bluuebunny/crossref_metadata_2025 huggingface dataset:
Redefinition of Successful Treatment of Patients With Hypothyroidism. Is TSH the Best Biomarker of Euthyroidism?
Authors: Fitzgerald Stephen P. , Falhammar Henrik
Published: June 2022

In recent years evidence has accumulated supporting a revised view of the nature of euthyroidism and the biomarkers of thyroid function. Within the normal range, variations in thyroid hormone levels are associated with variations in clinical parameters and outcomes. There are therefore no readily identified individually specific optimum levels of thyroid hormones for any individual. Levels around the middle of the normal population range may best reflect euthyroidism. These levels may have evolutionary advantages on the basis that adverse outcomes often increase with divergence from such levels, and physiological processes tend to minimise such inter-individual and intra-individual divergence. In populations of predominantly untreated individuals, levels of thyroid hormones and in particular levels of free thyroxine (FT4) correlate more often with clinical parameters than do levels of thyrotropin (TSH). Levels of thyroid hormones may therefore be regarded as the best available biomarkers of euthyroidism and dysthyroidism. It follows that ‘subclinical hypothyroidism’ (normal FT4/raised TSH levels), rather than being an accurate marker of peripheral tissue hypothyroidism is more a marker of decreased thyroid reserve and prognosis. The recent evidence suggests that treatment of hypothyroxinemia, regardless of the TSH level, and monitoring therapy using FT4 and/or triiodothyronine levels, depending on the replacement regime, may result in more successful treatment of hypothyroidism than relying on thyrotropin levels for patient selection and subsequent treatment monitoring. The equivalents of mid-range levels of thyroid hormones (especially FT4), adjusted by individual comorbidity concerns, may be rational general replacement targets. These implications of the new evidence may create opportunities for novel trials of thyroid replacement therapy.
Assessing Ecological Recovery of Reclaimed Well Sites: A Case Study From Alberta, Canada
Authors: Baah-Acheamfour Mark , Dewey Mark , Fraser Erin C. , Schreiber Stefan G. , Schoonmaker Amanda
Published: June 2022

Empirical evaluations of reclamation success are critical for understanding the speed of ecosystem recovery and improving best practices. In this study, we provide a quantitative evaluation of the effectiveness of past (pre-1995) and current (2010) reclamation criteria in creating functioning forest ecosystems on former industrial sites in boreal Alberta, Canada. We compared ecological indicators of ecosystem recovery (vegetation structure and soil properties) on mineral surface leases (MSLs) certified to the pre-1995 or 2010 reclamation criteria with nearby reference areas recovering from harvest (CUT) or fire (FIRE) disturbances. Six CUT and FIRE sites were chosen to compare six 1995MSLs and five 2010MSLs. Averaging 8 years since reclamation, most of the 2010MSLs were characterized by many of the same vegetation structure and soil properties as the FIRE and CUT sites. The 1995MSLs tended to support more agronomic species, notably grasses and non-native forbs, and fewer shrubs, trees, and native forbs than CUT or FIRE sites. Sites with the greatest coverage of herbaceous species (native and non-native grasses as well as non-native forbs) were the most ecologically impaired sites, based on the extreme deviation from reference site conditions. Based on these results, 2010 reclamation criteria appear to be more effectively promoting ecosystem recovery on reclaimed industrial sites than the pre-1995 criteria. While this case study illustrated the potential benefits of straightforward changes to reclamation criteria in terms of including metrics around soil quality and conservation, woody stem requirements and native plant coverage, there is ultimately always room for improvement. For jurisdictions where the objective of the criteria is to restore a forest ecosystem, including criteria geared toward tree establishment would likely be of value in ensuring the speedy return to a forest canopy state. Adding criteria with measures of native plant species diversity may also be of utility as it is well understood that having plant diversity is also a beneficial metric in creating a more resilient vegetation community.
Competition and Cooperation of Autonomous Ridepooling Services: Game-Based Simulation of a Broker Concept
Authors: Engelhardt Roman , Malcolm Patrick , Dandl Florian , Bogenberger Klaus
Published: June 2022

