Background and purpose: Structural brain damage was discovered in patients after aneurysmal subarachnoid hemorrhage (SAH). However, changes of cortical gray matter characteristics remain unknown. The aim of this study was to test the hypothesis that cortical morphometry features were disrupted after aneurysmal SAH. Methods: Structural MRI were acquired from 115 aneurysm patients and 32 healthy controls. The FreeSurfer pipeline was used to cortical construction for all subjects. Further, patients were separately divided into subgroups based on presence of SAH, clipping or coiling, and length of follow-up after treatment. Differences in cortical thickness, surface area and volume between groups were compared after controlling for covariates. Subsequently, correlation analyses were performed between abnormal cortical features and clinical data. Results: The vertex-wise analyses revealed that aneurysm patients present smaller cortical volume in the right superiorfrontal gyrus than healthy controls, but there was no significant difference for cortical thickness or surface area. As expected, both microsurgical clipping and postoperative follow-up time had no significant effect on cortical morphological measures following subgroups analyses. We only found patients who with ruptured aneurysm had decreased surface area in the left superiorparietal gyrus, left precuneus, and right superiorfrontal gyrus in comparison to the unruptured group. However, positive finding of decreased regional gray matter volume and surface area were disappeared after adding the total intracranial volume as additional covariate. Conclusion: These findings enhance our understanding for the mechanism of brain damage following aneurysmal SAH, and additional support the advantages of brain protection of keyhole surgery for aneurysm treatment.

Although the dispersal is important for riparian plants, few studies have evaluated the patterns in species richness and composition of propagules deposited by different dispersal types. In the present study we evaluate the temporal and spatial patterns in the diversity of propagules deposited by hydrochory and by other types of dispersal along mountain rivers. To do this, we sampled the propagules deposited in the riparian zone in a distance gradient with respect to the site of origin of the rivers in two seasons. Regarding the temporal analyses, we found no differences in the number of propagules between seasons. In the rainy season we observed a greater number of species deposited by hydrochory, while for other types of dispersal there was a greater number of species in the dry season. Differences in composition were observed for hydrochory but not for other types of dispersal. Regarding the spatial analyses, there were no changes in the number of propagules deposited along the river by hydrochory, while for other types of dispersal an increase was observed in the dry season. A lower number of species deposited by hydrochory along the river in the rainy season was observed. Finally, we observed that turnover increases by other types of dispersal in the dry season but not for hydrochory. The results underline the importance of types of dispersal other than hydrochory in the contribution of propagules dispersed and the temporal and spatial particularities of the hydrochory in mountain rivers.

Atomoxetine is mainly metabolized by CYP2D6 while CYP2C19 plays a secondary role. It is known that patients carrying genotypes encoding decreased/absent CYP2D6 metabolism obtain higher atomoxetine concentrations and are at increased risk of adverse effects. Here, we aimed to investigate the added effects of reduced-function CYP2C19 genotype on atomoxetine concentrations in real-world settings. Serum atomoxetine concentrations and CYP2D6/2C19 genotypes were included from a therapeutic drug monitoring service. Patients were first subgrouped according to CYP2D6 encoding normal, reduced or absent CYP2D6 metabolism, referred to as normal (NM), intermediate (IM) or poor metabolizers (PM). Then, the effect of reduced-function CYP2C19 genotypes was investigated. Genotyping of the CYP2D6 nonfuctional or reduced variant alleles comprised CYP2D6*3-*5, *9-*10 and *41. For CYP2C19, the CYP2C19*2 was analysed to define metabolizer phenotype. Dose-adjusted serum atomoxetine concentration was the exposure measure. Using a patient cohort (n=315), it was found that CYP2D6 IM and PM patients had 1.9-fold (95%CI: 1.4-2.7) and 9.6-fold (5.9-16) higher exposure of atomoxetine compared with CYP2D6 NMs. CYP2C19*2 carriers had 1.5-fold (1.1-2.2) higher atomoxetine exposure than non-carriers regardless of CYP2D6 genotype. CYP2D6 genotype has a great impact on atomoxetine exposure, where our real-world data suggest atomoxetine dose requirements to be around half and one-tenth in CYP2D6 IM and PM vs. NM patients, respectively. When adding CYP2C19 genotype as a factor of relevance for personalized atomoxetine dosing, CYP2C19*2 carriers should further reduce the dose by a third. These findings suggest that pre-emptive CYP2D6/CYP2C19 genotyping should be performed to individualize atomoxetine dosing and prevent adverse effects.

