Component Of Response Research Articles

Interferon and autoantigens: intersection in autoimmunity.

Interferon (IFN) is a key component of the innate immune response. For reasons that remain incompletely understood, the IFN system is upregulated in several rheumatic diseases, particularly those that feature autoantibody production, such as SLE, Sjögren's syndrome, myositis and systemic sclerosis. Interestingly, many of the autoantigens targeted in these diseases are components of the IFN system, representing IFN-stimulated genes (ISGs), pattern recognition receptors (PRRs), and modulators of the IFN response. In this review, we describe features of these IFN-linked proteins that may underlie their status as autoantigens. Note is also made of anti-IFN autoantibodies that have been described in immunodeficiency states.

Agronomic response of two experimental varieties of habanero chili in the application of band vermicomposting

The habanero chili pepper has great productive potential in Mexico, with an annual growth of 12.5% ​​in the planted area in the last five years. Objective: was to evaluate the agronomic response of two experimental varieties of habanero chili called HNC-6 orange color and HCC-8 chocolate color, belonging to the Center for Training and Development in Seed Technology. Methodology: the study was established under five doses of vermicompost, 0, 0.3, 0.6, 0.9 and 1.2 kg plant-1 using a completely random design with a 2x5 factorial arrangement. Results: the HNC-6 variety had a better agronomic response than HCC-8, its yield was 95 % higher, the number of fruits per plant 84 %, fruit length (FL) 25 %, pericarp thickness 28 %, fruit firmness 11 %, and average fruit weight 4.7 %. The HCC-8 variety exceeded the height of HNC-6 by 38 % and the fruit diameter (FD) by 14 %. The vermicompost doses exerted a similar effect on both varieties. In conclusion, the experimental variety HNC-6 showed a better agronomic response under the conditions tested. The vermicompost doses exerted a response effect and similar trend in the two experimental varieties of habanero pepper tested, the significant interactions found in FL, FD, and total soluble solids indicate that the application of vermicompost influenced the quality of the fruits in some aspects. Conclusions: the main factors that determined the response of the crop are its genetic component in response to the environment and the degree of maturity of the vermicompost.

Theory for computing vehicle-rail contact responses from a multi-DOF test vehicle and detecting track modulus and rail damages

The vibration data recorded for the test vehicle cannot be directly used to detect the rail and bridge frequencies due to the overshadowing effect of vehicle's frequencies. To overcome this problem, the vehicle-rail contact response may be used instead. However, current techniques on this are available only for simple test vehicles with single or two degrees of freedom (DOFs). Normally, a train car contains a car body and two bogies (each of two wheelsets), and should be modeled by a multi-DOF system. The objective of this paper is first to solve the four wheelset-rail contact responses from the six measured vehicle responses. Then the contact responses are employed to retrieve the track modulus, while detecting the rail damages, for their salient feature of being free of the vehicle's frequencies. The railway track is modeled by a dual-beam system, with the upper (rail) and lower (bridge) beams connected by a spring-dashpot layer. The track modulus is retrieved through identification of the first “plus” frequency of the dual-beam, and the rail damage is detected from the instantaneous amplitude squared (IAS) generated from the driving component of the contact response. Through comparison with results by the finite element method (FEM), it is confirmed that: (1) the proposed procedure for computing the multi contact responses from the multi-DOF vehicle responses is reliable; (2) track irregularity presents a limited influence even for high disturbance; (3) to trade-off between efficiency and accuracy, a medium vehicle speed is suggested for the field measurement; (4) for the dual-beam with sufficient length, the use of simply supported condition is acceptable for rails; and (5) the effect of track damping is small and can be ignored.

