bluuebunny/crossref_metadata_2025 huggingface dataset:
Functionally Active Antibodies to the Angiotensin II Type 1-Receptor Measured by a Luminometric Bioassay Do Not Correlate With Clinical Manifestations in Systemic Sclerosis: A Comparison With Antibodies to Vascular Receptors and Topoisomerase I Detected by ELISA
Authors: Bankamp Lukas , Preuß Beate , Pecher Ann-Christin , Beucke Nicola , Henes Jörg , Klein Reinhild
Published: December 2021

Objectives

1) To detect functionally active antibodies(abs) to the angiotensin II type-1-receptor (AT1R) by a novel luminometric assay. 2) To assess their prevalence in systemic sclerosis (SSc), other collagen disorders, as well as in further chronic inflammatory disorders including autoimmune, toxic and chronic viral diseases. 3) To compare these abs with anti-AT1R antibodies by ELISA as well as with antibodies to endothelin-type-A receptors (ETA1) and to topoisomerase I (topo-I) with respect to their specificity and clinical relevance.

Methods

Sera from 98 SSc-patients, 110 patients with other chronic inflammatory rheumatic disorders, 97 patients with autoimmune liver diseases, 57 patients with toxic or chronic viral liver diseases and 36 healthy controls were analyzed. A luminometric bioassay was established with Huh-7-cells constitutively expressing the AT1R. Patients’ sera were also tested by commercially available ELISA for anti-AT1R, -ETA1- and by an in-house ELISA for anti–topo-I-abs.

Results

Fifty-two percent of the SSc-patients had functionally active anti-AT1R-abs with stimulatory (34%) or inhibitory capacity (18%). They were present also in up to 59% of patients with other rheumatic diseases but only 22% of healthy individuals (sensitivity 52%, specificity 53%). The functionally active antibodies detected by the luminometric assay did not correlate with anti-AT1R-, -ETA1- or -topo-I-abs measured by ELISA, but there was a strong correlation between anti-topo-I-, AT1R-, and -ETA1-ab reactivity measured by ELISA. Sensitivities of 55%, 28% and 47% and specificities of 66%, 87%, and 99% were calculated for these anti-AT1R-, -ETA1-, and anti-topo-I-abs, respectively. Functionally active abs did not correlate with disease severity or any organ manifestation. In contrast, abs to topo-I, AT1R, and ETA1 were associated with digital ulcers, pulmonary- and esophageal manifestation.

Conclusions

Functionally active anti-AT1R-abs can be detected in SSc-patients but do not correlate with disease activity. They are not specific for this disease and occur also in other autoimmune disorders and even viral or toxic diseases. Also, the vascular antibodies detected by ELISA are not SSc-specific but correlated with disease manifestations. In contrast, anti-topo-I-abs were confirmed to be a highly specific biomarker for both, diagnosis and organ manifestations of SSc.
Regulatory Role of Non-Coding RNAs on Immune Responses During Sepsis
Authors: Ghafouri-Fard Soudeh , Khoshbakht Tayyebeh , Hussen Bashdar Mahmud , Taheri Mohammad , Arefian Normohammad
Published: December 2021

Sepsis is resulted from a systemic inflammatory response to bacterial, viral, or fungal agents. The induced inflammatory response by these microorganisms can lead to multiple organ system failure with devastating consequences. Recent studies have shown altered expressions of several non-coding RNAs such as long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs) during sepsis. These transcripts have also been found to participate in the pathogenesis of multiple organ system failure through different mechanisms. NEAT1, MALAT1, THRIL, XIST, MIAT and TUG1 are among lncRNAs that participate in the pathoetiology of sepsis-related complications. miR-21, miR-155, miR-15a-5p, miR-494-3p, miR-218, miR-122, miR-208a-5p, miR-328 and miR-218 are examples of miRNAs participating in these complications. Finally, tens of circRNAs such as circC3P1, hsa_circRNA_104484, hsa_circRNA_104670 and circVMA21 and circ-PRKCI have been found to affect pathogenesis of sepsis. In the current review, we describe the role of these three classes of noncoding RNAs in the pathoetiology of sepsis-related complications.
Multiple Novel Clades of Anopheline Mosquitoes Caught Outdoors in Northern Zambia
Authors: Jones Christine M. , Ciubotariu Ilinca I. , Muleba Mbanga , Lupiya James , Mbewe David , Simubali Limonty , Mudenda Twig , Gebhardt Mary E. , Carpi Giovanna , Malcolm Ashley N. , Kosinski Kyle J. , Romero-Weaver Ana L. , Stevenson Jennifer C. , Lee Yoosook , Norris Douglas E.
Published: December 2021