When performing bimanual tasks, hands are typically not controlled individually but rather as a coupled system to achieve high spatiotemporal coordination. On a brain level, intra- and interhemispheric connections networks that control the left and right hand are necessary to exchange information between hemispheres and to couple movements. Behaviorally, coupling is, however, highly task-specific requiring, for example, to maintain a specific relative phase in cyclic tasks (e.g., in- or antiphase) or to perform a role differentiated task where one hand is modulating and the other hands is stabilizing and needs to be kept as still as possible (e.g., holding a notepad and writing on it). In this study, we used electroencephalography to investigate functional brain network characteristics (task-related activation and connectivity) in bimanual force-control tasks with different coordination modes: inphase, antiphase and role-differentiated with the left- or right-hand stabilizing and the other hand manipulating. We aimed to examine i) how network characteristics differ with respect to the coordination mode and ii) how they are related to the performance. Results showed, task-related differences in the overall activation and connectivity, but no task-specific patterns (i.e., different regions being more active or integrated during some tasks than others). We did show, however, that the strength of bimanual coupling is modulated in a task-specific way through networks including C3, FC3 and F3 electrodes. Results suggest that interhemispheric crosstalk for bimanual coordination is modulated in a task-specific way through left frontocentral networks.

Temporal processing of auditory data plays a crucial role in our proposed model of tinnitus development through stochastic resonance (SR). The model assumes a physiological mechanism optimizing auditory information transmission (as quantified by autocorrelation (AC) analysis) into the brain by adding the optimal amount of neuronal noise to otherwise subthreshold signals. We hypothesize that this takes place at the second synapse of the auditory pathway in the dorsal cochlear nucleus (DCN). We propose that after hearing loss, this neuronal noise is tuned up in the affected frequency-band to improve hearing thresholds on the cost of upward propagation of this added noise, which finally may be perceived as tinnitus. We could already show the improvement of hearing thresholds in a large population of patients. Until now, we did not investigate the differences in hearing thresholds based on the biological constrains of early auditory temporal processing (phase locking) that is only possible up to frequencies of 5 kHz. In this report, we grouped our patient database (N=47986) according to tinnitus pitch (TP) of below (TP<5kHz) or above (TP>5kHz) the 5 kHz limit or having no tinnitus (NT) and compared their mean audiograms. We found that TP<5kHz patients showed significantly better hearing thresholds than all other patient groups independent of age. No improvement was seen for TP>5kHz patients who even showed worse thresholds than NT patients for high frequencies. These results are further evidence for our SR model of tinnitus development and the existence of AC analysis at the level of the DCN.

In nature, biological systems such as the human brain are characterized by complex and non-linear dynamics. One way of quantifying signal complexity is Multiscale Entropy (MSE), which is suitable for structures with long-range correlation at different time scales. In developmental neuroscience, MSE can be taken as an index of brain maturation, and can differentiate between healthy and pathological development. In our current work, we explored the developmental trends of MSE on the basis of 30 simultaneous EEG – fNIRS recordings in premature infants between 27 and 34 weeks of gestational age (wGA). To explore potential factors impacting MSE, we determined the relation between MSE and the EEG Power Spectrum Density (PSD) and Spontaneous Activity Transients (SATs). As a result, via wGA, the MSE calculated on the EEG increases, thus reflecting the maturational processes in the brain networks, whereas in the fNIRS, MSE decreases, which might indicate a maturation of the brain blood supply. Moreover, we propose that the EEG power in the beta band (13 – 30 Hz) might be the main contributor to MSE in the EEG. Finally, we highlight the importance of SATs in determining MSE as calculated from the fNIRS recordings.

Solitary fibrous tumors are rare vascular tumours.Their occurrence in parapharyngeal space is very rare.Hence, they should also be considered in the differential diagnosis of parapharyngeal soft tissue tumours.

Streptococcus equi subspecies equi (S. equi) is the causative organism of the upper respiratory disease of equids, strangles, characterised by pyrexia, lymphadenopathy, and mucopurulent nasal discharge. Strangles was first reported over 750 years ago and continues to be of significance in equine populations across the globe. This review discusses how S. equi has adapted, the clinical manifestation of strangles, and how clinicians and caregivers can tackle the disease in the future. S. equi evolved from the commensal, and occasionally opportunistic pathogen, Streptococcus equi subspecies zooepidemicus refining its capabilities as it became host restricted. The success of S. equi can be attributed to its ability to cause both acute and persistent infection, the latter occurring in about 10% of those infected. In this carrier state, S. equi persists in the guttural pouch without causing clinical signs, intermittently shedding into the environment, and encountering naïve animals. Insight into the S. equi genome and lifestyle has led to advances in diagnostic assays and the development of a safe and efficacious recombinant-fusion vaccine, giving clinicians and caregivers the tools to better combat this infection. Alongside rigorous biosecurity protocols and pragmatic control measures such as screening new arrivals for exposure and carrier status, these new technologies demonstrate that strangles can be an increasingly preventable infection.

