Early Region Research Articles

Hamster Polyomavirus Research: Past, Present, and Future.

Hamster polyomavirus (Mesocricetus auratus polyomavirus 1, HaPyV) was discovered as one of the first rodent polyomaviruses at the end of the 1960s in a colony of Syrian hamsters (Mesocricetus auratus) affected by skin tumors. Natural HaPyV infections have been recorded in Syrian hamster colonies due to the occurrence of skin tumors and lymphomas. HaPyV infections of Syrian hamsters represent an important and pioneering tumor model. Experimental infections of Syrian hamsters of different colonies are still serving as model systems (e.g., mesothelioma). The observed phylogenetic relationship of HaPyV to murine polyomaviruses within the genus Alphapolyomavirus, and the exclusive detection of other cricetid polyomaviruses, i.e., common vole (Microtus arvalis polyomavirus 1) and bank vole (Myodes glareolus polyomavirus 1) polyomaviruses, in the genus Betapolyomavirus, must be considered with caution, as knowledge of rodent-associated polyomaviruses is still limited. The genome of HaPyV shows the typical organization of polyomaviruses with an early and a late transcriptional region. The early region encodes three tumor (T) antigens including a middle T antigen; the late region encodes three capsid proteins. The major capsid protein VP1 of HaPyV was established as a carrier for the generation of autologous, chimeric, and mosaic virus-like particles (VLPs) with a broad range of applications, e.g., for the production of epitope-specific antibodies. Autologous VLPs have been applied for entry and maturation studies of dendritic cells. The generation of chimeric and mosaic VLPs indicated the high flexibility of the VP1 carrier protein for the insertion of foreign sequences. The generation of pseudotype VLPs of original VP1 and VP2–foreign protein fusion can further enhance the applicability of this system. Future investigations should evaluate the evolutionary origin of HaPyV, monitor its occurrence in wildlife and Syrian hamster breeding, and prove its value for the generation of potential vaccine candidates and as a gene therapy vehicle.

First detection and complete genome analysis of the Lyon IARC polyomavirus in China from samples of diarrheic cats.

Lyon IARC polyomavirus (LIPyV), a newly discovered polyomavirus (PyV), was first identified in 2017 in human skin samples in the USA. Later, it was detected in several other countries in samples of human and feline origin. Our aim was to find out if the virus occurs in China. To this end, 100 fecal samples were collected from cats with diarrhea in Guangxi Province during 2016 and 2018 and tested with polymerase chain reaction (PCR). Only 2 samples that originated from two related individuals were found to be positive. Based on the sequence identity of the 240-bp PCR products, the two positive samples supposedly contained identical viruses. Therefore, only one of them, which was designated as LIPyV-GXNN01, was selected for full genome amplification, cloning, sequencing and analysis. LIPyV-GXNN01, which comprises 5,263 nucleotides, has an early region that consists of small T antigen (ST-Ag) and large T antigen (LT-Ag) and a late region coding for the VP1, VP2, and VP3 structural proteins. Moreover, the LIPyV-GXNN01 strain structural proteins share 95.9–99.4%, 97.6–99.2%, and 97.1–99.2% nucleic acid identity with the VP1, VP2, and VP3of other LIPyV reference strains, respectively. A phylogenetic analysis revealed that GXNN01 clustered together with previously reported LIPyV strain. This present study is the first report of LIPyV in China.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11262-021-01840-1.

Numerical investigation of turbulent flow in a wavy channel partially filled with a porous layer