Residual vector populations that do not come in contact with the most frequently utilized indoor-directed interventions present major challenges to global malaria eradication. Many of these residual populations are mosquito species about which little is known. As part of a study to assess the threat of outdoor exposure to malaria mosquitoes within the Southern and Central Africa International Centers of Excellence for Malaria Research, foraging female anophelines were collected outside households in Nchelenge District, northern Zambia. These anophelines proved to be more diverse than had previously been reported in the area. In order to further characterize the anopheline species, sequencing and phylogenetic approaches were utilized. Anopheline mosquitoes were collected from outdoor light traps, morphologically identified, and sent to Johns Hopkins Bloomberg School of Public Health for sequencing. Sanger sequencing from 115 field-derived samples yielded mitochondrial COI sequences, which were aligned with a homologous 488 bp gene segment from known anophelines (n = 140) retrieved from NCBI. Nuclear ITS2 sequences (n = 57) for at least one individual from each unique COI clade were generated and compared against NCBI’s nucleotide BLAST database to provide additional evidence for taxonomical identity and structure. Molecular and morphological data were combined for assignment of species or higher taxonomy. Twelve phylogenetic groups were characterized from the COI and ITS2 sequence data, including the primary vector species Anopheles funestus s.s. and An. gambiae s.s. An unexpectedly large proportion of the field collections were identified as An. coustani and An. sp. 6. Six phylogenetic groups remain unidentified to species-level. Outdoor collections of anopheline mosquitoes in areas frequented by people in Nchelenge, northern Zambia, proved to be extremely diverse. Morphological misidentification and underrepresentation of some anopheline species in sequence databases confound efforts to confirm identity of potential malaria vector species. The large number of unidentified anophelines could compromise the malaria vector surveillance and malaria control efforts not only in northern Zambia but other places where surveillance and control are focused on indoor-foraging and resting anophelines. Therefore, it is critical to continue development of methodologies that allow better identification of these populations and revisiting and cleaning current genomic databases.
Physiological and Molecular Responses in the Gill of the Swimming Crab Portunus trituberculatus During Long-Term Ammonia Stress
Authors: Zhang Jingyan , Zhang Mengqian , Jayasundara Nishad , Ren Xianyun , Gao Baoquan , Liu Ping , Li Jian , Meng Xianliang
Published: December 2021

Ammonia is a common environmental stressor encountered during aquaculture, and is a significant concern due to its adverse biological effects on vertebrate and invertebrate including crustaceans. However, little information is available on physiological and molecular responses in crustaceans under long-term ammonia exposure, which often occurs in aquaculture practices. Here, we investigated temporal physiological and molecular responses in the gills, the main ammonia excretion organ, of the swimming crab Portunus trituberculatus following long-term (4 weeks) exposure to three different ammonia nitrogen concentrations (2, 4, and 8 mg l–1), in comparison to seawater (ammonia nitrogen below 0.03 mg l–1). The results revealed that after ammonia stress, the ammonia excretion and detoxification pathways were initially up-regulated. These processes appear compromised as the exposure duration extended, leading to accumulation of hemolymph ammonia, which coincided with the reduction of adenosine 5′-triphosphate (ATP) and adenylate energy charge (AEC). Considering that ammonia excretion and detoxification are highly energy-consuming, the depression of these pathways are, at least partly, associated with disruption of energy homeostasis in gills after prolonged ammonia exposure. Furthermore, our results indicated that long-term ammonia exposure can impair the antioxidant defense and result in increased lipid peroxidation, as well as induce endoplasmic reticulum stress, which in turn lead to apoptosis through p53-bax pathway in gills of the swimming crab. The findings of the present study further our understanding of adverse effects and underlying mechanisms of long-term ammonia in decapods, and provide valuable information for aquaculture management of P. trituberculatus.
Exploring the Occurrence Characteristics of Microplastics in Typical Maize Farmland Soils With Long-Term Plastic Film Mulching in Northern China
Authors: Zhang Jiajia , Zou Guoyuan , Wang Xuexia , Ding Wencheng , Xu Li , Liu Baoyin , Mu Yunsen , Zhu Xuran , Song Lianjie , Chen Yanhua
Published: December 2021

Microplastics pollution has been threatening the global environmental security, in which agricultural activities are considered as a main source of microplastics occurrence in soils. However, little is known about the occurrence characteristics of microplastics in agricultural soils with long-term plastic film mulching. Therefore, the abundance, distribution, and composition of microplastics were investigated by analyzing 225 soil samples collected from typical maize (Zea mays L.) planting zones with and without long-term (>20 years) plastic film mulching in northern China. Microplastics abundance in mulched soils (754 ± 477 items kg–1) was significantly higher than that in non-mulched soils (376 ± 149 items kg–1), which indicated that plastic film mulching contributed half of microplastics in soils. Moreover, microplastics abundance was significantly positively related to the length of time with film mulching applied. The percentage of microplastics <0.5 mm in mulched soils (50.9%) was significantly lower than that in non-mulched soils (62.2%). Microplastics abundance and size in mulched and non-mulched soils decreased with increased soil depth. Most microplastics were fragments of polypropylene, films of polyethylene, and fibers of polyester. The proportion of films in mulched soils was significantly higher than in non-mulched soils, whereas that of fibers was significantly higher in non-mulched soils. This study confirmed that long-term plastic film mulching increases microplastics pollution in agricultural soils, warranting further evaluation of the associated ecological risks of microplastics in soil ecosystems.
The Involvement of Mycobacterium Type III-A CRISPR-Cas System in Oxidative Stress
Authors: Yang Fan , Xu Lingqing , Liang Lujie , Liang Wanfei , Li Jiachen , Lin Daixi , Dai Min , Zhou Dianrong , Li Yaxin , Chen Yong , Zhao Hui , Tian Guo-bao , Feng Siyuan
Published: December 2021