Antihypertensives in pregnant women with mild chronic hypertension.Paulino Vigil-De Gracia, MD.Complejo Hospitalario Dr. AAM Caja de Seguro Social. Investigador distinguido del Sistema Nacional de Investigación, SENACYT Panamá, e-mail: pvigild@hotmail.comDisclosure: ¨The authors report no conflict of interest¨Funding: NOWord count: Abstract: 94 Main Text: 1085Running Title: Treatment of pregnancy with chronic hypertension.AbstractPregnant women with chronic hypertension have increased worldwide and with it more maternal and perinatal complications such as hypertensive crisis, preeclampsia, placental abruption, growth restriction, prematurity, perinatal mortality. In addition to correct diagnosis and strict follow-up during the pregnancy, antihypertensive drugs have been controversially used. An adequate randomized controlled study recently published shows the benefit of antihypertensives. The antihypertensive drug used seems to be the explanation why previous studies were not conclusive in denoting benefits. The drugs that have shown benefits are beta-blockers (labetalol), calcium channel blockers (nifedipine, amlodipine) and with minimal effectiveness methyldopa.Keywords: Chronic hypertension, pregnancy, antihypertensive drugs, labetalol, methyldopa.Pregnant women with chronic hypertension increase considerably in the world. This group of patients and especially the black population have a higher risk of presenting obstetric complications such as preeclampsia, placental abruption, growth restriction, prematurity, perinatal mortality. In addition, there are more maternal risks such as acute pulmonary edema, kidney damage, heart failure, stroke and death.1,2. The management of the patient with chronic hypertension requires follow-up, evaluations and the main management focuses on giving antihypertensive drugs. When these patients become pregnant or chronic hypertension is diagnosed for the first-time during pregnancy, there was no convincing evidence on the usefulness and necessity of giving antihypertensive treatments if the hypertension is not severe, which is usually defined as a blood pressure of <160/110 mm Hg. A recently published study shows convincing evidence on the need to give antihypertensive drugs in this population group.3. Until before this study 3, a Cochrane systematic review (CSR) 4 including in the meta-analysis 58 studies (5909 women) showed controversial results that prevented a clear recommendation, also a randomized study5 of adequate quality published in 2015, in which strict blood pressure control was done or not, it failed to prove benefits in perinatal or maternal outcomes, except less severe hypertension in the group with strict control of blood pressure. The findings of the CSR 4 and the study by Tita et al.3 show that the possible explanation for the controversial findings is the drugs used to treat hypertension.Most of the randomized studies examining the effectiveness of drugs in the management of pregnant women with non-severe chronic hypertension have small numbers of patients. There are only 4 studies that have evaluated at least 300 patients, two of them analyzed in CSR4 (one in the USA in 1990 with 300 women and the other in Pakistan in 2016 with 314 women), the study by Magge et al.5 published in 2015 with 981 women and the study by Tita et al. 3 published in the year 2022 with 2408 pregnant women. The study by Magee et al. 5, used antihypertensives in both groups, without randomization to the type of antihypertensives and therefore is not analyzed in the CSR4 and the study by Tita et 3 was published after the CSR 4. We currently have three big studies: a systematic review with 5909 women, a randomized study with 981 patients using antihypertensives in both groups, and a randomized study with 2408 women comparing using versus not using antihypertensives. Due to the relevance of the topic and the findings of these three studies, a narrative description and comments are necessary.The outcomes of maternal and perinatal complications according to the medication used to manage hypertension are described according to the findings of each of the three studies, table 1.Hypertensive crisis (systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥ 110 mmHg): The reduction in hypertensive crises using antihypertensives was demonstrated in the CSR 4 and in the two big and randomized studies already mentioned3,5. The study by Magee et al. 5, for the strict control of hypertension, labetalol was used as the main antihypertensive, however, methyldopa was used in more than 40% of the population studied. The findings show that there is a significant decrease in hypertensive crises. The CSR 4 showed a decrease in hypertensive crises independent of the antihypertensive used, but a better result is observed when using beta-blockers. In addition, the CRS shows that in two studies (310 women) with methyldopa, hypertensive crises were also reduced. The Tita et al study3 shows a significant decrease in hypertensive crises and they used labetalol, nifedipine and amlodipine in 99% of patients in the treatment group, methyldopa was only used in 0.3%. The results of these investigations suggest benefits in avoiding hypertensive crises using beta-blockers, calcium channel blockers and methyldopa.Preeclampsia/severe preeclampsia and premature birth: The study by Tita et 3 shows significant decrease in severe preeclampsia and births before 35 weeks and the CSR 4 showed a decrease in preeclampsia only when using beta-blockers and a slight increase is observed when using calcium channel blockers, this systematic review does not find a decrease in preterm deliveries. The study by Magee et al. 5 showed no benefit in those outcomes. The findings of these studies show us that using methyldopa as an antihypertensive does not reduce preeclampsia or prematurity.Placental abruption, fetal/perinatal death: The CSR 4and the other two randomized studies 3,5 did not find any change in these findings, so there seems to be no benefit for these variables when antihypertensives are used in pregnant women with mild/moderate chronic hypertension. Nevertheless, the Tita et al study3 shows a significant decrease when adding both findings as a component of the set of primary results.Neonatal complications (respiratory distress syndrome, bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, intraventricular hemorrhage grade 3 or 4, hypoglycemia, bradycardia, seizure, hypotension): The study by Tita et al 3 does not show differences in these variables when giving you antihypertensive treatment, nor did the study by Magee et al. 5. The CSR 4 shows similar results to the two randomized studies, except that less respiratory distress syndrome is observed at the expense of the group that received antihypertensive treatment with beta-blockers.Small for gestational age: This is a result that has been questioned as a possible adverse effect of antihypertensives, however, the CSR4 and the two randomized studies 3,5they found no change in fetal growth.Cesarean section: Cesarean births did not vary significantly in the two randomized studies 3,5, however, in a sub-analysis of the CSR 4 shows that there is a significantly higher chance of cesarean section if the antihypertensive used is methyldopa, this emerges from the analysis of 13 studies with 1330 women.Conclusion: Antihypertensives generate benefits in pregnant women with mild chronic hypertension. The main antihypertensives used in these patients are labetalol, nifedipine, amlodipine, and methyldopa; these drugs reduce severe hypertension. Preeclampsia and especially severe preeclampsia is reduced by beta-blockers and calcium channel blockers. Using methyldopa there is no decrease in preeclampsia, there is a greater possibility of cesarean section and there are side effects such as sedation, depression, dizziness. In addition, the randomized controlled trial that includes the largest number of pregnant women with mild chronic hypertension, demonstrating several benefits with antihypertensives, did not use methyldopa. Methyldopa should not be considered as an antihypertensive in pregnant women with mild chronic hypertension due to its minimal usefulness and the existence of other more effective drugs.Table 1.Antihypertensives used in chronic hypertension without hypertensive crisis