Invasion strategies of Cynodon dactylon: Competitive ability under low‐nutrient conditions

AbstractCynodon dactylon is one of the five most important invasive alien species worldwide. It is the invasive alien species with the broadest distribution range in Uruguay, and its expansion is frequently associated with disturbances. Since natural grasslands are facing processes of productive intensification, C. dactylon represents a threat as it could displace native species. However, the mechanisms that explain its invasion success remain unclear. The objective of this study was to analyse interspecific interactions under low nutrient conditions between C. dactylon and two species that are native to the Campo grasslands in Uruguay. Specifically, we assessed differences in the components of competitive ability effects and responses (or tolerance) as possible mechanisms involved in C. dactylon invasiveness. We performed a greenhouse experiment in pots with low‐nutrient substrate assessing pair‐wise interactions between C. dactylon, Mnesithea selloana and Paspalum notatum plus control pots consisting of single individual of each species. The invasive species showed greater competitive ability than both native grasses, as it reduced their below and above‐biomass. Conversely, the size of C. dactylon plants interacting with native species was similar to that of single C. dactylon plants growing alone (controls). This reveals that the greater competitive ability of the invasive species was due to a greater tolerance to grow with neighbouring plants. The reason underlying this tolerance was a marked increase in biomass allocation towards stolons and leaves, at the expense of roots. Conversely, native species barely changed their shoot‐root allocation pattern when interacting with neighbours. Furthermore, C. dactylon induced reproductive development solely when interacting with neighbours. Along with the fact that the potential growth rate of the invasive and native species was quite similar, these results suggest that sensitive and rapidly triggered shade avoidance responses could be one mechanism involved in the invasion success of C. dactylon.

Electrophysiological underpinnings of dysfunctional inhibitory control in adults with attention-deficit/hyperactivity disorder: evidence for reduced NoGo anteriorization

Our aim was to delineate the electrophysiological basis of dysfunctional inhibitory control of adult ADHD via investigating the anteriorization of the P3 component of the event-related brain response associated with the NoGo task condition (i.e., NoGo anteriorization, NGA). NGA is a neurophysiological measure of brain topography for cognitive response control, which indexes an overall shift of the brain’s electrical activity in anterior direction towards the prefrontal areas. While the NoGo P3 received considerable attention in the adult ADHD literature, the brain topography of this component, which reflects the inhibitory process, remains largely unaddressed. EEG recordings were obtained during a Go/NoGo task from 51 subjects (n = 26 adult patients with ADHD, n = 25 healthy controls) using a high-density, 128-channel BioSemi ActiveTwo recording system. ADHD patients had significantly lower P3 NGA response compared to controls. The decrease in NGA was related to impulsivity scores as measured by the Conners’ Adult ADHD Rating Scale: patients with higher impulsivity scores had significantly lower NGA. Treatment with stimulant medication, as compared to the lack of such treatment, was associated with a correction of the lower NGA response in ADHD patients. The current study revealed a lower NGA in adult ADHD, a finding which is consistent with the inhibitory control and frontal lobe dysfunctions described in the disorder. Our finding of the inverse relationship between NGA and impulsivity suggests that clinically more severe impulsivity is linked to a more pronounced frontal dysfunction in adult ADHD subjects.

The effect of metformin on influenza vaccine responses in nondiabetic older adults: a pilot trial

BackgroundAging is associated with progressive declines in immune responses leading to increased risk of severe infection and diminished vaccination responses. Influenza (flu) is a leading killer of older adults despite availability of seasonal vaccines. Geroscience-guided interventions targeting biological aging could offer transformational approaches to reverse broad declines in immune responses with aging. Here, we evaluated effects of metformin, an FDA approved diabetes drug and candidate anti-aging drug, on flu vaccination responses and markers of immunological resilience in a pilot and feasibility double-blinded placebo-controlled study.ResultsHealthy older adults (non-diabetic/non-prediabetic, age: 74.4 ± 1.7 years) were randomized to metformin (n = 8, 1500 mg extended release/daily) or placebo (n = 7) treatment for 20 weeks and were vaccinated with high-dose flu vaccine after 10 weeks of treatment. Peripheral blood mononuclear cells (PBMCs), serum, and plasma were collected prior to treatment, immediately prior to vaccination, and 1, 5, and 10 weeks post vaccination. Increased serum antibody titers were observed post vaccination with no significant differences between groups. Metformin treatment led to trending increases in circulating T follicular helper cells post-vaccination. Furthermore, 20 weeks of metformin treatment reduced expression of exhaustion marker CD57 in circulating CD4 T cells.ConclusionsPre-vaccination metformin treatment improved some components of flu vaccine responses and reduced some markers of T cell exhaustion without serious adverse events in nondiabetic older adults. Thus, our findings highlight the potential utility of metformin to improve flu vaccine responses and reduce age-related immune exhaustion in older adults, providing improved immunological resilience in nondiabetic older adults.