Type I and type II CRISPR-Cas systems are employed to evade host immunity by targeting interference of bacteria’s own genes. Although Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis, possesses integrated type III-A CRISPR-Cas system, its role in mycobacteria remains obscure. Here, we observed that seven cas genes (csm2∼5, cas10, cas6) were upregulated in Mycobacterium bovis BCG under oxidative stress treatment, indicating the role of type III-A CRISPR-Cas system in oxidative stress. To explore the functional role of type III-A CRISPR-Cas system, TCC (Type III-A CRISPR-Cas system, including cas6, cas10, and csm2-6) mutant was generated. Deletion of TCC results in increased sensitivity in response to hydrogen peroxide and reduced cell envelope integrity. Analysis of RNA-seq dataset revealed that TCC impacted on the oxidation-reduction process and the composition of cell wall which is essential for mycobacterial envelop integrity. Moreover, disrupting TCC led to poor intracellular survival in vivo and in vitro. Finally, we showed for the first time that TCC contributed to the regulation of regulatory T cell population, supporting a role of TCC in modulating host immunity. Our finding reveals the important role of TCC in cell envelop homeostasis. Our work also highlights type III-A CRISPR-Cas system as an important factor for intracellular survival and host immunoregulation in mycobacteria, thus may be a potential target for therapy.
Regulatory Connections Between the Cyanobacterial Factor PipX and the Ribosome Assembly GTPase EngA
Authors: Jerez Carmen , Salinas Paloma , Llop Antonio , Cantos Raquel , Espinosa Javier , Labella Jose I. , Contreras Asunción
Published: December 2021

Cyanobacteria, phototrophic organisms performing oxygenic photosynthesis, must adapt their metabolic processes to important environmental challenges, like those imposed by the succession of days and nights. Not surprisingly, certain regulatory proteins are found exclusively in this phylum. One of these unique proteins, PipX, provides a mechanistic link between signals of carbon/nitrogen and of energy, transduced by the signaling protein PII, and the control of gene expression by the global nitrogen regulator NtcA. PII, required for cell survival unless PipX is inactivated or downregulated, functions by protein–protein interactions with transcriptional regulators, transporters, and enzymes. PipX also functions by protein–protein interactions, and previous studies suggested the existence of additional interacting partners or included it into a relatively robust six-node synteny network with proteins apparently unrelated to the nitrogen regulation system. To investigate additional functions of PipX while providing a proof of concept for the recently developed cyanobacterial linkage network, here we analyzed the physical and regulatory interactions between PipX and an intriguing component of the PipX synteny network, the essential ribosome assembly GTPase EngA. The results provide additional insights into the functions of cyanobacterial EngA and of PipX, showing that PipX interacts with the GD1 domain of EngA in a guanosine diphosphate-dependent manner and interferes with EngA functions in Synechococcus elongatus at a low temperature, an environmentally relevant context. Therefore, this work expands the PipX interaction network and establishes a possible connection between nitrogen regulation and the translation machinery. We discuss a regulatory model integrating previous information on PII–PipX with the results presented in this work.
A Review: Gaseous Interventions for Listeria monocytogenes Control in Fresh Apple Cold Storage
Authors: Guan Jiewen , Lacombe Alison , Rane Bhargavi , Tang Juming , Sablani Shyam , Wu Vivian C. H.
Published: December 2021

Listeria monocytogenes (L. monocytogenes) causes an estimated 1600 foodborne illnesses and 260 deaths annually in the U.S. These outbreaks are a major concern for the apple industry since fresh produce cannot be treated with thermal technologies for pathogen control before human consumption. Recent caramel apple outbreaks indicate that the current non-thermal sanitizing protocol may not be sufficient for pathogen decontamination. Federal regulations provide guidance to apple processors on sanitizer residue limits, organic production, and good manufacturing practices (GMPs). However, optimal methods to control L. monocytogenes on fresh apples still need to be determined. This review discusses L. monocytogenes outbreaks associated with caramel apples and the pathogen’s persistence in the environment. In addition, this review identifies and analyzes possible sources of contaminant for apples during cold storage and packing. Gaseous interventions are evaluated for their feasibility for L. monocytogenes decontamination on apples. For example, apple cold storage, which requires waterless interventions, may benefit from gaseous antimicrobials like chlorine dioxide (ClO2) and ozone (O3). In order to reduce the contamination risk during cold storage, significant research is still needed to develop effective methods to reduce microbial loads on fresh apples. This requires commercial-scale validation of gaseous interventions and intervention integration to the current existing apple cold storage. Additionally, the impact of the interventions on final apple quality should be taken into consideration. Therefore, this review intends to provide the apple industry suggestions to minimize the contamination risk of L. monocytogenes during cold storage and hence prevent outbreaks and reduce economic losses.
Not All That Glitters Is Gold: The Paradox of CO-dependent Hydrogenogenesis in Parageobacillus thermoglucosidasius
Authors: Aliyu Habibu , de Maayer Pieter , Neumann Anke
Published: December 2021