With advances in digitization and automation, autonomous mobility on demand services have the potential to disrupt the future mobility system landscape. Ridepooling services in particular can both decrease land consumption by reducing the need for parking and increase transportation efficiency by increasing the average vehicle occupancy. Nevertheless, because ridepooling services require a sufficient user base for pooling to take effect, their performance can suffer if multiple operators offer such a service and must split the demand. This study presents a simulation framework for evaluating the impact of competition and cooperation among multiple ridepooling providers. Two different kinds of interaction via a broker platform are compared with the base cases of a single monopolistic operator and two independent operators with divided demand. In the first, the broker presents trip offers from all operators to customers (similar to a mobility-as-a-service platform), who can then freely choose an operator. In the second, a regulated broker platform can manipulate operator offers with the goal of shifting the customer-operator assignment from a user equilibrium towards a system optimum. To model adoptions of the service design depending on the different interaction scenario, a game setting is introduced. Within alternating turns between operators, operators can adapt parameters of their service (fleet size and objective function) to maximize profit. Results for a case study based on Manhattan taxi data, show that operators generate the highest profit in the broker setting while operating the largest fleet. Additionally, pooling efficiency can nearly be maintained compared to a single operator. The regulated competition benefits not only operators (profit) and cities (increased pooling efficiency), but customers also experience higher service rate, though they need to accept slightly increased waiting and travel time due to increased pooling efficiency. Contrarily, when users can decide freely, the lowest pooling efficiency and operator profit is observed.
Systematic Analysis of NB-ARC Gene Family in Rice and Functional Characterization of GNP12
Authors: Pan Ying-Hua , Chen Lei , Guo Hai-Feng , Feng Rui , Lou Qi-Jin , Rashid Muhammad Abdul Rehman , Zhu Xiao-Yang , Qing Dong-Jin , Liang Hai-Fu , Gao Li-Jun , Huang Cheng-Cui , Zhao Yan , Deng Guo-Fu
Published: June 2022

The NB-ARC (nucleotide-binding adaptor shared by APAF-1, R proteins, and CED-4) gene family plays a critical role in plant development. However, our understanding of the mechanisms of how NB-ARC genes regulate plant development in the plant panicle is still limited. Here, we subjected 258 NB-ARC genes in rice to genome-wide analysis to characterize their structure, function, and expression patterns. The NB-ARC genes were classified into three major groups, and group II included nine subgroups. Evolutionary analysis of NB-ARC genes in a dicotyledon plant (Arabidopsis thaliana) and two monocotyledonous plants (Oryza sativaL. andTriticum aestivum) indicated that homologous genome segments were conserved in monocotyledons and subjected to weak positive selective pressure during evolution. Dispersed and proximal replication events were detected. Expression analysis showed expression of most NB-ARC genes in roots, panicles, and leaves, and regulation at the panicle development stage in rice Ce253. TheGNP12gene encodes RGH1A protein, which regulates rice yield according to panicle length, grain number of panicle, and grain length, with eight major haplotypes. Most members of NB-ARC protein family are predicted to contain P-loop conserved domains and localize on the membrane. The results of this study will provide insight into the characteristics and evolution of NB-ARC family and suggest thatGNP12positively regulates panicle development.
Potential Targets for CRISPR/Cas Knockdowns to Enhance Genetic Resistance Against Some Diseases in Wheat (Triticum aestivum L.)
Authors: Taj Mehwish , Sajjad Muhammad , Li Mingju , Yasmeen Arooj , Mubarik Muhammad Salman , Kaniganti Sirisha , He Chi
Published: June 2022