The Effect of Tinnitus and Related Characteristics on Subcortical Auditory Processing.

The primary aim of this study was to evaluate whether individuals with tinnitus exhibited evidence of reduced inhibition and increased excitation at the subcortical auditory processing level. Based on the proposed mechanism of tinnitus generation, including peripheral auditory insult that triggers reduced inhibition and subcortical hyperactivity, it was hypothesized that a tinnitus group would yield reduced amplitudes for the most peripheral auditory brainstem response (ABR) component (wave I) and larger amplitudes for the most central ABR component (wave V) relative to controls matched on factors of age, sex, and hearing loss. Further, this study assessed the relative influence of tinnitus presence versus other related individual characteristics, including hearing loss, age, noise exposure history, and speech perception in noise on these ABR outcomes. Subcortical processing was examined using click-evoked ABR in an independent groups experimental design. A group of adults who perceived daily unilateral or bilateral tinnitus were matched with a control group counterpart without tinnitus by age, hearing, and sex (in each group n = 18; 10 females, 8 males). Amplitudes for ABR waves I, III, V, and the V/I ratio were compared between groups by independent t-tests. The relative influence of tinnitus (presence/absence), age (in years), noise exposure history (subjective self-report), hearing loss (audiometric thresholds), and speech perception in noise (SNR-50) was determined based on the proportional reduction in error associated with accounting for each variable of interest using multiple regression. Between-group trends were consistent with smaller amplitudes for all ABR components in individuals with tinnitus. Contrary to our hypotheses, however, none of the tinnitus compared with control group differences in ABR outcomes were statistically significant. In the multiple regression models, none of the factors including tinnitus presence, age, noise exposure history, hearing loss, and speech perception in noise significantly predicted ABR V/I ratio outcomes. The presence of reduced inhibition and subcortical hyperactivity in the tinnitus group was not supported in the current study. There were trends in ABR outcomes consistent with reduced peripheral to central brainstem auditory activity in the tinnitus group, but none of the group differences reached significance. It should also be noted that the tinnitus group had poorer extended high-frequency thresholds compared with controls. Regardless, neither tinnitus presence nor any of the proposed related characteristics were found to significantly influence the ABR V/I ratio. These findings suggest that either reduced subcortical inhibition was not a primary underlying mechanism for the tinnitus perceived by these subjects, or that ABR was not a reliable indicator of reduced subcortical inhibition possibly due to characteristics of the sample including a skewed distributions toward young and normal hearing individuals with little tinnitus distress.

The environmental cellular stress response: the intertidal as a multistressor model.

The wild poses a multifaceted challenge to the maintenance of cellular function. Therefore, a multistressor approach is essential to predict the cellular mechanisms which promote homeostasis and underpin whole-organism tolerance. The intertidal zone is particularly dynamic, and thus, its inhabitants provide excellent models to assess mechanisms underpinning multistressor tolerance. Here, we critically review our current understanding of the regulation of the cellular stress response (CSR) under multiple abiotic stressors in intertidal organisms and consider to what extent a multistressor approach brings us closer to understanding responses in the wild. The function of theCSR has been well documented in laboratory and field exposures with a view to understanding single-stressor thermal effects. Multistressor studies still remain relatively limited in comparison but have applied three main approaches: (i) laboratory application of multiple stressors in isolation, (ii) multiple stressors applied in combination, and (iii) field-based correlation of multiple stressors against the CSR. The application of multiple stressors in isolation has allowed the identification of putative,shared stress pathways but overlooks non-additive stressor interactions on the CSR. Combined stressor studies are relatively limited in number but already highlight variable effects onthe CSR dependent upon stressor type, timing, and magnitude. Field studies have allowed the identification of responsive components ofthe CSR to various stressors in situ but are correlative, not causative. A combined approach involving laboratory multistressor studies linkingthe CSR to whole-organism tolerance as well as field studies is required if we are to understand the role ofthe CSR in the natural environment.

Somatic Integration of Incoherent Dendritic Inputs in the Gerbil Medial Superior Olive.