The thermophilic bacterium Parageobacillus thermoglucosidasius has recently gained interest due to its ability to catalyze the water gas shift reaction, where the oxidation of carbon monoxide (CO) is linked to the evolution of hydrogen (H2) gas. This phenotype is largely predictable based on the presence of a genomic region coding for a carbon monoxide dehydrogenase (CODH—Coo) and hydrogen evolving hydrogenase (Phc). In this work, seven previously uncharacterized strains were cultivated under 50% CO and 50% air atmosphere. Despite the presence of the coo—phc genes in all seven strains, only one strain, Kp1013, oxidizes CO and yields H2. The genomes of the H2 producing strains contain unique genomic regions that code for proteins involved in nickel transport and the detoxification of catechol, a by-product of a siderophore-mediated iron acquisition system. Combined, the presence of these genomic regions could potentially drive biological water gas shift (WGS) reaction in P. thermoglucosidasius.
Novel Perspectives on the Development of the Amygdala in Rodents
Authors: Aerts Tania , Seuntjens Eve
Published: December 2021

The amygdala is a hyperspecialized brain region composed of strongly inter- and intraconnected nuclei involved in emotional learning and behavior. The cellular heterogeneity of the amygdalar nuclei has complicated straightforward conclusions on their developmental origin, and even resulted in contradictory data. Recently, the concentric ring theory of the pallium and the radial histogenetic model of the pallial amygdala have cleared up several uncertainties that plagued previous models of amygdalar development. Here, we provide an extensive overview on the developmental origin of the nuclei of the amygdaloid complex. Starting from older gene expression data, transplantation and lineage tracing studies, we systematically summarize and reinterpret previous findings in light of the novel perspectives on amygdalar development. In addition, migratory routes that these cells take on their way to the amygdala are explored, and known transcription factors and guidance cues that seemingly drive these cells toward the amygdala are emphasized. We propose some future directions for research on amygdalar development and highlight that a better understanding of its development could prove critical for the treatment of several neurodevelopmental and neuropsychiatric disorders.
The Stop Signal Task for Measuring Behavioral Inhibition in Mice With Increased Sensitivity and High-Throughput Operation
Authors: Caglayan Alican , Stumpenhorst Katharina , Winter York
Published: December 2021

Ceasing an ongoing motor response requires action cancelation. This is impaired in many pathologies such as attention deficit disorder and schizophrenia. Action cancelation is measured by the stop signal task that estimates how quickly a motor response can be stopped when it is already being executed. Apart from human studies, the stop signal task has been used to investigate neurobiological mechanisms of action cancelation overwhelmingly in rats and only rarely in mice, despite the need for a genetic model approach. Contributing factors to the limited number of mice studies may be the long and laborious training that is necessary and the requirement for a very loud (100 dB) stop signal. We overcame these limitations by employing a fully automated home-cage-based setup. We connected a home-cage to the operant box via a gating mechanism, that allowed individual ID chipped mice to start sessions voluntarily. Furthermore, we added a negative reinforcement consisting of a mild air puff with escape option to the protocol. This specifically improved baseline inhibition to 94% (from 84% with the conventional approach). To measure baseline inhibition the stop is signaled immediately with trial onset thus measuring action restraint rather than action cancelation ability. A high baseline allowed us to measure action cancelation ability with higher sensitivity. Furthermore, our setup allowed us to reduce the intensity of the acoustic stop signal from 100 to 70 dB. We constructed inhibition curves from stop trials with daily adjusted delays to estimate stop signal reaction times (SSRTs). SSRTs (median 88 ms) were lower than reported previously, which we attribute to the observed high baseline inhibition. Our automated training protocol reduced training time by 17% while also promoting minimal experimenter involvement. This sensitive and labor efficient stop signal task procedure should therefore facilitate the investigation of action cancelation pathologies in genetic mouse models.
Efficacy and Durability of Intratympanic Gentamicin Treatment for Meniere's Disease
Authors: Guan Yafeng , Chari Divya A. , Liu Yu-Hsi , Rauch Steven D.
Published: December 2021

Objective: To study the success of intratympanic gentamicin (ITG) treatment in reducing vertigo attacks in Meniere's disease (MD) and the value of the Halmagyi head thrust test (HTT) in predicting treatment durability.

Study Design: Retrospective cohort study.

Setting: Tertiary care vestibular clinic.

Patients: Unilateral MD patients treated with ITG from 2006–2019 with ≥6 months follow-up.

Main Outcome Measures: Demographics, audiometric data, subjective symptomatology, and HTT results were collected. Treatment success was defined as sufficient symptom relief. Treatment failure indicated vertigo control of less than 6 months duration. Treatment relapse indicated vertigo recurrence after 6 months.

Results: Of 255 patients, treatment success, failure, and relapse occurred in 226 (88.6%), 29 (11.4%), and 121 (47.1%) patients, respectively. 48 (18.8%) patients who failed to respond or relapsed underwent labyrinthectomy. Mean follow-up time was 3.7 yrs (range 0.5–12.8). After ITG treatment, 25% patients reported worse hearing; mean pure tone average (PTA) increased by 18.6 ± 11.3 dB and mean word recognition score (WRS) decreased by 33 ± 21%. Of the 148 patients with negative pre-treatment HHT, 103 (69.6%) converted to positive after ITG treatment. Mean time-to-relapse in the converted and non-converted HTT cohorts was significantly different (49.7 vs. 27.0 months, p = 0.009) even after adjusting for gender, age, laterality, duration of symptoms, and number of ITG treatments. There were no significant differences between the two groups in hearing outcomes or subjective symptoms (e.g. lingering disequilibrium).