Snowpack dynamics have a major influence on wildlife movement ecology and predator-prey interactions. Specific snow properties such as density, hardness, and depth determine how much an animal sinks into the snowpack, which in turn drives both the energetic cost of locomotion and predation risk. Here, we quantified the relationships between 15 field-measured snow variables and snow track sink depths for widely distributed predators (bobcats [Lynx rufus], coyotes [Canis latrans], wolves [C. lupus]) and sympatric ungulate prey (caribou [Rangifer tarandus], white-tailed deer [Odocoileus virginianus], mule deer [O. hemionus], and moose [Alces alces]) in interior Alaska and northern Washington, USA. We first used generalized additive models to identify which snow metrics best predicted sink depths for each species and across all species. For species occurring in both sites, we then tested whether the snow metric-sink depth relationship differed across regions. Finally, we used breakpoint regression to identify thresholds for the best-performing predictor of sink depth for each species (i.e., values wherein tracks do not appreciably sink into the snow). Near-surface (0-10cm) snow density was the strongest predictor of sink depth across species. This relationship varied slightly by region for wolves and moose but did not differ for coyotes. Thresholds of support occurred at snow densities of 230 kg/m3 for coyotes, 280 kg/m3 for bobcats, 290 kg/m3 for wolves, 340 kg/m3 for deer, 440 kg/m3 for caribou, and 550 kg/m3 for moose. Together, these critical thresholds define the bounds of “danger zones,” the range of snow density in which carnivores have a comparative movement advantage over ungulates. These results can be used to link predator-prey relationships with spatially explicit snow modeling outputs and projected future changes in snow density. As climate change rapidly reshapes snowpack dynamics, these danger zones provide a useful framework to anticipate likely winners and losers of future winter conditions.