The medial superior olive (MSO) is a binaural nucleus that is specialized in detecting the relative arrival times of sounds at both ears. Excitatory inputs to its neurons originating from either ear are segregated to different dendrites. To study the integration of synaptic inputs both within and between dendrites, we made juxtacellular and whole-cell recordings from the MSO in anesthetized female gerbils, while presenting a "double zwuis" stimulus, in which each ear received its own set of tones, which were chosen in a way that all second-order distortion products (DP2s) could be uniquely identified. MSO neurons phase-locked to multiple tones within the multitone stimulus, and vector strength, a measure for spike phase-locking, generally depended linearly on the size of the average subthreshold response to a tone. Subthreshold responses to tones in one ear depended little on the presence of sound in the other ear, suggesting that inputs from different ears sum linearly without a substantial role for somatic inhibition. The "double zwuis" stimulus also evoked response components in the MSO neuron that were phase-locked to DP2s. Bidendritic subthreshold DP2s were quite rare compared with bidendritic suprathreshold DP2s. We observed that in a small subset of cells, the ability to trigger spikes differed substantially between both ears, which might be explained by a dendritic axonal origin. Some neurons that were driven monaurally by only one of the two ears nevertheless showed decent binaural tuning. We conclude that MSO neurons are remarkably good in finding binaural coincidences even among uncorrelated inputs.SIGNIFICANCE STATEMENT Neurons in the medial superior olive are essential for precisely localizing low-frequency sounds in the horizontal plane. From their soma, only two dendrites emerge, which are innervated by inputs originating from different ears. Using a new sound stimulus, we studied the integration of inputs both within and between these dendrites in unprecedented detail. We found evidence that inputs from different dendrites add linearly at the soma, but that small increases in somatic potentials could lead to large increases in the probability of generating a spike. This basic scheme allowed the MSO neurons to detect the relative arrival time of inputs at both dendrites remarkably efficient, although the relative size of these inputs could differ considerably.

IL-17 Receptor A protects against Helicobacter pylori-induced gastric cancer

Abstract Infection with Helicobacter pylori is the predominant risk factor for the development of gastric cancer. Risk is enhanced by specific H. pylori virulence factors, diet, and the inflammatory response. Chronic activation of T helper (Th) 1 and Th17 pathways contribute to inflammation. Previous work suggests that while IL-17 activates several antimicrobial components of the innate immune response, IL-17 is also required to prevent a hyper-inflammatory adaptive immune response. To investigate if IL-17 receptor signaling contributes to the development of carcinogenesis, the transgenic InsGAS mouse, which is susceptible to H. pylori-induced gastric cancer, was used. InsGAS mice and InsGAS Il17ra −/−mice were infected with a cag T4SS positive strain for up to 6 months. By 6 weeks post infection, IL-17RA deficiency led to increased bacterial burden and increased gastritis, concomitant with an exacerbated Th1/Th17 cytokine profile, increased B cell infiltration and enhanced production of IgA despite reduced Pigr expression. Paragastric lymph nodes of InsGAS Il17ra −/−mice, while enlarged relative to InsGAS mice, exhibited altered gene expression profiles and potential loss of fibroblastic reticular cells. Gastric pathologies, including intramucosal carcinoma and adenocarcinoma with submucosal invasion, developed more frequently by 3 and 6 months post infection in H. pylori-infected InsGASIl17ra −/−mice. These increases in severe gastric disease were accompanied by loss of parietal cells, loss of mucin-producing cells and enhanced expression of ceacam1. These data suggest that IL-17RA signaling activates a protective pathway to prevent excessive inflammation which can drive gastric carcinogenesis after H. pylori infection. This work was supported in part by Merit Review I01BX000915 (Algood) from the U.S. Department of Veterans Affairs, Biomedical Laboratory Research and Development Service. We acknowledge the Translational Pathology Shared Resource supported by NCI.NIH Cancer Center Support Grant 5P30 CA68485-19. Core Services performed through Vanderbilt University Medical Center's Digestive Disease Research Center supported by NIH grant P30DK058404.