Conclusions: ITG treatment effectively reduces the number of vertigo attacks in MD. HTT is valuable in predicting durability of treatment benefit.
Differences in Dual Task Performance After Robotic Upper Extremity Rehabilitation in Hemiplegic Stroke Patients
Authors: Lee Kuem Ju , Park Gyulee , Shin Joon-Ho
Published: December 2021

Background: Cognitive–motor interference is a phenomenon in which the concomitant performance of cognitive and motor tasks results in poorer performance than the isolated performance of these tasks. We aimed to evaluate changes in dual-task performance after robotic upper extremity rehabilitation in patients with stroke-induced hemiplegia.

Methods: This prospective study included patients with left upper limb weakness secondary to middle cerebral artery stroke who visited a rehabilitation hospital. Participants performed a total of 640 robot-assisted planar reaching movements during a therapist-supervised robotic intervention that was conducted five times a week for 4 weeks. Cognitive and motor performance was separately evaluated in single- and dual-task conditions. The digit span test and Controlled Oral Word Association Test (COWAT) were used to assess cognitive performance, whereas motor performance was evaluated through kinematic assessment of the motor task.

Results: In single-task conditions, motor performance showed significant improvement after robotic rehabilitation, as did the scores of the COWAT subdomains of animal naming (p < 0.001), supermarket item naming (p < 0.06), and phonemes (p < 0.05). In dual-task conditions, all motor task performance variables except mean velocity showed improvement after robotic rehabilitation. The type of cognitive task did not affect the dual-task effect, and there were no significant differences in the dual-task effects of motor, cognitive, or the sum of motor and cognitive performance after robotic rehabilitation.

Conclusion: Post-stroke robotic rehabilitation has different effects on motor and cognitive function, with more consistent effects on motor function than on cognitive function. Although motor and cognitive performance improved after robotic rehabilitation, there were no changes in the corresponding dual-task effects.
Inter-subject Correlation While Listening to Minimalist Music: A Study of Electrophysiological and Behavioral Responses to Steve Reich's Piano Phase
Authors: Dauer Tysen , Nguyen Duc T. , Gang Nick , Dmochowski Jacek P. , Berger Jonathan , Kaneshiro Blair
Published: December 2021

Musical minimalism utilizes the temporal manipulation of restricted collections of rhythmic, melodic, and/or harmonic materials. One example, Steve Reich'sPiano Phase, offers listeners readily audible formal structure with unpredictable events at the local level. For example, pattern recurrences may generate strong expectations which are violated by small temporal and pitch deviations. A hyper-detailed listening strategy prompted by these minute deviations stands in contrast to the type of listening engagement typically cultivated around functional tonal Western music. Recent research has suggested that the inter-subject correlation (ISC) of electroencephalographic (EEG) responses to natural audio-visual stimuli objectively indexes a state of “engagement,” demonstrating the potential of this approach for analyzing music listening. But can ISCs capture engagement with minimalist music, which features less obvious expectation formation and has historically received a wide range of reactions? To approach this question, we collected EEG and continuous behavioral (CB) data while 30 adults listened to an excerpt from Steve Reich'sPiano Phase, as well as three controlled manipulations and a popular-music remix of the work. Our analyses reveal that EEG and CB ISC are highest for the remix stimulus and lowest for our most repetitive manipulation, no statistical differences in overall EEG ISC between our most musically meaningful manipulations and Reich's original piece, and evidence that compositional features drove engagement in time-resolved ISC analyses. We also found that aesthetic evaluations corresponded well with overall EEG ISC. Finally we highlight co-occurrences between stimulus events and time-resolved EEG and CB ISC. We offer the CB paradigm as a useful analysis measure and note the value of minimalist compositions as a limit case for the neuroscientific study of music listening. Overall, our participants' neural, continuous behavioral, and question responses showed strong similarities that may help refine our understanding of the type of engagement indexed by ISC for musical stimuli.
Cardiovagal Baroreflex Hysteresis Using Ellipses in Response to Postural Changes
Authors: Dabiri Babak , Brito Joana , Kaniusas Eugenijus
Published: December 2021

The cardiovagal branch of the baroreflex is of high clinical relevance when detecting disturbances of the autonomic nervous system. The hysteresis of the baroreflex is assessed using provoked and spontaneous changes in blood pressure. We propose a novel ellipse analysis to characterize hysteresis of the spontaneous respiration-related cardiovagal baroreflex for orthostatic test. Up and down sequences of pressure changes as well as the working point of baroreflex are considered. The EuroBaVar data set for supine and standing was employed to extract heartbeat intervals and blood pressure values. The latter values formed polygons into which a bivariate normal distribution was fitted with its properties determining proposed ellipses of baroreflex. More than 80% of ellipses are formed out of nonoverlapping and delayed up and down sequences highlighting baroreflex hysteresis. In the supine position, the ellipses are more elongated (by about 46%) and steeper (by about 4.3° as median) than standing, indicating larger heart interval variability (70.7 versus 47.9 ms) and smaller blood pressure variability (5.8 versus 8.9 mmHg) in supine. The ellipses show a higher baroreflex sensitivity for supine (15.7 ms/mmHg as median) than standing (7 ms/mmHg). The center of the ellipse moves from supine to standing, which describes the overall sigmoid shape of the baroreflex with the moving working point. In contrast to regression analysis, the proposed method considers gain and set-point changes during respiration, offers instructive insights into the resulting hysteresis of the spontaneous cardiovagal baroreflex with respiration as stimuli, and provides a new tool for its future analysis.
The Menstrual Cycle Modulates Whole-Brain Turbulent Dynamics
Authors: De Filippi Eleonora , Uribe Carme , Avila-Varela Daniela S. , Martínez-Molina Noelia , Gashaj Venera , Pritschet Laura , Santander Tyler , Jacobs Emily G. , Kringelbach Morten L. , Sanz Perl Yonatan , Deco Gustavo , Escrichs Anira
Published: December 2021