In this paper, the effect of inserting a porous layer inside a wavy channel on the mean flow and turbulent characteristics in both developing and repeated flow regions have been investigated numerically. The modified Launder-Sharma low-Reynolds number k−ε turbulence model, which was used in a previous study [1] with two extensions model, has been utilised to represent the turbulence in the porous region. For validation, the flow in a clear channel with wavy bottom wall has been considered. The results of clear channel have been compared with the experimental data produced by [2], where the results computed were in a good agreement with the experimental data. In the porous wavy channel flow case, the same dimensions of the clear wavy channel have been adopted but with covering the bottom wavy wall with a porous layer formed of an open-cell metal foam. Three values for the wave amplitude of the wavy bottom wall and porous layer thickness have been considered, which are (0,0.1,0.2) and (0,0.15H,0.3H), respectively. Three samples of metal foams have been tested along with the effect of the wave amplitude of the wavy surface and the thickness of the wavy porous layer on the turbulent flow. These types are (ϕ=0.9486&ω=10PPI), (ϕ=0.952&ω=40PPI) and (ϕ=0.81&ω=13PPI). For all calculations, a Reynolds number equals to 20,600 has been considered. In the near fluid-porous interface region, damping functions have been used. The results show that the repeated flow pattern tends to occur in earlier region towards upstream than the flow over solid wavy surface when the permeability of the porous layer is decreased. Moreover, the repeated flow pattern also tends to occur in early region of the wavy part of the channel when the wave amplitude and porous layer thickness are increased, compared to the lower wave amplitude and low porous layer thickness. Decreasing the permeability increases the size of the recirculation cell in the repeated flow region and also increases the turbulent energy in the clear region. Increasing porous layer thickness, on the other hand, reduces the size of circulation cell and the turbulent energy.

Interactive rather than independent effect of APOE and sex potentiates tau deposition in women.

The apolipoprotein E gene (APOE) is the most important genetic risk factor for sporadic Alzheimer disease, with the ε4 allele being associated with increased cerebral amyloid-β and tau pathologies. Although APOE has been suggested to have a stronger effect in women as compared to men, there is a lack of comprehensive assessment on how the interactive effect of APOE and sex modulates regional vulnerability to tau accumulation. We previously have shown the regional vulnerability to the interactive effect of tau and APOE, yet the sex difference was not specifically addressed. In this study, we leveraged PET imaging data from the Translational Biomarkers in Aging and Dementia cohort at McGill University Research Centre for Studies in Aging to elucidate the APOE-by-sex interactive effect on tau burden. We hypothesized sex-dependent regional vulnerability to tau deposition. PET radiopharmaceuticals [18F]AZD4694 and [18F]MK6240 were used to assess amyloid-β and tau level respectively in 277 subjects from the Translational Biomarkers in Aging and Dementia cohort. We found that the interaction between APOE and sex, rather than their independent main effects, was associated with abnormal tau accumulation in medial temporal regions. Specifically, we found that female APOEε4 carriers showed significantly higher tau burden in early tau deposition regions including the hippocampus, entorhinal and parahippocampal cortices, after accounting for age, educational attainment, clinical diagnosis and neocortical amyloid load. We replicated these findings in 221 subjects from the Alzheimer’s Disease Neuroimaging Initiative cohort, in which a different tau-PET radioligand, [18F]flortaucipir, was used to assess tau burden. In conclusion, this study provides evidence from two cohort studies that interactive rather than independent effect of APOE and sex potentiates early tau deposition in women. Our results have important implications for clinical trials and practice, which should take into consideration both APOEε4 carriage status and sex for identifying individuals with the highest probability of developing tau accumulation and clinical progression.

Individual Alpha Frequency Determines the Impact of Bottom-Up Drive on Visual Processing.

Endogenous alpha oscillations propagate from higher-order to early visual cortical regions, consistent with the observed modulation of these oscillations by top-down factors. However, bottom-up manipulations also influence alpha oscillations, and little is known about how these top-down and bottom-up processes interact to impact behavior. To address this, participants performed a detection task while viewing a stimulus flickering at multiple alpha band frequencies. Bottom-up drive at a participant’s endogenous alpha frequency either impaired or enhanced perception, depending on the frequency, but not amplitude, of their endogenous alpha oscillation. Fast alpha drive impaired perceptual performance in participants with faster endogenous alpha oscillations, while participants with slower oscillations displayed enhanced performance. This interaction was reflected in slower endogenous oscillatory dynamics in participants with fast alpha oscillations and more rapid dynamics in participants with slow endogenous oscillations when receiving high-frequency bottom-up drive. This central tendency may suggest that driving visual circuits at alpha band frequencies that are away from the peak alpha frequency improves perception through dynamical interactions with the endogenous oscillation. As such, studies that causally manipulate neural oscillations via exogenous stimulation should carefully consider interacting effects of bottom-up drive and endogenous oscillations on behavior.