Wheat is one of the most important food crops worldwide. Even though wheat yields have increased considerably in recent years, future wheat production is predicted to face enormous challenges due to global climate change and new versions of diseases. CRISPR/Cas technology is a clean gene technology and can be efficiently used to target genes prone to biotic stress in wheat genome. Herein, the published research papers reporting the genetic factors corresponding to stripe rust, leaf rust, stem rust, powdery mildew, fusarium head blight and some insect pests were critically reviewed to identify negative genetic factors (Susceptible genes) in bread wheat. Out of all reported genetic factors related to these disease, 33 genetic factors (S genes) were found as negative regulators implying that their down-regulation, deletion or silencing improved disease tolerance/resistance. The results of the published studies provided the concept of proof that these 33 genetic factors are potential targets for CRISPR/Cas knockdowns to improve genetic tolerance/resistance against these diseases in wheat. The sequences of the 33 genes were retrieved and re-mapped on the latest wheat reference genome IWGSC RefSeq v2.1. Phylogenetic analysis revealed that pathogens causing the same type of disease had some common conserved motifs and were closely related. Considering the significance of these disease on wheat yield, the S genes identified in this study are suggested to be disrupted using CRISPR/Cas system in wheat. The knockdown mutants of these S genes will add to genetic resources for improving biotic stress resistance in wheat crop.
Beta-Hydroxybutyrate: A Dual Function Molecular and Immunological Barrier Function Regulator
Authors: Qi Jiancheng , Gan Linli , Fang Jing , Zhang Jizong , Yu Xin , Guo Hongrui , Cai Dongjie , Cui Hengmin , Gou Liping , Deng Junliang , Wang Zhisheng , Zuo Zhicai
Published: June 2022

Ketone bodies are crucial intermediate metabolites widely associated with treating metabolic diseases. Accumulating evidence suggests that ketone bodies may act as immunoregulators in humans and animals to attenuate pathological inflammation through multiple strategies. Although the clues are scattered and untrimmed, the elevation of these ketone bodies in the circulation system and tissues induced by ketogenic diets was reported to affect the immunological barriers, an important part of innate immunity. Therefore, beta-hydroxybutyrate, a key ketone body, might also play a vital role in regulating the barrier immune systems. In this review, we retrospected the endogenous ketogenesis in animals and the dual roles of ketone bodies as energy carriers and signal molecules focusing on beta-hydroxybutyrate. In addition, the research regarding the effects of beta-hydroxybutyrate on the function of the immunological barrier, mainly on the microbiota, chemical, and physical barriers of the mucosa, were outlined and discussed. As an inducible endogenous metabolic small molecule, beta-hydroxybutyrate deserves delicate investigations focusing on its immunometabolic efficacy. Comprehending the connection between ketone bodies and the barrier immunological function and its underlining mechanisms may help exploit individualised approaches to treat various mucosa or skin-related diseases.
Development of a Risk Nomogram Model for Identifying Interstitial Lung Disease in Patients With Rheumatoid Arthritis
Authors: Xue Jing , Hu Wenfeng , Wu Shuang , Wang Jing , Chi Shuhong , Liu Xiaoming
Published: June 2022

The clinical features of rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (RA-ILD) usually manifest to an advanced stage of lung disease, which leads the challenge of early diagnosis and the difficulty in guiding treatments for patients with RA-ILD in clinical settings. The aim of this study was to construct a nomogram for identifying ILD in RA patients. Through the incorporation of the level of matrix metalloproteinase-3 (MMP-3) in plasma, demographics, clinical feature, and laboratory parameters of 223 RA patients (85 RA-ILD) which were grouped as training cohorts and validation cohorts, an identifying nomogram of RA-ILD was built. Candidate variables for the nomogram were screened using univariable analysis and multivariable logistic regression analysis. The accuracy of the diagnostic nomogram was measured via concordance index (C-index), calibration plots, and decision curve analysis (DCA). Results showed that plasma MMP-3 protein was elevated in RA-ILD patients compared with non-ILD RA patients in both training cohorts (p = 0.0475) and validation cohorts (p = 0.0006). Following a final regression analysis, the gender of male, current smoking state, levels of circulating rheumatoid factor (RF), C-reactive protein (CRP), and MMP-3 were identified as risk factors for the construction of the nomogram. The calibration plots further showed a favorable consistency between the identifying nomogram and actual clinical findings. In consistence, the C-index (0.826 for both training cohorts and validation cohorts) indicated the satisfactory discriminative ability of the nomogram. Although the incorporation of MMP-3 failed to significantly improve identified outcomes of the nomogram as determined by DCA, including the level of circulating MMP-3 increased the diagnostic accuracy of the nomogram for ILD in RA patients. Thus, our proposed model can serve as a non-invasive tool to identify ILD in RA patients, which may assist physicians to make treatment decisions for RA patients.
Resistin Associated With Cytokines and Endothelial Cell Adhesion Molecules Is Related to Worse Outcome in COVID-19
Authors: Ebihara Takeshi , Matsumoto Hisatake , Matsubara Tsunehiro , Togami Yuki , Nakao Shunichiro , Matsuura Hiroshi , Onishi Shinya , Kojima Takashi , Sugihara Fuminori , Okuzaki Daisuke , Hirata Haruhiko , Yamamura Hitoshi , Ogura Hiroshi
Published: June 2022