Unraveling novel crosstalk between distinct neutrophil subsets and soluble plasma factors in sepsis and ARDS

Abstract Sepsis is a life-threatening condition caused by an aberrant immune response to infection and subsequent organ dysfunction. Further, due to shared mechanisms such as severe inflammation and endothelial dysfunction, sepsis remains the most common etiology in acute respiratory distress syndrome (ARDS) patients. Despite multiple efforts to identify a distinct signature to support the development of new therapeutics, sepsis remains a significant unmet clinical need. While singular components of the dysregulated immune response have been explored, studies linking different data layers are lacking. Using an integrated systems immunology approach, we evaluated neutrophil phenotypes and related changes in soluble plasma factors in sepsis versus healthy donors. Results from our studies identify differentially expressed mature and immature neutrophil subsets in sepsis patients. Further, we show that expression of neutrophil CD10 is associated with factors such as pentraxin-3, angiopoietin-2, and lysophosphatidylcholines, in the sepsis cohort. These findings detail a novel correlation between increased presence of immature neutrophils and endothelial dysfunction/metabolic alterations in sepsis patients. Additionally, we profiled the neutrophil landscape and evaluated levels of soluble plasma factors, in a subset of ARDS patients and healthy donors. Here, we present distinct findings that reveal a novel crosstalk between neutrophil subsets and parameters indicative of endothelial dysfunction, in sepsis and ARDS patients. Overall, our study reinforces the importance of data integration and provides novel insights that could help inform future mechanistic studies, early patient stratification and treatment options.

A Review on Vitamin D Deficiency and Related Disorders: What is the Right Serum Vitamin D Level?

To maintain a healthy skeleton, vitamin D is crucial for phosphate as well as calcium uptake. It is of great significance for maintaining the various adaptive and innate immune response components. To reduce the development of various immune-related disorders, such as diabetes, hypertension, cardiovascular diseases, rheumatoid arthritis, and coronavirus disease 2019 (COVID-19), numerous studies evaluating the optimal threshold levels for serum 25-hydroxyvitamin D [25(OH)D]. It is documented in various evidence to increase the serum 25(OH)D intake from the current mindset of 30-50 ng/mL to attain the best overall vitamin D benefits. These values are in line with the results of various research showing that increased vitamin D intake is linked to a decreased risk of cancer and cardiovascular diseases. Therefore, it becomes vital to understand the "right" vitamin D levels to avoid deficiency along with its related disorders. In contrast to 30 ng/mL, this review emphasizes the significance of increasing vitamin D levels to 50 ng/mL to obtain several physiological benefits. An individual needs at least 60000 IU for 12 weeks to maintain serum vitamin D levels above 30 ng/mL. The article will interest physicians who desire to profit fully from vitamin D's influence on clinical practice.

Investigating the Serotonergic Modulation of Orientation Tuning of Neurons in Primary Visual Cortex of Anesthetized Mice

Introduction: Sensory processing is profoundly regulated by brain neuromodulatory systems. One of the main neuromodulators is serotonin which influences higher cognitive functions, such as different aspects of perceptual processing. Accordingly, malfunction in the serotonergic system may lead to visual illusion in psychiatric disorders, such as autism and schizophrenia. This study aims to investigate the serotonergic modulation of visual responses of neurons to stimulus orientation in the primary visual cortex. Methods: Eight-week-old naive mice were anesthetized and a craniotomy was done on the region of interest in the primary visual cortex. Spontaneous and visual-evoked activities of neurons were recorded before and during the electrical stimulation of the dorsal raphe nucleus using in vivo whole-cell patch-clamp recording. The square-wave grating of 12 orientations was presented. The data were analyzed and the Wilcoxon signed-rank test was used to compare the data of two conditions that belong to the same neurons, with or without electrical stimulation. Results: The serotonergic system changed the orientation tuning of nearly 60% of recorded neurons by decreasing the mean firing rate in two independent visual response components, namely gain and baseline response. It also increased the mean firing rate in a small number of neurons (about 20%). Additionally, it left the preferred orientation and sensitivity of neurons unchanged. Conclusion: Serotonergic modulation showed a bidirectional effect. It causes predominately divisive and subtractive decreases in the visual responses of the neurons in the primary visual cortex that can modify the balance between internal and external sensory signals and result in disorders.