Root traits and functioning: from individual plants to ecosystemsFine roots, the most distal portions of the root system, are responsible for the uptake of water and nutrients by plants, represent the main type of plant tissue contributing to soil organic matter accrual, and are key drivers of mineral weathering and soil microbial dynamics (Bardgett et al. 2014). Despite the overwhelming importance of fine root traits for plant and plant community functioning and biogeochemical cycles, basic information about their ecology is lacking, particularly compared to the wealth of information developed for leaves and stems. Testing hypotheses on how root traits underlie these ecosystem processes has been particularly hampered due to (1) a paucity of systematically collected data and (2) the complexity of the relationships between root traits and root, plant and ecosystem functioning. Nonetheless, the development of the field of root ecology in the last two decades has been outstanding, in particular in the compilation of belowground trait datasets (Iversen et al. 2017), methodological root ecological handbooks (Freschet et al. 2021b), novel conceptual frameworks to describe root trait diversity (Bergmann et al. 2020), its connection with belowground plant and community function (Bardgett et al. 2014, Freschet et al. 2021a), species’ distributions (Laughlin et al. 2021), and scaling up traits from the individual root to the ecosystem level (McCormack et al. 2017). The papers that feature in this Special Issue on Root traits and functioning: from individual plants to ecosystems cover different climate regions, taxonomic and spatial scales, and a diversity of traits (Table 1) and form perfect examples of this upward moment of the belowground component in plant ecology.

Managing forests for increased structural complexity as well as acknowledging them as ‘complex adaptive systems’ has become a paradigm in modern silviculture. Primary forests usually show greater structural complexity than managed forests since forest management often aims for several reasons at less complex but specific structures, e.g. for the production of desired wood assortments. Therefore, the question why natural forests seem to gravitate towards maximum structural complexity, at least aboveground, remains. Here we argue that the consideration of thermodynamic theory in forest ecosystem research holds great potential for a deeper understanding as to why structural complexity is beneficial to forests when it comes to evolutionary adaptation. We bring together several existing theories and highlight how structural complexity relates to thermodynamic principles and correspondingly forest productivity, potentially also providing us a means to quantify forests’ adaptive capacity.

Indirect genetic effects describe phenotypic variation that results from differences in the genotypic composition of social partners. Such effects represent heritable sources of environmental variation in eusocial organisms because individuals are typically reared by their siblings. In the fire ant Solenopsis invicta, a social supergene exhibits striking indirect genetic effects on worker regulation of colony queen number, such that the genotypic composition of workers at the supergene determines whether colonies contain a single or multiple queens. We assessed the direct and indirect genetic effects of this supergene on gene expression in brains and abdominal tissues from lab-reared workers and compared these with previously published data from field-collected pre-reproductive queens. We found that direct genetic effects caused larger gene expression changes and were more consistent across tissue types and castes than indirect genetic effects. Indirect genetic effects influenced the expression of many loci but were generally restricted to the abdominal tissues. Further, indirect genetic effects were only detected when the genotypic composition of social partners differed throughout the development and adult life of focal workers, and were often only significant with relatively lenient statistical cutoffs. Our study provides insight into direct and indirect genetic effects of a social supergene on gene regulatory dynamics across tissues and castes in a complex society.

Increasing rice yield has always been one of the primary objectives of rice breeding. However, panicle degeneration, a complex phenomenon regulated by many genetic and environmental factors, often occurs in rice-growing regions and severely curbs rice yield. In this study, we obtained a new apical panicle degeneration mutant named ym48, which induces a marked degeneration rate and diminishes the final grain yield. Cellular and physiological analyses revealed that the apical panicle in ym48 undergoes programmed cell death, accompanied by excessive accumulations of peroxides. Following, the panicle degeneration gene OsCAX1a was identified, which was involved in Ca2+ transport in the ym48 mutant. In OsCAX1a, a relative conserved T to A substitution was noted at the 64th amino acid, which disrupted Ca2+ transport. Hydroponics assays and Ca2+ quantification confirmed that Ca2+ transport and distribution to apical tissues were restricted and over-accumulated in mutant sheath. Ca2+ transport between cytoplasm and vacuole was affected, and the reduced content of Ca2+ in vacuole and cell wall and the decreased of Ca2+ absorption were appeared in ym48 mutant. RNA-Seq data indicated that the abnormal CBL (calcineurin b-like proteins) pathway mediated by deficient Ca2+ might occur in mutant, resulting in the burst of ROS and programmed cell death in panicles. Our results explained the key role of OsCAX1a in Ca2+ transport and distribution and laid a foundation to further explore the genetic and molecular mechanisms of panicle degeneration and the efficiency of Ca2+ fertilization in rice.