Brain dynamics have recently been shown to be modulated by rhythmic changes in female sex hormone concentrations across an entire menstrual cycle. However, many questions remain regarding the specific differences in information processing across spacetime between the two main follicular and luteal phases in the menstrual cycle. Using a novel turbulent dynamic framework, we studied whole-brain information processing across spacetime scales (i.e., across long and short distances in the brain) in two open-source, dense-sampled resting-state datasets. A healthy naturally cycling woman in her early twenties was scanned over 30 consecutive days during a naturally occurring menstrual cycle and under a hormonal contraceptive regime. Our results indicated that the luteal phase is characterized by significantly higher information transmission across spatial scales than the follicular phase. Furthermore, we found significant differences in turbulence levels between the two phases in brain regions belonging to the default mode, salience/ventral attention, somatomotor, control, and dorsal attention networks. Finally, we found that changes in estradiol and progesterone concentrations modulate whole-brain turbulent dynamics in long distances. In contrast, we reported no significant differences in information processing measures between the active and placebo phases in the hormonal contraceptive study. Overall, the results demonstrate that the turbulence framework is able to capture differences in whole-brain turbulent dynamics related to ovarian hormones and menstrual cycle stages.
Similar Supine Heart Rate Variability Changes During 24-h Exposure to Normobaric vs. Hypobaric Hypoxia
Authors: Tanner Valérian , Faiss Raphael , Saugy Jonas , Bourdillon Nicolas , Schmitt Laurent , Millet Grégoire P.
Published: December 2021

Purpose: This study aimed to investigate the differences between normobaric (NH) and hypobaric hypoxia (HH) on supine heart rate variability (HRV) during a 24-h exposure. We hypothesized a greater decrease in parasympathetic-related parameters in HH than in NH.

Methods: A pooling of original data from forty-one healthy lowland trained men was analyzed. They were exposed to altitude either in NH (FIO2 = 15.7 ± 2.0%; PB = 698 ± 25 mmHg) or HH (FIO2 = 20.9%; PB = 534 ± 42 mmHg) in a randomized order. Pulse oximeter oxygen saturation (SpO2), heart rate (HR), and supine HRV were measured during a 7-min rest period three times: before (in normobaric normoxia, NN), after 12 (H12), and 24 h (H24) of either NH or HH exposure. HRV parameters were analyzed for time- and frequency-domains.

Results: SpO2 was lower in both hypoxic conditions than in NN and was higher in NH than HH at H24. Subjects showed similarly higher HR during both hypoxic conditions than in NN. No difference in HRV parameters was found between NH and HH at any time. The natural logarithm of root mean square of the successive differences (LnRMSSD) and the high frequency spectral power (HF), which reflect parasympathetic activity, decreased similarly in NH and HH when compared to NN.

Conclusion: Despite SpO2 differences, changes in supine HRV parameters during 24-h exposure were similar between NH and HH conditions indicating a similar decrease in parasympathetic activity. Therefore, HRV can be analyzed similarly in NH and HH conditions.
Ischemic Stroke, Glucocorticoids, and Remote Hippocampal Damage: A Translational Outlook and Implications for Modeling
Authors: Gulyaeva Natalia V. , Onufriev Mikhail V. , Moiseeva Yulia V.
Published: December 2021

Progress in treating ischemic stroke (IS) and its delayed consequences has been frustratingly slow due to the insufficient knowledge on the mechanism. One important factor, the hypothalamic-pituitary-adrenocortical (HPA) axis is mostly neglected despite the fact that both clinical data and the results from rodent models of IS show that glucocorticoids, the hormones of this stress axis, are involved in IS-induced brain dysfunction. Though increased cortisol in IS is regarded as a biomarker of higher mortality and worse recovery prognosis, the detailed mechanisms of HPA axis dysfunction involvement in delayed post-stroke cognitive and emotional disorders remain obscure. In this review, we analyze IS-induced HPA axis alterations and supposed association of corticoid-dependent distant hippocampal damage to post-stroke brain disorders. A translationally important growing point in bridging the gap between IS pathogenesis and clinic is to investigate the involvement of the HPA axis disturbances and related hippocampal dysfunction at different stages of SI. Valid models that reproduce the state of the HPA axis in clinical cases of IS are needed, and this should be considered when planning pre-clinical research. In clinical studies of IS, it is useful to reinforce diagnostic and prognostic potential of cortisol and other HPA axis hormones. Finally, it is important to reveal IS patients with permanently disturbed HPA axis. Patients-at-risk with high cortisol prone to delayed remote hippocampal damage should be monitored since hippocampal dysfunction may be the basis for development of post-stroke cognitive and emotional disturbances, as well as epilepsy.
Multiple Functions of the Dmrt Genes in the Development of the Central Nervous System
Authors: Kikkawa Takako , Osumi Noriko
Published: December 2021

