more than 16% up to a distance of 12 μm from the implant. Our data suggest that neuronal survival is affected only in a very small area around the implant. The glial scar surrounding the implant is thin, and the presence of glial elements is low in the neuropil, although the signs of astrogliosis could be observed up to about 500 μm from the track. Subsequently, the biocompatibility of the SU-8 material is high. Due to its low cost fabrication and more flexible nature, SU-8 based devices may offer a promising approach to experimental and clinical applications in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Orosháza site no. 10 (Southeast Hungary) contains the partially excavated archaeological remains of an 11-13 th century CE Muslim merchant village and its cemetery located in close proximity to Christian villages of the same era. The skeleton of a young woman (grave no. 16) from the last phase of the cemetery use was identified with rhinomaxillary lesions associated with lepromatous leprosy. The right parietal bone also exhibited signs of cranial trauma, possibly caused by symbolic trepanation, a well-known ritual practice in the 9-11 th century CE Carpathian Basin. The retrospective diagnosis of the disease was supported by ancient DNA analysis, as the samples were positive for Mycobacterium leprae aDNA, shown to be of genotype 3. Contrary to the general practice of the era, the body of the young female with severe signs of leprosy was interred among the regular graves of the Muslim cemetery in Orosháza, which may reflect the unique cultural background of the community.

Background: Low back pain is a primary health care utilization driver in the US population. Health care evaluation visits for low back pain are as common as medical evaluation for the common cold. Low back pain is the most common reason for reductions in activities of daily living and work activity in the general population. Although these statistics are compelling, in the military population, there is arguably a significantly greater economic impact on the military population, as the cost to train, retain, and deploy a service member is a tremendous cost., Methods: The current study retrospectively examines surgical outcomes, return to duty, and patient-centric outcomes among 82 active duty or reserve military patients who underwent an outpatient minimally invasive spine surgery Laminotomy Foraminotomy Decompression for the treatment of lumbar spinal stenosis in an ambulatory surgery center., Findings: Overall, our results indicate that within the 82 active duty military service members, 100% of the service members return to duty within 3 mo. Additionally, there was a significant reduction in self-reported pain and disability 12 mo postoperative, whereas the average length of surgery was 62 min with an average estimated blood loss of 30.64 mL., Discussion: The current study indicates that minimally invasive procedures for the treatment of lumbar spinal stenosis in an ambulatory surgery center setting are an effective option for active duty servicemen to reduce return-to-duty rates and symptomatic back-related pain and disability., (© Association of Military Surgeons of the United States 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The AD 16-17(th) century skeletal series from Bácsalmás-Óalmás (southern Hungary) has already been the subject of previous paleopathological studies concerning TB-related bone lesions. Due to recent development of macroscopic and molecular diagnostic methods in paleopathology and paleomicrobiology, a five-year international research program was recently started in order to re-evaluate the TB-related lesions in the complete series, comprising 481 skeletons. The skeletal material of these individuals was examined using macromorphological methods focusing on both classical/advanced stage skeletal TB alterations and atypical/early-stage TB lesions. Paleomicrobial analysis was used to study the presence of Mycobacterium tuberculosis complex (MTBC) DNA both in morphologically positive and negative cases. Samples were tested for the repetitive element IS6110 and further characterized by spoligotyping. In the whole series, 283 possible cases of TB infections were identified based on morphological alterations. Skeletal samples of eighteen individuals, morphologically positive as well as negative cases, were selected for further biomolecular examinations. Among them, seven individuals were PCR positive for the repetitive IS6110 sequence of the MTBC genome. Compared to the few cases of TB from the Bácsalmás-Óalmás series previously described, a much higher prevalence of MTBC infected skeletons was revealed in this study. The atypical/early stage skeletal lesions occurred significantly more frequently than the so-called classical alterations. Paleomicrobial analysis confirmed a prevalence of MTBC infection nearing 40% among the selected sample. Preliminary results also indicated better preservation of bacterial DNA in the compact layer of long bones and teeth, while spoligotyping suggested infection by different MTBC pathogens., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