Introduction

Resistin is reported to form a cytokine network and cause endothelial damage. The pathogenesis of coronavirus disease 2019 (COVID-19) remains unknown, but the association between cytokine storm and endothelial damage is crucial. This study aimed to evaluate resistin in COVID-19 pathogenesis compared with sepsis.

Materials and Methods

First, we evaluated the association of plasma resistin levels and disease severity and clinical outcome in two large cohorts: a publicly available cohort including 306 COVID-19 patients in the United States (MGH cohort) and our original cohort including only intubated 113 patients in Japan (Osaka cohort 1). Second, to understand pathogenesis, we evaluate resistin, cytokines and endothelial cell adhesion molecules in COVID-19 compared with sepsis. Blood samples were collected from 62 ICU-treated COVID-19 patients and 38 sepsis patients on day 1 (day of ICU admission), days 2-3, days 6-8, and from 18 healthy controls (Osaka cohort 2). The plasma resistin, inflammatory cytokines (IL-6, IL-8, MCP-1 and IL-10) and endothelial cell adhesion molecules (ICAM-1 and VCAM-1) were compared between patients and control. Correlations among resistin, inflammatory cytokines and endothelial cell adhesion molecules were evaluated in COVID-19 and sepsis.

Results

In the MGH cohort, the day 1 resistin levels were associated with disease severity score. The non-survivors showed significantly greater resistin levels than survivors on days 1, 4 and 8. In the Osaka cohort 1, 28-day non-survivors showed significantly higher resistin levels than 28-day survivors on days 6-8. Patients with late recovery (defined as the day of weaning off mechanical ventilation >12 or death) had significantly higher resistin levels than those with early recovery on day 1 and days 6-8. In the Osaka cohort 2, plasma resistin levels were elevated in COVID-19 and sepsis patients compared to controls at all measurement points and were associated with inflammatory cytokines and endothelial cell adhesion molecules.

Conclusion

Resistin was elevated in COVID-19 patients and was associated with cytokines and endothelial cell adhesion molecules. Higher resistin levels were related to worse outcome.
ILC2s and Adipose Tissue Homeostasis: Progress to Date and the Road Ahead
Authors: Misawa Takuma , Wagner Marek , Koyasu Shigeo
Published: June 2022

Group 2 innate lymphoid cells (ILC2s) were initially identified as a new type of lymphocytes that produce vigorous amounts of type 2 cytokines in adipose tissue. Subsequent studies revealed that ILC2s are present not only in adipose tissue but also in various other tissues such as lung and skin. ILC2s are generally recognized as tissue-resident immune cells that regulate tissue homeostasis. ILC2s express receptors for various humoral factors and thus can change their functions or distribution depending on the environment and circumstances. In this review, we will outline our recent understanding of ILC2 biology and discuss future directions for ILC2 research, particularly in adipose tissue and metabolic homeostasis.
Molecular and Functional Analyses of the Primordial Costimulatory Molecule CD80/86 and Its Receptors CD28 and CD152 (CTLA-4) in a Teleost Fish
Authors: Lu Tao-Zhen , Liu Xun , Wu Chang-Song , Ma Zi-You , Wang Yang , Zhang Yong-An , Zhang Xu-Jie
Published: June 2022