The Dmrt genes encode the transcription factor containing the DM (doublesex and mab-3) domain, an intertwined zinc finger-like DNA binding module. While Dmrt genes are mainly involved in the sexual development of various species, recent studies have revealed that Dmrt genes, which belong to the DmrtA subfamily, are differentially expressed in the embryonic brain and spinal cord and are essential for the development of the central nervous system. Herein, we summarize recent studies that reveal the multiple functions of the Dmrt genes in various aspects of vertebrate neural development, including brain patterning, neurogenesis, and the specification of neurons.
The Safety of Micro-Implants for the Brain
Authors: Dabbour Abdel-Hameed , Tan Sheryl , Kim Sang Ho , Guild Sarah-Jane , Heppner Peter , McCormick Daniel , Wright Bryon E. , Leung Dixon , Gallichan Robert , Budgett David , Malpas Simon C.
Published: December 2021

Technological advancements in electronics and micromachining now allow the development of discrete wireless brain implantable micro-devices. Applications of such devices include stimulation or sensing and could enable direct placement near regions of interest within the brain without the need for electrode leads or separate battery compartments that are at increased risk of breakage and infection. Clinical use of leadless brain implants is accompanied by novel risks, such as migration of the implant. Additionally, the encapsulation material of the implants plays an important role in mitigating unwanted tissue reactions. These risks have the potential to cause harm or reduce the service of life of the implant. In the present study, we have assessed post-implantation tissue reaction and migration of borosilicate glass-encapsulated micro-implants within the cortex of the brain. Twenty borosilicate glass-encapsulated devices (2 × 3.5 × 20 mm) were implanted into the parenchyma of 10 sheep for 6 months. Radiographs were taken directly post-surgery and at 3 and 6 months. Subsequently, sheep were euthanized, and GFAP and IBA-1 histological analysis was performed. The migration of the implants was tracked by reference to two stainless steel screws placed in the skull. We found no significant difference in fluoroscopy intensity of GFAP and a small difference in IBA-1 between implanted tissue and control. There was no glial scar formation found at the site of the implant’s track wall. Furthermore, we observed movement of up to 4.6 mm in a subset of implants in the first 3 months of implantation and no movement in any implant during the 3–6-month period of implantation. Subsequent histological analysis revealed no evidence of a migration track or tissue damage. We conclude that the implantation of this discrete micro-implant within the brain does not present additional risk due to migration.
A Recombinant Human Adenovirus Type 5 (H101) Combined With Chemotherapy for Advanced Gastric Carcinoma: A Retrospective Cohort Study
Authors: Zhang Ran , Cui Yanxin , Guan Xin , Jiang Xiangjun
Published: December 2021

Background

This retrospective cohort study aimed to evaluate the clinical outcomes of H101 combined with chemotherapy for advanced gastric carcinoma (GC) patients.

Methods

The advanced GC patients, who were treated with H101 and/or chemotherapy, were enrolled and divided into three groups according to treatment method. The clinical characteristics of patients, clinical short-term and long-term outcomes, followed up, and complication were analyzed.

Results

A total of 95 patients (30 patients in group A were treated with H101, 33 in group B patients were treated with chemotherapy, 32 patients in group C were treated with H101 combined with chemotherapy) were retrospectively reviewed. The disease control rate (DCR) and overall response rate (ORR) were significantly greater in group C (81.3% and 50.0%) than in groups A (63.3% and 30.0%) and B (66.7% and 33.3%, all p < 0.05). The 1- and 2-year survival rates and progression-free survival were significantly greater in group C than in groups A and B (all p < 0.05). There was no significant difference in complication among the three groups. At dose levels of 0.5 × 1012 vp/day, 1.0 × 1012 vp/day, and 1.5 × 1012 vp/day, complications were not increased as increased of dose.

Conclusions

H101 combined with chemotherapy may be a potential therapeutic option for patients with advanced GC, and prospective studies with proper assessment of toxicity will be needed in the future.
Overexpression of Reactive Oxygen Species Modulator 1 Predicts Unfavorable Clinical Outcome in EGFR-Mutant Lung Adenocarcinomas Treated With Targeted Therapy
Authors: Kwack Won Gun , Sung Ji-Youn , Lee Seung Hyeun
Published: December 2021

Purpose

Reactive oxygen species modulator 1 (Romo1) is a novel protein that regulates the production of intracellular reactive oxygen species. Romo1 has been shown to be associated with poor survival in various clinical settings for the treatment of lung cancer. In this study, we evaluated whether tissue Romo1 expression was associated with clinical outcomes in epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma treated with tyrosine kinase inhibitors (TKIs).