Objective: Midwives in Greenland observe that people give birth faster, with fewer complications tentatively due to early maternal expulsive efforts in second stage. Our aim was to quantify these observations and potential geographical differences. Design: Bicentre observational prospective cohort study. Method: Between October and December 2020, 50 participants in labour in Aabenraa (Denmark) and Nuuk (Greenland) participated. Transperineal head-perineum distance was measured with a handheld ultrasound scanner. Negative binomial regression was used to calculate incidence rate ratio. Fetomaternal outcome was recorded and compared Results: The median duration of maternal expulsive efforts was 23 minutes in Denmark compared to 10 minutes in Greenland (p=0.046). This was adjusted for parity, epidural use and gestational age. In Denmark 22 % and in Greenland 81 % started maternal expulsive efforts before the fetal head was at the pelvic floor (p-value< 0.001). Conclusion: Although the duration of maternal expulsive efforts and head-perineum distance was significantly different in the univariate analysis, in the multivariate analysis this was not affected by ethnicity. There was no significant difference in bleeding, perineal tears, or Apgar scores. There is a tendency of a shorter duration of maternal expulsive efforts in the active phase of the second stage of labour distance in Greenland compared to practice in Denmark. However, it seems that epidural and parity could be the main confounders to explain the difference between the two groups, but this needs further investigation.

Mycobacterium tuberculosis (Mtb) is the pathogen that causes tuberculosis and develops resistance to many of the existing drugs. The sole licensed TB vaccine, BCG, is unable to provide a comprehensive defence. So, it is crucial to maintain the immunological response to eliminate tuberculosis. Our previous in silico study reported five uncharacterized proteins as potential vaccine antigens. In this article, we considered the uncharacterized Mtb H37Rv regions of difference (RD-2) Rv1987 protein as a promising vaccine candidate. The vaccine quality of the protein was analyzed using reverse vaccinology and immunoinformatics-based quality checking parameters followed by an ex-vivo preliminary investigation. In silico analysis of Rv1987 protein predicted it as surface localized, secretory, single helix, antigenic, non-allergenic, and non-homologous to the host protein. Immunoinformatics analysis of Rv1987 by CD4+ and CD8+ T-cells via MHC-I and MHC-II binding affinity and presence of B-cell epitope predicted its immunogenicity. The docked complex analysis of the 3D model structure of the protein with immune cell receptor TLR-4 revealed the protein’s capability for potential interaction. Furthermore, the target protein encoded gene Rv1987 was cloned, over-expressed, purified, and analysed by mass-spectrometry (MS) to report the target peptides. The qRT-PCR gene expression analysis shows that it is capable of activating macrophages and significantly increasing the production of a number of key cytokines (TNF-α, IL-1β, and IL-10). Our in silico analysis and ex-vivo preliminary investigations revealed the immunogenic potential of the target protein. These findings suggest that the Rv1987 be undertaken as a potent subunit vaccine antigen and that further animal model immuno-modulation studies would boost the novel TB vaccine discovery and/or BCG vaccine supplement pipeline.

Broad-spectrum antivirals that work against many viruses provide an immediate treatment for diseases caused by novel pathogenic viruses. Notably, there is no universal drug against all four genera of the coronaviridae family, in particular d-coronaviruses, which have recently spilled over from pigs to humans. Here, we present and illustrate an in-silico strategy to evaluate potential broad-spectrum activity of an EUA-approved drug; viz., nirmatrelvir, for the porcine d-coronavirus (PDCoV) that has infected humans. First, we show that the sequence-based protein structure prediction method, ColabFold, can provide structures for the M pro dimer of a-, b-, and g-coronaviruses that are highly similar to the respective X-ray structures. Next, we validated the performance of the docking software, AutoDock Vina 1.2.3 on ColabFold-predicted SARS-CoV-2 and MERS-CoV M pro structures by showing that AutoDock Vina 1.2.3 can yield poses of nirmatrelvir that are near the catalytic Cys, as seen in the respective nirmatrelvir-bound X-ray structures. By using AutoDock Vina 1.2.3 to dock nirmatrelvir to the ColabFold-predicted M pro structure of PDCoV, we provide evidence that nirmatrelvir may inhibit PDCoV M pro. These results show the feasibility of using state-of-the-art sequence-based protein structure prediction and docking methods to assess broad-spectrum antivirals for known viruses against novel viruses lacking solved structures but sharing highly similar conserved viral domains.