The moderate activation of T cells in mammals requires the costimulatory molecules, CD80 and CD86, on antigen-presenting cells to interact with their respective T cell receptors, CD28 and CD152 (CTLA-4), to promote costimulatory signals. In contrast, teleost fish (except salmonids) only possess CD80/86 as their sole primordial costimulatory molecule. However, the mechanism, which underlies the interaction between CD80/86 and its receptors CD28 and CD152 still requires elucidation. In this study, we cloned and identified the CD80/86, CD28, and CD152 genes of the grass carp (Ctenopharyngodon idella). The mRNA expression analysis showed that CD80/86, CD28, and CD152 were constitutively expressed in various tissues. Further analysis revealed that CD80/86 was highly expressed in IgM+ B cells. Conversely, CD28 and CD152 were highly expressed in CD4+ and CD8+ T cells. Subcellular localization illustrated that CD80/86, CD28, and CD152 are all located on the cell membrane. A yeast two-hybrid assay exhibited that CD80/86 can bind with both CD28 and CD152. In vivo assay showed that the expression of CD80/86 was rapidly upregulated in Aeromonas hydrophila infected fish compared to the control fish. However, the expression of CD28 and CD152 presented the inverse trend, suggesting that teleost fish may regulate T cell activation through the differential expression of CD28 and CD152. Importantly, we discovered that T cells were more likely to be activated by A. hydrophila after CD152 was blocked by anti-CD152 antibodies. This suggests that the teleost CD152 is an inhibitory receptor of T cell activation, which is similar to the mammalian CD152. Overall, this study begins to define the interaction feature between primordial CD80/86 and its receptors CD28 and CD152 in teleost fish, alongside providing a cross-species understanding of the evolution of the costimulatory signals throughout vertebrates.
Case Report: ITP Treatment After CAR-T Cell Therapy in Patients With Multiple Myeloma
Authors: Du Mengyi , Huang Linlin , Kou Haiming , Li Chenggong , Hu Yu , Mei Heng
Published: June 2022

Chimeric antigen receptor T (CAR-T) cell therapy is an attractive strategy for patients with relapsed or refractory hematological malignancies including multiple myeloma (MM). T cells are engineered to attack malignant cells that express tumor-associated antigens and better efficacy could be achieved. However, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematologic toxicity are still challenges for CAR-T cell therapy. Among them, hematologic toxicity including thrombocytopenia has a longer duration and lasting effect during and after the treatment for some patients. Here, we present 3 cases of hematologic toxicity manifested as refractory thrombocytopenia with platelet autoantibodies positive and plasma thrombopoietin (TPO) concentration elevated after bispecific CAR-T cell therapy in relapsed/refractory (R/R) MM patients who were successfully treated with standard therapy of immune thrombocytopenia (ITP). Without clear pathogenesis or guidance on therapy published, our cases provide a reference for the treatment of thrombocytopenia after CAR-T cell therapy and inspire exploration of the underlying pathophysiological mechanisms.
Helios Expression Is Downregulated on CD8+ Treg in Two Mouse Models of Lupus During Disease Progression
Authors: París-Muñoz Andrés , Aizpurua Gonzalo , Barber Domingo F.
Published: June 2022

T-cell–mediated autoimmunity reflects an imbalance in this compartment that is not restored by tolerogenic immune cells, e.g., regulatory T cells or tolerogenic dendritic cells (tolDCs). Although studies into T-cell equilibrium have mainly focused on regulatory CD4+FoxP3+ T cells (CD4+ Tregs), recent findings on the lesser known CD8+ Tregs (CD44+CD122+Ly49+) have highlighted their non-redundant role in regulating lupus-like disease and their regulatory phenotype facilitated by the transcription factor Helios in mice and humans. However, there are still remaining questions about Helios regulation and dynamics in different autoimmune contexts. Here, we show the absence of CD8+ Tregs in two lupus-prone murine models: MRL/MPJ and MRL/lpr, in comparison with a non-prone mouse strain like C57BL/6. We observed that all MRL animals showed a dramatically reduced population of CD8+ Tregs and a greater Helios downregulation on diseased mice. Helios induction was detected preferentially on CD8+ T cells from OT-I mice co-cultured with tolDCs from C57BL/6 but not in MRL animals. Furthermore, the Helios profile was also altered in other relevant T-cell populations implicated in lupus, such as CD4+ Tregs, conventional CD4+, and double-negative T cells. Together, these findings could make Helios a versatile maker across the T-cell repertoire that is capable of differentiating lupus disease states.
A Cycle of Wind-Driven Canyon Upwelling and Downwelling at Wilmington Canyon and the Evolution of Canyon-Upwelled Dense Water on the MAB Shelf
Authors: Wang Haixing , Gong Donglai , Friedrichs Marjorie A. M. , Harris Courtney K. , Miles Travis , Yu Hao-Cheng , Zhang Yinglong
Published: June 2022