Genotyping of Human Papilloma Virus Causing Skin Wart among Iraqi Patients

The papillomaviruses are a large group of tiny, non-enveloped DNA viruses that in several differentanatomical locations can cause squamous epithelial tumor’s (warts and papilloma’s). There is a closeassociation between HPV and cervical uterine cancer . The genome is composed of 7200–8000 base pairsand is divided into three parts, early region (E) comprising of E1, E2, E4–E8 and reflecting 50 percent of theL1 and L2 genome, Genomic DNA from wart tissue samples were extracted by using gSYAN DNA mini kitextraction kit . The Real Time PCR primers for detection and genotyping of DNA Human papillomavirustype 1 and type3 and type6 based on L1 gene that designed in this study using NCBI-Genbank Sequencedatabase and primer 3 plus . The genetic study included analysis of a common DNA to HPV that was foundin 20 % of cases and DNA fragment specific to HPV type 1, 3 and 6 based on real time PCR. Type 1 HPVwas not approved to present in any sample in the study. Type 3 HPV was identified in a single case. HPV 6was identified in 8 cases, Therefore, type 6 HPV is the most common genotype, followed by type 3.

AXL is crucial for E1A-enhanced therapeutic efficiency of EGFR tyrosine kinase inhibitors through NFI in breast cancer.

AXL which is a chemosensitizer protein for breast cancer cells in response to epidermal growth factor receptor-tyrosine kinase inhibitor and suppresses tumor growth. The clinical information show nuclear factor I (NFI)-C and NFI-X expression correlate with AXL expression in breast cancer patients. Following, we establish serial deletions of AXL promoter to identify regions required for Adenovirus-5 early region 1A (E1A)-mediated AXL suppression. All of the NFI family members were extensively studied for their expression and functions in regulating AXL. Moreover, E1A post-transcriptionally downregulates AXL expression through NFI. NFI-C and NFI-X, not NFI-A and NFI-B, resulting in cell death in response to EGFR-TKI. Our finding suggests that NFI-C and NFI-X are crucial regulators for AXL and significantly correlated with poor survival of breast cancer patients.

Cholinergic degeneration in association with tau pathology and evidence of sex differences

<h3>Introduction</h3> Nearly two-thirds of Alzheimer's disease (AD) patients are women. While AD is associated with several pathological and neurodegenerative processes, including the accumulation of amyloid-beta plaques, the spread of phosphorylated tau tangles, and the dysfunction of the cholinergic neurotransmission system, the neurobiological mechanisms contributing to the disproportional impact of AD on women remains unclear. While several recent studies, including our work, report elevated tau deposition in women, it remains unclear how sex differences in tau burden contribute to the progression of neurodegenerative processes leading to cognitive decline and higher AD prevalence in women. Throughout the progression of AD, the most consistent losses are seen in cholinergic neurons, where these losses negatively affect cognition, particularly in attention, learning, and memory formation. In-vitro models suggest that the cholinergic neuron loss may be due to the toxic interaction of extracellular tau with cholinergic muscarinic M1/M3 receptors leading to cholinergic cell death. This model is supported by post-mortem studies in both animal models and AD patients showing significant reduction of the cholinergic neurons in tau-affected brain regions. The relationship between tau and cholinergic loss has not yet been established in in-vivo human brain. <h3>Methods</h3> We examined cross-sectional imaging data from 84 clinically normal (CN) elderly participants from Alzheimer's Disease Neuroimaging Initiative (ADNI). These included structural magnetic resonance imaging (MRI) and [18F]flortaucipir positron emission tomography (PET). The degeneration of basal forebrain cholinergic system (BFCS) was measured using the VBM toolbox in SPM 12. As the BFCS nuclei lack clear anatomical borders on MRI scans, we used previously published cytoarchitectonic maps of BFCS sub-regions to identify the nucleus basalis of Meynert (NBM), which is one of the earliest AD-affected regions in BFCS. We used ADNI processed [18F]flortaucipir PET standardized uptake value ratios (SUVRs) in Braak stage composite regions I, II-II, II-IV, and V-VI that approximate the spread of tau as depicted by Braak and Braak to estimate the regional tau burden. Linear regression models were used to examine the associations between individual Braak composite regions (predictors) and NBM volume (outcome) while accounting for age, APOE status and amyloid-positivity as covariates. <h3>Results</h3> Our preliminary findings from CN women supports a significant association between early tau burden, measured with [18F]Flortaucipir SUVR in the entorhinal cortex and hippocampus, and NBM atrophy (beta = -0.17, p = 0.04;). By comparison, we did not find a significant association in age-matched men (beta = -0.1, p = 0.07). Women also exhibited a higher tau burden than men (p = 0.045 in Braak I-II ROI PET SUVR). Moreover, we detected neither a sex difference in Amyloid status nor an association between Amyloid positivity and NBM. <h3>Conclusions</h3> This is the first in-vivo study that examines the relationship between early tau pathology and cholinergic loss. Our preliminary data supports that higher tau burden in early Braak-stage regions is associated with greater degeneration in NBM. As tau is more extensive in women than men, the effects of tau on cholinergic neurons may contribute to sex differences in cholinergic loss. One of the limitations of our current structural method is that it does not capture the brain-wide degeneration of cholinergic neurons outside of the basal forebrain to identify significant sex differences in global cholinergic, particularly in subjects with mild cognitive impairment (MCI) where sex differences in [18F]Flortaucipir SUVR is more prominent than in CN and where sex differences are seen across multiple Braak-stage regions. <h3>Funding</h3> This research was supported by R01 AG066159-01 (Newhouse) and R01 MH121620 (Taylor)