This study derives from the macroscopic analysis of a Late Neolithic population from Hungary. Remains were recovered from a tell settlement at Hódmezővásárhely-Gorzsa from graves within the settlement as well as pits, ditches, houses and as stray finds. One of the most important discoveries from these remains was evidence of tuberculosis. Pathological analysis of the seventy-one individuals revealed numerous cases of infections and non-specific stress indicators on juveniles and adults, metabolic diseases on juveniles, and evidence of trauma and mechanical changes on adults. Several cases showed potential signs of tuberculosis and further analyses were undertaken, including biomolecular studies. The five individuals were all very young adults and included a striking case of Hypertrophic Pulmonary Osteopathy (HPO) with rib changes, one case with resorptive lesions on the vertebrae, two cases with hypervascularisation on the vertebrae and periosteal remodelling on the ribs, and one case with abnormal blood vessel impressions and a possible lesion on the endocranial surface of the skull. The initial macroscopic diagnosis of these five cases was confirmed by lipid biomarker analyses, and three of them were corroborated by DNA analysis. At present, these 7000-year-old individuals are among the oldest palaeopathological and palaeomicrobiological cases of tuberculosis worldwide., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Previous investigations carried out in some parts of the 16th-17th century AD series of Bácsalmás-Oalmás (southern Hungary) have already provided interesting paleopathological cases of tuberculosis (e.g. Molnár & Pálfi 1994). These studies were essentially based on macromorphological analysis, biomolecular methods were used only in a few cases (e.g. Haas et al. 2000). From a macromorphological point of view, former investigations have only considered 'classical' tuberculosis (TB) alterations (advanced-stage lesions in common skeletal locations). However, due to the recent development of diagnostic criteria in the field of the paleopathology of infectious diseases, new approaches have been introduced in the identification of skeletal TB lesions (Pálfi et al. 1999, Maczel 2003). Molecular methods for the detection of mycobacterial aDNA have also been developed considerably in the last few years (e.g. Donoghue 2008, Donoghue 2011). The good state of preservation of the material, the important chronological period of the series and the relative high prevalence of TB reported in preliminary studies encouraged us to carry out a revision of TB-related lesions in the complete Bácsalmás-Oalmás series. A five year international research program--including both macroscopic and biomolecular studies of the series--was recently started. The present paper summarizes the results ofa pilot project conducted to optimize the further systematic paleopathological and paleomicrobial studies. Skeletal material of 205 individuals was chosen forthe macromorphological test-investigation, which was focused both on classical/advanced stage skeletal TB alterations (tuberculous spondylitis, tuberculous arthritis) and atypical/early-stage TB lesions (rib lesions, superficial vertebral changes, endocranial alterations, early-stage spondylodiscitis). In addition, the association of possible stress factors (long bone periostitis, cribra orbitalia, cribra cranii) were also considered. Paleomicrobiological analysis was used to study the presence of Mycobacterium tuberculosis ancient DNA (aDNA) in morphologically positive and negative cases. A comparative paleomicrobial analysis was carried out on different samples, to test the presence of MTB DNA in different skeletal regions.

Head and neck cancer is a frequent malignancy with a complex, and up to now not clear etiology. The reactivation of telomerase activity and losses or gains of specific chromosomal regions, which point to deletions of tumor suppressor genes or amplification of oncogenes are supposed to be the molecular processes during the development and progression of head and neck cancer. Therefore, we analyzed telomerase activity and microsatellite markers using a genome wide panel of 28 microsatellite markers in 38 head and neck squamous-cell carcinomas (HNSCC). Our microsatellite marker set included distinct chromosomal areas that all likely harbor genes contributing to the carcinogenesis of HNSCC. DNA or protein lysates were obtained from primary tumors and compared to peripheral lymphocytes or corresponding normal tissue. At least one genomic alteration [loss of heterozygosity (LOH), or microsatellite instability (MSI)] was found in 31 of the 38 cases (82%). Most frequently we detected an LOH in the chromosomal region 9p12-21 where at least the tumor suppressor genes (TSG) p16INK4A, p14ARF and p15INKB are localized. The comparison between grade two and grade three tumors showed a highly changed frequency of LOH in the chromosomal region 7q31, where a putative TSG is predicted. Telomerase activity was present in 31/37 (83.8%) tumor samples independent of the histopathological staging and grading of the tumors. These molecular characterizations of HNSCC may be a further hint for the involvement of additional, so far unknown, TSGs in the tumor progression and will elucidate the regulation of telomerase.

A simple and efficient gene replacement method, based on the recombination and repair activities of the cell, was developed. The method permits the targeted construction of markerless deletions, insertions and point mutations in the Escherichia coli chromosome. A suicide plasmid, carrying the mutant allele and the recognition site of meganuclease I- Sce I, is inserted into the genome by homologous recombination between the mutant and the wild-type (wt) alleles. Resolution of this cointegrate by intramolecular recombination of the allele pair results in either a mutant or a wt chromosome which can be distinguished by allele-specific PCR screening. The resolution process is stimulated by introducing a unique double-strand break (DSB) into the chromosome at the I- Sce I site. Cleavage by the nuclease not only enhances the frequency of resolution by two to three orders of magnitude, but also selects for the resolved products. The DSB-stimulated gene replacement method can be used in recombination-proficient E.coli cells, does not require specific growth conditions, and is potentially applicable in other microorganisms. Use of the method was demonstrated by constructing a 17-bp and a 62-kb deletion in the MG1655 chromosome. Cleavage of the chromosome induces the SOS response but does not lead to an increased mutation rate.