Submarine canyons provide a conduit for shelf-slope exchange via topographically induced processes such as upwelling and downwelling. These processes in the Wilmington Canyon, located along the shelf-break of the Mid-Atlantic Bight (MAB), have not been previously studied, and the associated hydrographic variability inside the canyon and on the adjacent shelf are largely unknown. Observations from an underwater glider deployed in Wilmington Canyon (February 27 - March 8, 2016), along with wind and satellite altimetry data, showed evidence for a wind-driven canyon upwelling event followed by a subsequent downwelling event. Next, a numerical model of the MAB was developed to more fully represent these two events. Modeled results showed that under upwelling-favorable winds during February 25 - March 3, sea level increased seaward, shelf currents flowed northeastward, and canyon upwelling developed. Then under downwelling-favorable winds during March 4-7, sea level increased landward, shelf currents flowed southwestward, and canyon downwelling developed. Modeling experiments showed that canyon upwelling and downwelling were sub-tidal processes driven by winds and pressure gradients (associated with SSH gradients), and they would occur with or without tidal forcing. During the upwelling period, slope water originating from 150-215 m depths within the canyon (75 m below the canyon rim), was advected onto the shelf, forming a cold and dense canyon-upwelled slope-originated overflow water at the bottom of the outer shelf (75-150 m isobaths). The dense overflow current flowed was directed northeastward and expanded in the cross-shelf direction. It was 5-20 km wide and 10-30 m thick. The estimated volume of the plume overflow water exceeded 6×109 m3 at peak. The density front at the shoreward side of the dense overflow water caused a subsurface baroclinic frontal jet, which flowed northeastward and along-shelf with maximum speed exceeding 0.5 m/s. In the ensuing downwelling event, a portion of the previously upwelled dense water was advected back to the canyon, and then flowed down-slope in the upper canyon in ~0.3 m/s bottom-intensified currents. Dynamical investigation of the overflow current showed that its evolution was governed by unbalanced horizontal pressure gradient force in the cross-shelf direction and that the current was geostrophic.
A Novel Overall Survival Prediction Signature Based on Comprehensive Research in Prostate Cancer Bone Metastases
Authors: Hu Konghe , Hu Xinyue , Duan Yang , Li Wenqiang , Qian Jing , Chen Junjie
Published: June 2022

Background

Prostate adenocarcinoma (PRAD)-related bone metastases are a leading source of morbidity and mortality; however, good diagnostic biomarkers are not known yet. The aim of this study was to identify biomarkers and prognostic indicators for the diagnosis and treatment of PRAD-associated bone metastases.

Methods

By combining the data from The Cancer Genome Atlas(TCGA) and PRAD SU2C 2019, We performed a comprehensive analysis of the expression differences, biological functions, and interactions of genes associated with PRAD bone metastasis. Annotation, visualization, and integrated discovery were accomplished through the use of gene ontology enrichment and gene set enrichment analysis. The protein-protein interaction network was constructed using the STRING database, and the diagnostic value of prognostic genes was validated using receiver-operating-characteristic and Kaplan-Meier curves.