Dynamic and flexible transformation and reallocation of visual working memory representations

ABSTRACT In their recent review, Xu critically assesses the role of early visual areas in VWM storage in the light of new fMRI-decoding studies that seemingly support the sensory storage account. We would like to extend the discussion by highlighting recent findings which suggest that early visual areas can dynamically transform active VWM representations e.g., to activity silent or long-term memory representations. These latent codes evade detection via traditional paradigms as well as decoding methods and hence limit the conclusions that can be drawn about the role of certain brain regions in WM storage. More precisely we claim that a lack or a temporary disappearance of multivariate VWM evidence from early visual brain regions does not imply that these areas are not essentially required to store and maintain active, or currently attended, VWM representations.

Identification of African Elephant Polyomavirus in wild elephants and the creation of a vector expressing its viral tumor antigens to transform elephant primary cells.

Wild elephant populations are declining rapidly due to rampant killing for ivory and body parts, range fragmentation, and human-elephant conflict. Wild and captive elephants are further impacted by viruses, including highly pathogenic elephant endotheliotropic herpesviruses. Moreover, while the rich genetic diversity of the ancient elephant lineage is disappearing, elephants, with their low incidence of cancer, have emerged as a surprising resource in human cancer research for understanding the intrinsic cellular response to DNA damage. However, studies on cellular resistance to transformation and herpesvirus reproduction have been severely limited, in part due to the lack of established elephant cell lines to enable in vitro experiments. This report describes creation of a recombinant plasmid, pAelPyV-1-Tag, derived from a wild isolate of African Elephant Polyomavirus (AelPyV-1), that can be used to create immortalized lines of elephant cells. This isolate was extracted from a trunk nodule biopsy isolated from a wild African elephant, Loxodonta africana, in Botswana. The AelPyV-1 genome contains open-reading frames encoding the canonical large (LTag) and small (STag) tumor antigens. We cloned the entire early region spanning the LTag and overlapping STag genes from this isolate into a high-copy vector to construct a recombinant plasmid, pAelPyV-1-Tag, which effectively transformed primary elephant endothelial cells. We expect that the potential of this reagent to transform elephant primary cells will, at a minimum, facilitate study of elephant-specific herpesviruses.

What can classic Atari video games tell us about the human brain?