Vegetation studies establishing direct mechanistic linkages between stand transpiration and streamflow are rare from sub-tropical and tropical montane forests (TMFs) like Himalaya. We quantified the impact of diurnal and seasonal transpiration on lean season streamflow in a broad-leaved evergreen secondary TMF in Eastern Himalaya. Whole-tree and stand transpiration were measured using Granier’s thermal dissipiation sap flow probes at one of the wettest (4500 mm yr-1) and highest elevation (2100 m) sites in the world to date. The observed daily and annual transpiration rates were double of the reported values from TMFs in relatively drier Central Himalaya, but at the lower bound of TMFs globally. Solar radiation was the key driver of transpiration in energy-limited winter under hydrated conditions. Vapour pressure deficit (D) controlled transpiration in energy-abundant summer. We also found that moderate precipitation events (10-30 mm) followed by clear skies can induce significant increase (93±110 %) in stand transpiration. In turn, transpiration was the main driver of lean season streamflow in dry winter and to a lesser extent in wet summer. Thus, in winter, the transpiration-driven abstraction induced corresponding diurnal cycles in soil moisture and streamflow with an average lag of 1.3±1.8 hours and 2.9±2.5 hours, respectively, and strong negative correlations (-0.8±0.1). Thus, changes in vegetation cover and precipitation patterns are likely to impact local and regional moisture recycling by vegetation and lean season flow, thereby affecting regional water security in the Eastern Himalaya.

Linear IgA bullous dermatosis (LABD) is an autoimmune/inflammatory skin condition. Here, we report on a patient who developed treatment resistant LABD. At diagnosis, elevations of IL-6 and C-reactive protein in the blood and extreme elevations in LABD bullous fluid were seen. The patient responded well to tocilizumab (anti-IL-6 receptor) treatment.

The automatic collection of power grid situation information and the real-time multimedia interaction between the front and back end of the accident handling have generated massive power grid data. Wireless communication provides a convenient channel for grid terminal access and data transmission, but the bandwidth of wireless communication is limited, and its broadcasting nature makes information easy to be monitored by illegal eavesdroppers in the transmission process. In order to realize reliable, secure and real-time transmission of power grid data, an intelligent security transmission strategy based on sense-transfer linkage is proposed. The optimization problem is constructed with maximum system security capacity as the goal, interruption probability and interception probability as constraints, and a low complexity algorithm is designed to obtain the sub-optimal solution of the problem. Finally, simulation results verify the effectiveness of the proposed scheme in ensuring communication security, stability and real-time performance.

Total persistent omphalomesenteric canal as a cause of small-bowel obstruction is an exceptional finding. A neonate presented with occlusion due to volvulus of the small bowel around a total persistent omphalomesenteric canal. Remnants of the duct were successfully resected and the postoperative course was uneventful.