Interpretation of Fracture Initiation Points by In-Well Low-Frequency Distributed Acoustic Sensing in Horizontal Wells

Summary Low-frequency distributed acoustic sensing (LF-DAS) exploits the optical phase shift of Rayleigh backscatter in fiber-optic cables to obtain distributed measurements of changes in strain and temperature. Fiber-optic cables are often installed for multistage hydraulic fracture diagnostics in horizontal wells. LF-DAS in an untreated well provides far-field strain measurements, while offset wells are hydraulically fractured. Such a configuration is called crosswell LF-DAS sensing. Crosswell LF-DAS measurements have proved useful in diagnosing fracture hits, fracture azimuth, planarity, cluster efficiency, fracture propagation rates, and the dynamic distance to the fracture front. In contrast, in-well LF-DAS is conducted on the actively fractured well. Due to cool fracture fluid being injected at high injection rates, the strain component of the LF-DAS response is largely obscured by temperature changes. In permanent fiber-optic cable installations, distributed temperature sensing (DTS) is often conducted simultaneously with LF-DAS. An opportunity exists to decouple the temperature and strain components of LF-DAS sensors to observe strain changes on in-well LF-DAS. The LF-DAS response is modeled as linearly dependent on strain and temperature changes. Theoretical LF-DAS temperature and strain sensitivity coefficients are derived based on the changes to the index of refraction and length of the fiber. Using the DTS measurements, temperature changes are computed, smoothed, filtered, and compared to the LF-DAS response. Crossplots of the in-well LF-DAS measurements and temperature changes from DTS measurements far from the actively fractured region are used to validate the theoretical sensitivity coefficients. Uncertainty in the temperature component of the LF-DAS response is quantified. The difficulty in corresponding the different spatial and temporal resolutions of the DTS and LF-DAS measurements is overcome by comparing the responses over a moving temporal and spatial window. If the LF-DAS response at the center of the window agrees with the DTS response within uncertainty, the measurement is filtered out. After filtering, the remaining nonzero in-well LF-DAS measurements are due to changes in strain. The data are then visualized in waterfall plots. The results indicate that the theoretical and observed strain and temperature coefficients agree within 10%. After the temperature component of the in-well LF-DAS response is extracted, the remaining nonzero measurements are located primarily within the actively treated region. Locations with peaks in the strain response are interpreted to indicate fracture initiation points. These fracture initiation points are compared with in-well DTS and high-frequency DAS noise measurements across multiple stages to better understand fracture initiation along the horizontal well.

Getting off track: Cortical feedback processing network modulated by continuous error signal during target-feedback mismatch

Performance monitoring and feedback processing – especially in the wake of erroneous outcomes – represent a crucial aspect of everyday life, allowing us to deal with imminent threats in the short term but also promoting necessary behavioral adjustments in the long term to avoid future conflicts. Over the last thirty years, research extensively analyzed the neural correlates of processing discrete error stimuli, unveiling the error-related negativity (ERN) and error positivity (Pe) as two main components of the cognitive response. However, the connection between the ERN/Pe and distinct stages of error processing, ranging from action monitoring to subsequent corrective behavior, remains ambiguous. Furthermore, mundane actions such as steering a vehicle already transgress the scope of discrete erroneous events and demand fine-tuned feedback control, and thus, the processing of continuous error signals – a topic scarcely researched at present. We analyzed two electroencephalography datasets to investigate the processing of continuous erroneous signals during a target tracking task, employing feedback in various levels and modalities. We observed significant differences between correct (slightly delayed) and erroneous feedback conditions in the larger one of the two datasets that we analyzed, both in sensor and source space. Furthermore, we found strong error-induced modulations that appeared consistent across datasets and error conditions, indicating a clear order of engagement of specific brain regions that correspond to individual components of error processing.

Gene expression profiling of peripheral blood mononuclear cells from women with cervical lesions reveals new markers of cancer.