In this issue of Neuron, Cross et. al (2021) use a deep reinforcement learning algorithm to understand human neural activation evoked by playing different video games. The results shed light on the neural principles underlying reward-guided decisions in naturalistic domains.

Peripheral deficits and phase-locking declines in aging adults

Age-related difficulties in speech understanding may arise from a decrease in the neural representation of speech sounds. A loss of outer hair cells or decrease in auditory nerve fibers may lead to a loss of temporal precision that can affect speech clarity. This study's purpose was to evaluate the peripheral contributors to phase-locking strength, a measure of temporal precision, in recordings to a sustained vowel in 30 younger and 30 older listeners with normal to near normal audiometric thresholds. Thresholds were obtained for pure tones and distortion-product otoacoustic emissions (DPOAEs). Auditory brainstem responses (ABRs) were recorded in quiet and in three levels of continuous white noise (+30, +20, and +10 dB SNR). Absolute amplitudes and latencies of Wave I in quiet and of Wave V across presentation conditions, in addition to the slope of Wave V amplitude and latency changes in noise, were calculated from these recordings. Frequency-following responses (FFRs) were recorded to synthesized /ba/ syllables of two durations, 170 and 260 ms, to determine whether age-related phase-locking deficits are more pronounced for stimuli that are sustained for longer durations. Phase locking was calculated for the early and late regions of the steady-state vowel for both syllables. Group differences were found for nearly every measure except for the slopes of Wave V latency and amplitude changes in noise. We found that outer hair cell function (DPOAEs) contributed to the variance in phase locking. However, the ABR and FFR differences were present after covarying for DPOAEs, suggesting the existence of temporal processing deficits in older listeners that are somewhat independent of outer hair cell function.

Induction of Brain Tumors by the Archetype Strain of Human Neurotropic JCPyV in a Transgenic Mouse Model.

JC Virus (JCPyV), a member of the Polyomaviridiæ family, is a human neurotropic virus with world-wide distribution. JCPyV is the established opportunistic infectious agent of progressive multifocal leukoencephalopathy, a fatal demyelinating disease, which results from the cytolytic infection of oligodendrocytes. Mutations in the regulatory region of JCPyV determine the different viral strains. Mad-1 the strain associated with PML contains two 98 base pair repeats, whereas the archetype strain (CY), which is the transmissible form of JCPyV, contains only one 98 tandem with two insertions of 62 and 23 base pairs respectively. The oncogenicity of JCPyV has been suspected since direct inoculation into the brain of rodents and primates resulted in the development of brain tumors and has been attributed to the viral protein, T-Antigen. To further understand the oncogenicity of JCPyV, a transgenic mouse colony containing the early region of the archetype strain (CY), under the regulation of its own promoter was generated. These transgenic animals developed tumors of neural crest origin, including: primitive neuroectodermal tumors, medulloblastomas, adrenal neuroblastomas, pituitary tumors, malignant peripheral nerve sheath tumors, and glioblastomas. Neoplastic cells from all different phenotypes express T-Antigen. The close parallels between the tumors developed by these transgenic animals and human CNS tumors make this animal model an excellent tool for the study of viral oncogenesis.

Genomic characterisation of bovine papillomavirus types 1 and 2 identified in equine sarcoids in Japan.

Bovine papillomavirus types 1 and 2 (BPV1/2) infection in horses has been associated with the development of equine sarcoids. Previous findings revealed the presence of sarcoid-associated BPV sequence variants that have been proposed as a key factor of cross-species infection in horses. To verify this hypothesis, sarcoid-associated BPV variants should be identified regardless of geographic location. Sequence analyses of BPV1/2 derived from both horses and cattle were conducted to clarify the sarcoid-associated sequence variants. The aim of this study was to clarify the correlation between BPV phylogeny and the geographic origin/host species. Cross-sectional study. Conventional PCR to detect BPV1/2 was performed with genomic DNA extracted from equine sarcoid (n=10) and bovine papilloma (n=10) samples collected in Japan. Direct sequencing results were compared between equine and bovine (equine/bovine)-derived BPV to identify sarcoid-associated variants of two early regions (E2, E5), one late region (L1) and the long control region (LCR). Phylogenetic and phylogeny-trait correlation were analysed using Bayesian Markov chain Monte Carlo (MCMC) method and Bayesian tip-association significance testing (BaTS). Seven BPV1 and three BPV2 were identified from equine sarcoids using PCR and direct sequencing. Sequence analysis of equine/bovine-derived samples showed no sarcoid-associated variants in four regions (E2, E5, L1 and LCR) of either BPV1 or BPV2. The phylogenetic tree of BPV1 E2, L1 and LCR tended to cluster within its geographic origins. BaTS analysis demonstrated that BPV1 sequence variability may be due to the geographic origin rather than host species difference. There was a limitation in sample numbers. This study supports the geographic-specific hypothesis of sequence variability, suggesting that BPV1 is shared between local equids and bovids. However, more extensively collected sequences worldwide and functional evaluations are needed to verify the geographic-specific sequence variability of BPV1/2 between equine- and bovine-derived sequence.