Results

Six genes (DDX47, PRL17, AS3MT, KLRK1, ISLR, and S100A8) associated with PRAD bone metastases were identified; these had prognostic value as well. Among them, enrichment was observed for the biological processes extracellular matrix tissue, extracellular structural tissue, steroid hormone response, and cell oxidative detoxification. KEGG analysis revealed enrichment in interactions with extracellular matrix receptors, diseases including Parkinson's disease and dilated cardiomyopathy, and estrogen signaling pathways. The area under the curve values of 0.8938, 0.9885, and 0.979, obtained from time-dependent receiver-operating-characteristic curve analysis for 1, 3, and 5-year overall survival confirmed the good performance of the model under consideration. S100A8 expression was not detected in the normal prostate tissue but was detected in PRAD.

Conclusions

We identified ISLR as a potential biomarker for PRAD bone metastasis. Moreover, the genes identified to have prognostic value may act as therapeutic targets for PRAD bone metastasis.
Scoring Assessments in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
Authors: Dobry Allison S. , Himed Sonia , Waters Margo , Kaffenberger Benjamin H.
Published: June 2022

Epidermal necrolysis, the unifying term for Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), is a severe cutaneous drug reaction associated with high morbidity and mortality. Given the rarity of this disease, large-scale prospective research studies are limited. Significant institutional and geographical variations in treatment practices highlight the need for standardization of clinical assessment scores and prioritization of research outcome measures in epidermal necrolysis. At the present, clinical assessment is typically simplified to total body surface area (BSA) involvement, with little focus on morphology. Validated clinical scoring systems are used as mortality prognostication tools, with SCORTEN being the best-validated tool thus far, although the ABCD-10 has also been recently introduced. These tools are imperfect in that they tend to either overestimate or underestimate mortality in certain populations and are not designed to monitor disease progression. Although mortality is often used as a primary endpoint for epidermal necrolysis studies, this outcome fails to capture more nuanced changes in skin disease such as arrest of disease progression while also lacking a validated skin-directed inclusion criterion to stratify patients based on the severity of skin disease at study entry. In addition to mortality, many studies also use BSA stabilization or time to re-epithelialization as endpoints, although these are not clearly defined morphologically, and inter- and intra-rater reliability are unclear. More specific, validated cutaneous assessment scores are necessary in order advance therapeutic options for epidermal necrolysis. In this review, we summarize the strengths and weaknesses of current clinical assessment practices in epidermal necrolysis and highlight the need for standardized research tools to monitor cutaneous involvement throughout the hospitalization.
Does Dysmenorrhea Affect Clinical Features and Long-Term Surgical Outcomes of Patients With Ovarian Endometriosis? A 12-Year Retrospective Observational Cohort Study
Authors: Wu Yushi , Li Xiaoyan , Dai Yi , Shi Jinghua , Gu Zhiyue , Zhang Jing , Zhang Chenyu , Yan Hailan , Leng Jinhua
Published: June 2022

Background

To examine and compare the differences in clinical characteristics and long-term postoperative outcomes of ovarian endometriomas (OMA) patients with and without dysmenorrhea, including data from at least 8 years of postoperative follow-up examinations.

Methods

Retrospective analysis of 334 OMA patients, including their demographic and clinical data. Long-term follow-up record was also collected. All laparoscopic cystectomy procedures were performed by the same surgeon at Peking Union Medical College Hospital between January 2009 and April 2013. Patients were divided into the dysmenorrhea and non-dysmenorrhea groups to perform the analysis of their preoperative characteristics, relevant surgical findings, and postoperative outcomes at the follow-up.

Results

Out of 334 OMA patients, 257 (76.9%) patients were allocated to the dysmenorrhea group, while the rest 77 (23.1%) patients were included in the non-dysmenorrhea group. Compared with the dysmenorrhea group, the non-dysmenorrhea group exhibited a reduced proportion of chronic pelvic pain (CPP) (P = 0.003), dyspareunia (P < 0.001), tenesmus (P < 0.001), concurrency of deep infiltrating endometriosis (DIE) (P < 0.001), and adenomyosis (P = 0.032). Preoperative infertility was significantly higher in the dysmenorrhea group (P = 0.001). The mean operating time in the dysmenorrhea vs. the non-dysmenorrhea group was 68.0 vs. 56.0 min (P < 0.001). According to the revised American Fertility Society (rAFS) scoring system, the mean scores of the two groups were 52.1 vs. 44.6 (P = 0.033). During follow-up, the dysmenorrhea group showed a higher rate of disease relapse (P < 0.001). A minimum postoperative follow-up period of 8 years was required to evaluate the pregnancy outcomes. Successful pregnancies were identified in 97/257 (37.7%) cases in the dysmenorrhea group and 36/77(46.8%) cases in the non-dysmenorrhea group (P = 0.157), respectively. Though the dysmenorrhea group had a higher rate of postoperative infertility, differences were not significant between the two groups.