Method

Romo1 expression in tumor tissues was examined by immunohistochemistry and evaluated by histologic score. Univariate and multivariate analyses were performed to identify the clinicopathologic parameters, including Romo1 expression, which may be associated with progression-free survival (PFS), overall survival (OS), and incidence of secondary T790M mutation.

Results

A total of 96 tumor specimens were analyzed. With the cut-off value of 200, 71 (74.0%) and 25 (26.0%) patients were classified into low and high Romo1 groups, respectively. The median PFS of the high Romo1 group was significantly shorter than that of the low Romo1 group (13.1 vs 19.9 months,p= 0.0165). The median OS of the high Romo1 group was also significantly shorter than that of the low Romo1 group (19.8 vs 37.0 months,p= 0.0006). Multivariate analyses showed that high Romo1 expression was independently associated with both poor PFS (hazard ratio [HR] = 2.48, 95% confidence interval [CI]: 1.35–4.56,p= 0.0034) and poor OS (HR = 3.17, 95% CI: 1.57–6.41,p= 0.0013). In addition, the rate of secondary T790M mutation after TKI failure was significantly lower in the high Romo1 group than the low Romo1 group (16.7% vs. 38.3%,p= 0.0369).

Conclusions

Romo1 overexpression was associated with poor response to treatment and short survival in patients treated withEGFR-TKIs, suggesting a distinct subgroup warranting active surveillance and tailored therapeutic approach. In addition, our data highlight that Romo1 could be a potential predictive and prognostic biomarker for this patient population.
Treatment Approaches to Chronic Lymphocytic Leukemia With High-Risk Molecular Features
Authors: van der Straten Lina , Hengeveld Paul J. , Kater Arnon P. , Langerak Anton W. , Levin Mark-David
Published: December 2021

The clinical course of chronic lymphocytic leukemia (CLL) is highly variable. Over the past decades, several cytogenetic, immunogenetic and molecular features have emerged that identify patients suffering from CLL with high-risk molecular features. These biomarkers can clearly aid prognostication, but may also be capable of predicting the efficacy of various treatment strategies in subgroups of patients. In this narrative review, we discuss treatment approaches to CLL with high-risk molecular features. Specifically, we review and provide a comprehensive overview of clinical trials evaluating the efficacy of chemotherapy, chemoimmunotherapy and novel agent-based treatments in CLL patients with TP53 aberrations, deletion of the long arm of chromosome 11, complex karyotype, unmutated IGHV, B cell receptor stereotypy, and mutations in NOTCH1 or BIRC3. Furthermore, we discuss future pharmaceutical and immunotherapeutic perspectives for CLL with high-risk molecular features, focusing on agents currently under investigation in clinical trials.
Case Report: Unusual High-Grade Diffuse Leptomeningeal Glioneuronal Tumor Mimicking Tuberculous Meningitis in a Child From an Endemic Region
Authors: Teh Yong Guang , Azizan Nornazirah , Mohd Naim Nur Atifah , Ng Chiak Yot , Wong Ke Juin , Mohd Zaki Faizah
Published: December 2021

Background: Diffuse leptomeningeal glioneuronal tumor (DL-GNT) is a new entity described in the 2016 World Health Organization (WHO) classification of brain tumors. While DL-GNT is predominantly an indolent tumor that affects young boys, high-grade DL-GNT is unusual and seldom reported in children.

Case Presentation: In this report, we describe the challenges and pitfalls associated with diagnosing this high-grade variant in a tuberculosis-endemic region. We highlight the importance of identifying non-typical imaging findings, i.e., non-enhancing cystic lesions with high T2 signal along the leptomeningeal surface, that may expedite the diagnosis of this condition. Histopathologic correlations with MR spectroscopy findings are also discussed.

Conclusion: We provide the first clinical imaging report of utilizing MR spectroscopy to distinguish DL-GNT from tuberculosis with histopathologic correlation.
The Roles of Dipeptidyl Peptidase 4 (DPP4) and DPP4 Inhibitors in Different Lung Diseases: New Evidence
Authors: Zhang Tianli , Tong Xiang , Zhang Shijie , Wang Dongguang , Wang Lian , Wang Qian , Fan Hong
Published: December 2021

CD26/Dipeptidyl peptidase 4 (DPP4) is a type II transmembrane glycoprotein that is widely expressed in various organs and cells. It can also exist in body fluids in a soluble form. DPP4 participates in various physiological and pathological processes by regulating energy metabolism, inflammation, and immune function. DPP4 inhibitors have been approved by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes mellitus. More evidence has shown the role of DPP4 in the pathogenesis of lung diseases, since it is highly expressed in the lung parenchyma and the surface of the epithelium, vascular endothelium, and fibroblasts of human bronchi. It is a potential biomarker and therapeutic target for various lung diseases. During the coronavirus disease-19 (COVID-19) global pandemic, DPP4 was found to be an important marker that may play a significant role in disease progression. Some clinical trials on DPP4 inhibitors in COVID-19 are ongoing. DPP4 also affects other infectious respiratory diseases such as Middle East respiratory syndrome and non-infectious lung diseases such as pulmonary fibrosis, lung cancer, chronic obstructive pulmonary disease (COPD), and asthma. This review aims to summarize the roles of DPP4 and its inhibitors in infectious lung diseases and non-infectious diseases to provide new insights for clinical physicians.