Neurofibrillary tau depositions emerge with subthreshold cerebral beta-amyloidosis in down syndrome

IntroductionAdults with Down syndrome are genetically predisposed to develop Alzheimer’s disease and accumulate beta-amyloid plaques (Aβ) early in life. While Aβ has been heavily studied in Down syndrome, its relationship with neurofibrillary tau is less understood. The aim of this study was to evaluate neurofibrillary tau deposition in individuals with Down syndrome with varying levels of Aβ burden. MethodsA total of 161 adults with Down syndrome (mean age = 39.2 (8.50) years) and 40 healthy, non-Down syndrome sibling controls (43.2 (12.6) years) underwent T1w-MRI, [C-11]PiB and [F-18]AV-1451 PET scans. PET images were converted to units of standardized uptake value ratios (SUVrs). Aβ burden was calculated using the amyloid load metric (AβL); a measure of global Aβ burden that improves quantification from SUVrs by suppressing the nonspecific binding signal component and computing the specific Aβ signal from all Aβ-carrying voxels from the image. Regional tau was assessed using control-standardized AV-1451 SUVr. Control-standardized SUVrs were compared across Down syndrome groups of Aβ-negative (A-) (AβL < 13.3), subthreshold A+ (13.3 ≤ AβL < 20) and conventionally A+ (AβL ≥ 20) individuals. The subthreshold A + group was identified as having significantly higher Aβ burden compared to the A- group, but not high enough to satisfy a conventional A + classification. ResultsA large-sized association that survived adjustment for chronological age, mental age (assessed using the Peabody Picture Vocabulary Test), and imaging site was observed between AβL and AV-1451 within each Braak region (p < .05). The A + group showed significantly higher AV-1451 retention across all Braak regions compared to the A- and subthreshold A + groups (p < .05). The subthreshold A + group showed significantly higher AV-1451 retention in Braak regions I-III compared to an age-matched sample from the A- group (p < .05). DiscussionThese results show that even the earliest detectable Aβ accumulation in Down syndrome is accompanied by elevated tau in the early Braak stage regions. This early detection of tau can help characterize the tau accumulation phase during preclinical Alzheimer’s disease progression in Down syndrome and suggests that there may be a relatively narrow window after Aβ accumulation begins to prevent the downstream cascade of events that leads to Alzheimer’s disease.

Field Research in the Targowisko Region in 2018–2019

The article presents the results of test excavations at three sites in the early Neolithic settlement region of Targowisko, carried out in 2018–2019. The goal of these investigations was the detection of fragments of Neolithic settlement zones where only one building phase has survived. It was decided to perform this task using a magnetometer as part of a slightly wider program of geomagnetic prospection. The second goal was to acquire sets of arti- and ecofacts related to the shortest possible period of time, i.e. equal to the existence of one family living in one house, representing one cultural tradition. The third goal was to explain the generators and mechanisms of early Neolithic cultural transformation from a micro-regional perspective.