Title: Sublingual-swallow immunotherapy was effective and safe in severe cow’s milk protein allergy: A pediatric case　Author: Masaya kato, M.D.; Shigemi Yoshihara, M.D., Ph.DAffiliations: Department of Pediatrics, Dokkyo Medical University, Tochigi 321-0293, JapanCorresponding author: Masaya KatoDepartment of Pediatrics, Dokkyo Medical University880 Kitakobayashi, Mibu, Shimotsuga, Tochigi 321-0293, JapanPhone: +81-282-87-2155, Fax: +81-282-86-7521E-mail: m-kato@dokkyomed.ac.jpWord, figure, and table count: 746 words, 1 figure.Financial support: This research received no external funding.Consent statement: Written informed consent was obtained from the patient’s parent and the patient for publication of this report and images.To the editor: Although an increasing number of patients with food allergy have been able to achieve tolerance and desensitization through oral immunotherapy, many children with severe Cow‘s milk (CM) allergy do not progress to oral immunotherapy and do not reach desensitization. We report a case in which sublingual-swallow immunotherapy was used to safely increase the dose of CM to 25 ml in a 12-year-old male patient who had a threshold of 1.2 ml of CM for induction of allergy symptoms.The patient had a history of five anaphylactic shocks since infancy after consuming less than 3 ml of CM, and had, therefore, eliminated CM completely from his diet. At age 11, the patient participated in a clinical study involving epicutaneous immunotherapy; however, that did not improve his symptom elicitation threshold. At age 12, casein-specific IgE 6.83 UA/ml, casein-specific IgG4 0.59 mgA/L and oral food challenge (OFC) of CM showed urticaria at 1.2 ml. Tingling of oral cavity was observed in OFC of 0.2 ml of CM, but no other symptoms were noted.We started sublingual-swallow immunotherapy, in which the patient held 0.2 ml of CM under his tongue for 2 minutes before consuming it orally, once a day. Initially, the patient complained of tingling in the oral cavity; however this disappeared within one week of therapy. The dose of CM was increased by 0.1 ml every week with no adverse events observed. As the amount increased, it could not be held only under the tongue, so it was held in the oral cavity. The dose was increased by 0.1 ml per day, 2 months after the start of therapy, but no allergic reaction was observed. After 3 months, the patient was able to consume 10 ml, and after 6 months, up to 30 ml of CM. Since he could not hold more than 20 ml, this amount was held in the oral cavity for 2 minutes before swallowing, while the rest was swallowed without holding. We performed OFC using a pancake containing 25 ml of CM, but no allergy-related symptoms were observed. Thereafter, at the patient’s request, he was given dairy products equivalent to 25 ml of milk 2–3 times a week. After a 2-week ban on CM at 14 months, an oral tolerance test (sweet bread equivalent to 25 ml of milk) was conducted, and the patient complained of mild oral discomfort, but consumed the entire amount without major symptoms. Casein-specific IgG4 levels increased, whereas casein-specific IgE levels decreased for the duration of this therapy.　(Figure 1).Keet et al.1 reported that sublingual immunotherapy (SLIT) with CM was inferior to oral immunotherapy (OIT). However, the study compared three milk protein doses during the maintenance phase of immunotherapy: 7 mg in the SLIT group, 1 g in the OIT B group, and 2 g in the OIT A group, suggesting that increasing the SLIT dose may increase efficacy. A French pilot study reported that milk thresholds increased from an average of 39 ml (range 4–106 ml) to 143 ml (range 44–≥200 ml) after 6 months of treatment by holding milk under the tongue for 2 minutes and then spitting it out (starting at 0.1 ml and increasing to 1.0 ml).2 SLIT induces IL-10-producing regulatory T cells,3 promotes antigen-specific IgG4 production, and suppresses IgE production.4 In addition, since the oral mucosa is devoid of inflammatory cells, such as mast cells, basophils, and eosinophils, and rich in antigen-presenting cells, such as dendritic cells, SLIT induces immune tolerance with fewer adverse reactions.5During OFC and OIT for milk allergy, we experience that food such as pancakes require chewing, and are more successful than swallowing milk. This may lead to sublingual immune tolerance. In addition, holding the food in the oral cavity allows the patient to spit it out if symptoms are strong, which is safer than swallowing it. There have been reports of success with the combination of OIT and omalizumab,6.7 but not everyone can afford this treatment due to the high cost of medical care. In this respect, the present method is easy to perform because the dairy product is simply held in the oral cavity for two minutes and then swallowed. In this case, the patient’s oral tingling disappeared after one week of treatment, suggesting that the treatment induced immune tolerance by the sublingual mucosa, and we believe it is worthwhile to try it for severe CM allergy. We plan to perform this therapy on more cases and conduct a comparative study with OIT in future.

Conventional solid-state power amplifier (SSPA) design approach isolates RF design from communication theory. In this paper, a unified SSPA design approach is proposed which optimizes SSPA parameters (bias voltage and input RF signal power) to minimize total DC power consumption while satisfying received SNR constraint specified by the link budget. The effect of SSPA nonlinearity is quantified by the error vector magnitude measured at its output and the corresponding received SNR degradation is analyzed. Using the quantitative metrics for received SNR, it is possible to evaluate highly nonlinear SSPA classes such as Class-B or deep-Class AB which are normally not considered in conventional SSPA design approach to be used in satellite communication applications.

：A 41-year-old man suffered a sudden death outside the hospital.He survived after receiving ACLS in the hospital. Through the ECG monitoring in the hospital and a series of medical examinations, we found that his sudden death may be related to the dynamic evolution of the ST segment of the inferior leads of the ECG.