Cervical cancer (CC) is a multifactorial disease of which human papillomavirus (HPV) is the main etiological agent. Despite cervical Pap smear screening and anti‑HPV vaccination, CC remains a major public health issue. Identification of specific gene expression signatures in the blood could allow better insight into the immune response of CC and could provide valuable information for the development of novel biomarkers. The present study performed a transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) from Senegalese patients with CC (n=31), low‑grade cervical intraepithelial neoplasia (CIN1; n=27) and from healthy control (CTR) subjects (n=29). Individuals in the CIN1 and CTR groups exhibited similar patterns in gene expression. A total of 182 genes were revealed to be differentially expressed in patients with CC compared with individuals in the CIN1 and CTR groups. The IL1R2, IL18R1, MMP9 and FKBP5 genes were the most upregulated, whereas the T‑cell receptor α gene TRA was the most downregulated in the CC group compared with in the CIN1 and CTR groups. The pathway enrichment analysis of the differentially expressed genes revealed pathways directly and indirectly linked to inflammation. To the best of our knowledge, the present study is the first large transcriptomic study on CC performed using PBMCs from African women; the results revealed the involvement of genes and pathways related to inflammation, most notably the IL‑1 pathway, and the involvement of downregulation of the T‑cell receptor α, a key component of the immune response. Several of the stated genes have already been reported in other cancer studies as putative blood biomarkers, thus reinforcing the requirement for deeper investigation. These findings may aid in the development of innovative clinical biomarkers for CC prevention and should be further replicated in other populations.

Application of Lactobacillus reuteri B1/1 (Limosilactobacillus reuteri) Improves Immunological Profile of the Non-Carcinogenic Porcine-Derived Enterocytes.

In our previous studies, Lactobacillus reuteri B1/1, which was renamed Limosilactobacillus reuteri (L. reuteri), was able to modulate the production of pro-inflammatory cytokines and other components of the innate immune response in vitro and in vivo. In this study, we evaluated the effect of Lactobacillus reuteri B1/1 in two concentrations (1 × 107 and 1 × 109 CFU) on the metabolic activity, adherence ability and relative gene expression of pro-inflammatory interleukins (IL-1β, IL-6, IL-8, IL-18), lumican and olfactomedin 4 produced by non-carcinogenic porcine-derived enterocytes (CLAB). CLAB cells were cultured in a 12-well cell culture plate at a concentration of 4 × 105 cells/well in DMEM medium in a controlled humidified atmosphere for 48 h. A 1 mL volume of each probiotic bacterial suspension was added to the CLAB cells. Plates were incubated for 2 h and 4 h. Our results revealed that L. reuteri B1/1 was able to adhere to CLAB cells in sufficient numbers in both concentrations. In particular, the concentration of 109L. reuteri B1/1 allowed to modulate the gene expression of pro-inflammatory cytokines, as well as to increase the metabolic activity of the cells. In addition, administration of L. reuteri B1/1 in both concentrations significantly stimulated gene expression for both proteins in the CLAB cell line after 4 h of incubation.