Uterine leiomyoma at women of reproductive age: frequency and structure of concomitant pathology (Retrospective analysis)

The objective: to establish the frequency, structure and interconnection with accompanying gynecological pathology incidence of patients with uterine leiomyoma by retrospective analysis.Materials and methods. A retrospective analysis of 12241 case histories of patients treated during 2012–2016 in the Department of Gynecology with minimally invasive technologies, beds of fetal medicine and pathology of early pregnancy Khmelnytsky Regional Perinatal Center, as a department of general gynecology, as well as a specialized department assistance to women interested in the preservation and restoration of reproductive function, namely the Department of Family Planning and Operational Rehabilitation of the Reproductive Function of Women SI «Institute of Pediatrics, Obstetrics and Gynecology named Academician OM Lukyanova National Academy of Medical Sciences of Ukraine «.The results of the examination in a specially developed formalized medical history for further input and processing of information were recorded.Results. As a result of the retrospective analysis, it was found that, according to the Khmelnytsky Regional Perinatal Center, the frequency of LM ranged from 17.3% with a gradual increase to 21.6%. Radical interventions were performed in 55.5% of women without a tendency to decrease by age. Only in 5% of cases organ-preserving intervention was performed, and in 8.4% hysteroscopy (HS) was used. However, there is a positive trend to increase the frequency of both conservative myomectomy (CM) and HS over the years. .As a result of the retrospective analysis, it was found that uterine leiomyoma occurred in 824 patients, which amounted at 18.3% of patients. There is a steady increase in the incidence of uterine leiomyoma among patients treated in the family planning and surgical rehabilitation department. Among these patients, to 305 (37%) patients were held underwent surgery (surgical group – SG), such as conservative myomectomy or radical surgery with different approaches. The remaining 519 (63%) women received conservative therapy (conservative group – CG). The mean age of the examined patients was 38,3±0,4 years at women of the surgical group and 39,2±0,3 years at the conservative group. The LM up to 25 years was rare, less than 1% of cases, but in the surgical group four times more often. From the age of 26, the frequency of LM begins to increase in both groups to 8.5% with a sharp increase after 30 years, in 3 times. It peaks at the age of 36-40 years in the surgical group and at 41-45 in the conservative group, with a gradual decrease after 45 years. It peaks at the age of 36-40 years in the surgical group and at 41-45 in the conservative group, with a gradual decrease after 45 years. At women, CG significantly more often LM occurred on the background of chronic inflammatory diseases of the pelvic organs (HZZOMT), at 207 patients (39.9%) against 92 women (30.2%) in HG, p&lt;0.05. Whereas pelvic adhesions were diagnosed in both groups with the same frequency (54 women (17.7%) in CG and 82 patients (15.8%) in CG). With regard to endometriosis, external genital endometriosis was significantly more common in women with CG, namely in 40 patients (13.1%) against 31 women (6.0%) in CG, p &lt;0.05. Whereas internal endometriosis (adenomyosis) in both groups was detected with the same frequency (49 patients (16.1%) in CG and 90 patients (17.3%) in CG). Surgical interventions were dominated by organ-sparing operations (262 patients or 85.9%) against 72 women (23.6%) who underwent radical intervention. Laparoscopy (LS) was used twice as rarely, mostly in infertile women, to remove small leiomatous nodules with a predominantly subserous location (60 patients or 19.7%). At 41 women (13.4%) the submucosal nodes were removed by hysteroresectoscopy. Anemia was significantly more common at women with LM who required surgery (47 patients (15.4%) in HCG versus 48 patients (9.2%) in CG, p &lt;0.05). The infertility among UL occurred in every fourth patient, slightly more often in HG (83 women (27.2%) against 124 patients (23.9%) in CG).Conclusions. The UL occurred in one in five women with a tendency to increase in frequency in this department. One in three women with LM (37%) required surgery, organ-sparing interventions predominated (85.9%), and laparotomy access was preferred (42.6%). For women of the conservative group is characterized by a more frequent combination with chronic inflammatory diseases of the pelvic organs (39.9%), pathology of the endometrium (43.9%) and cervix (20.0%). Infertility occurred in every fourth woman with LM without differences both between groups and between primary and secondary infertility.

Differential Splicing of Human Adenovirus 5 E1A RNA Expressed in cis versus in trans.

Human adenovirus (HAdV) is used extensively as a vector for gene delivery for a variety of purposes, including gene therapy and vaccine development. Most adenoviral vectors used for these approaches have a deletion of early region 1 (E1), which is complemented by the cell line. Most commonly, these are 293 cells for HAdV serotype 2 or 5. The 293 cells have the left end of HAdV5 integrated into chromosome 19 and express the E1 genes and protein IX. We observed that viruses with the E1 region deleted often grow less well on 293 cells than E1 wild-type viruses. Therefore, we investigated whether this poor growth is caused by splicing differences between the E1A RNA provided by the cell line (in trans) and the E1A RNA provided by the infecting viral genome (in cis). We observed that E1A RNA that was expressed from the genomes of 293 cells was spliced differently during infection with an E1A-deleted dl312 virus than E1A RNA from the same cells infected with dl309 or wt300. Importantly, 293 cells were not able to fully complement the late E1A transcripts, specifically 11S, 10S, and 9S RNA, which express the E1A217R, E1A171R, and E1A55R isoforms, respectively. We observed that these splicing differences likely arise due to different subnuclear localizations of E1A RNA. E1A RNA expressed from the viral genome was localized to viral replication centers, while E1A RNA expressed from the cell's genome was not. This loss of the late E1A mRNAs and their associated proteins impacts viral growth, gene expression, and protein levels. Complementation of the late E1A mRNAs in 293 cells restored some of the growth defect observed with dl312 and resulted in higher virus growth.IMPORTANCE Human adenovirus has become an important tool for medicine and research, and 293 cells and various similar cell lines are used extensively for virus production in situations where high viral yields are important. Such complementing cell lines are used for the production of viral vectors and vaccines, which often have deletions and replacements in various viral genes. Deletions in essential genes, such as E1, are often complemented by the cell line that is used for virus propagation in trans Here, we show that even complete genetic complementation of a viral gene does not result in full protein complementation, a defect that compromises virus growth. This is particularly important when high viral yields are crucial, as in virus production for vaccine development or gene therapy.

Two Unique Prophages of 'Candidatus Liberibacter asiaticus' Strains from Pakistan.

'Candidatus Liberibacter asiaticus' (CLas) is a pathogen causing Huanglongbing (HLB, yellow shoot disease), which is highly destructive to citrus production. The CLas strains harbor prophages. We identified two unique prophages, designated as P-PA19-1 and P-PA19-2, in CLas strain PA19 from Pakistan using next-generation sequencing analysis. P-PA19-1 prophage has high sequence similarity (identity: 78.23%) at the early-gene region of prophage SC1 (Type 1), but it is significantly divergent in the late-gene region (identity: 62.03%). P-PA19-2 was highly similar to SC2 (Type 2) in the late gene region (identity: 97.96%), and also in the early gene region except for a deletion of a 7,179-bp nucleotide sequence that contains a CRISPR/cas system in SC2. Both P-PA19-1 and P-PA19-2 had circular plasmid forms, and only P-PA19-2 was found integrated in the PA19 chromosome. The two new prophages were only found in Pakistani samples. Identification of prophages enhances our understanding of CLas genomic diversity and also the biology and evolution of CLas prophages.

Medial Temporal Tau Pathology Is Associated With Verbal Memory

Medial temporal tau pathology is frequently observed in individuals over 70 regardless of cognitive status. To understand the link between tau and cognitive performance, we evaluated tau pathology using 18F-flortaucipir positron emission tomography among 95 cognitively normal participants from the Baltimore Longitudinal Study of Aging. We examined tau levels in early Braak regions (entorhinal cortex and hippocampus) in relation to verbal episodic memory performance concurrent with and prior to the tau scan using linear mixed effects models adjusted for age, sex, amyloid status, and time from PET scan. Higher hippocampal tau burden had a trend-level association with lower concurrent memory performance (p=0.05). Greater tau pathology in the hippocampus and entorhinal cortex was associated with steeper decline in memory performance prior to tau scan (p=0.013 and 0.026, respectively). These findings suggest that therapeutic interventions targeting tau pathology may need to be administered early among cognitively normal individuals to prevent memory decline.