Early-stage business model experimentation and pivoting

Recent literature suggests entrepreneurs struggle to pivot—or fundamentally change aspects of their venture—due to identity-based resistance to change. Yet, when entrepreneurs receive negative feedback, overcoming this resistance may be important to pivoting their business model. We adopt a convergent, mixed methods research design to explore when and why some entrepreneurs overcome resistance to change in response to negative feedback during early-stage business model experimentation. Building upon qualitative data that we gathered and analyzed, we theorize entrepreneurs may resist pivoting their value proposition relative to other business model components despite receiving negative feedback on this aspect of their business model. However, we find three factors – entrepreneurial experience, startup mentoring, and team size – may enable entrepreneurs to pivot in response to negative feedback. We theorize that these factors broaden a startup team's perspective, enabling value proposition pivoting during early-stage business model experimentation. We test these relationships with quantitative data from 80 startups engaged in business model experimentation and find support across hypotheses. We contribute to understanding when and why entrepreneurs pivot aspects of their business models in response to negative feedback during early-stage business model experimentation. Executive summaryThe entrepreneurship literature suggests startups may benefit from experimentation and pivoting different parts of their business model in response to negative feedback from stakeholders (Andries et al., 2021; Camuffo et al., 2020; Shepherd and Gruber, 2021). In early stages of starting a new venture, a business model refers to a cognitive schema or belief about an activity system that could potentially create and capture value (Massa et al., 2017; Shepherd and Gruber, 2021). Business model experimentation is the process of testing assumptions underlying this potential business model and pivoting business model assumptions in response to negative feedback (Andries et al., 2013; McDonald and Eisenhardt, 2020; Leatherbee and Katila, 2020). Building upon prior literature, we define business model pivoting as a fundamental change to parts of the business model (Berends et al., 2021; Snihur and Clarysse, 2022; Shepherd and Gruber, 2021). Yet, literature also suggests founders often struggle to pivot assumptions despite negative feedback. Motives to preserve and protect certain assumptions relevant to founders' identities can interfere with pivoting (Grimes, 2018; Kirtley and O'Mahony, 2023; Zuzul and Tripsas, 2020). Despite the general understanding that founders struggle to change their ideas, however, the entrepreneurship literature currently lacks precise insight into when and why founders can overcome resistance to pivoting.In this research, we explore when and why startups pivot different parts of their business model. We do so within the context of early-stage business model experimentation, where founders explicitly state assumptions about different parts of their potential business model, test those assumptions against stakeholder feedback, and are encouraged to pivot business model components in response to negative feedback. Through a mixed methods research design, we find (1) founders tend to resist pivoting their value propositions relative to other parts of a business model in response to negative feedback; and (2) entrepreneurial experience, startup mentoring, and team size enables startups to overcome this resistance to pivoting in response to negative feedback. We theorize these factors broaden founders' perspectives (Warshay, 1962), contributing to a greater willingness to pivot during experimentation.We contribute to the literature on entrepreneurial pivoting by explaining nuanced variation in pivoting distinct business model components during experimentation. This contribution is important because it reveals that resistance to pivoting the business model may be more complex than previously thought. We also contribute to the literature at the nexus of business model experimentation and entrepreneurial cognition by finding that entrepreneurial experience, startup mentoring, and team size enable startups to pivot despite psychological resistance to pivoting in response to negative feedback because it broadens founders' perspectives. This insight is important theoretically because it advances what we know about enabling experimenting with business models under conditions of uncertainty. The research presented here has clear and important implications for practice. This research suggests founders often resist changing the value proposition versus other components of their business models in early stages of venture development. This resistance can impede experimentation and pivoting in response to negative feedback. To the extent founders want to broaden their perspective to enable pivoting their value propositions in response to negative feedback during early stages of venture development, our data suggest they may be able to do so by recruiting members with entrepreneurial experience on their team (or gain entrepreneurial experience themselves), engage frequently with startup mentors, and increase the size of their team. Overall, we view the breath of perspective that comes from experience and interactions with others as an advantage for entrepreneurs when experimenting with their business models during early stages of venture development.

The RNA editor ADAR2 promotes immune cell trafficking by enhancing endothelial responses to interleukin-6 during sterile inflammation

Immune cell trafficking constitutes a fundamental component of immunological response to tissue injury, but the contribution of intrinsic RNA nucleotide modifications to this response remains elusive. We report that RNA editor ADAR2 exerts a tissue- and stress-specific regulation of endothelial responses to interleukin-6 (IL-6), which tightly controls leukocyte trafficking in IL-6-inflamed and ischemic tissues. Genetic ablation of ADAR2 from vascular endothelial cells diminished myeloid cell rolling and adhesion on vascular walls and reduced immune cell infiltration within ischemic tissues. ADAR2 was required in the endothelium for the expression of the IL-6 receptor subunit, IL-6 signal transducer (IL6ST; gp130), and subsequently, for IL-6 trans-signaling responses. ADAR2-induced adenosine-to-inosine RNA editing suppressed the Drosha-dependent primary microRNA processing, thereby overwriting the default endothelial transcriptional program to safeguard gp130 expression. This work demonstrates a role for ADAR2 epitranscriptional activity as a checkpoint in IL-6 trans-signaling and immune cell trafficking to sites of tissue injury.

The impact of COVID-19 vaccination in the US: Averted burden of SARS-COV-2-related cases, hospitalizations and deaths.

By August 1, 2022, the SARS-CoV-2 virus had caused over 90 million cases of COVID-19 and one million deaths in the United States. Since December 2020, SARS-CoV-2 vaccines have been a key component of US pandemic response; however, the impacts of vaccination are not easily quantified. Here, we use a dynamic county-scale metapopulation model to estimate the number of cases, hospitalizations, and deaths averted due to vaccination during the first six months of vaccine availability. We estimate that COVID-19 vaccination was associated with over 8 million fewer confirmed cases, over 120 thousand fewer deaths, and 700 thousand fewer hospitalizations during the first six months of the campaign.