Conclusions

Compared with the dysmenorrhea group, OMA patients without dysmenorrhea exhibited lower proportions of CPP, dyspareunia, tenesmus, lower concurrency of DIE and adenomyosis, shorter mean operating time, lower mean rAFS scores, and lower infertility rates. During the long-term follow-up, a lower recurrence rate was observed in the non-dysmenorrhea group. Regarding fertility outcomes, non-dysmenorrhea patients had a higher likelihood of successful pregnancy after surgery. Postoperative management needs to be evaluated separately according to dysmenorrhea pathology.
Thiol Metabolism and Volatile Metabolome of Clostridioides difficile
Authors: Biwer Peter , Neumann-Schaal Meina , Henke Petra , Jahn Dieter , Schulz Stefan
Published: June 2022

Clostridioides difficile (previously Clostridium difficile) causes life-threatening gut infections. The central metabolism of the bacterium is strongly influencing toxin production and consequently the infection progress. In this context, the composition and potential origin of the volatile metabolome was investigated, showing a large number of sulfur-containing volatile metabolites. Gas chromatography/mass spectrometry (GC/MS)-based headspace analyses of growing C. difficile 630Δerm cultures identified 105 mainly sulfur-containing compounds responsible of the typical C. difficile odor. Major components were identified to be 2-methyl-1-propanol, 2-methyl-1-propanethiol, 2-methyl-1-butanethiol, 4-methyl-1-pentanethiol, and as well as their disulfides. Structurally identified were 64 sulfur containing volatiles. In order to determine their biosynthetic origin, the concentrations of the sulfur-containing amino acids methionine and cysteine were varied in the growth medium. The changes observed in the volatile metabolome profile indicated that cysteine plays an essential role in the formation of the sulfur-containing volatiles. We propose that disulfides are derived from cysteine via formation of cystathionine analogs, which lead to corresponding thiols. These thiols may then be oxidized to disulfides. Moreover, methionine may contribute to the formation of short-chain disulfides through integration of methanethiol into the disulfide biosynthesis. In summary, the causative agents of the typical C. difficile odor were identified and first hypotheses for their biosynthesis were proposed.
Antibiofilm and Antimicrobial Activities of Chloroindoles Against Uropathogenic Escherichia coli
Authors: Boya Bharath Reddy , Lee Jin-Hyung , Lee Jintae
Published: June 2022

Uropathogenic Escherichia coli (UPEC) is a nosocomial pathogen associated with urinary tract infections and expresses several virulence factors that cause recurring infections and cystitis of the bladder, which can lead to pyelonephritis. UPEC uses different types of extracellular appendages like fimbriae and pili that aid colonization and adherence to bladder epithelium and can form persistent biofilm-like bacterial communities that aid its survival after the deployment of host immune responses. We investigated the antibiofilm, antimicrobial, and antivirulence properties of three indole derivatives namely, 4-chloroindole, 5-chloroindole, and 5-chloro 2-methyl indole. All the three chloroindoles had MICs of 75 μg/ml and inhibited biofilm formation by an average of 67% at 20 μg/ml. In addition, they inhibited swarming and swimming motilities, which are essential for dissemination from bacterial communities and colonization, reduced cell surface hydrophobicity, and inhibited indole production and curli formation. Gene expression analysis showed all three chloroindoles significantly downregulated the expressions of virulence genes associated with adhesion, stress regulation, and toxin production. A 3D-QSAR analysis revealed substitutions at the fourth and fifth positions of the indole moiety favored antimicrobial activity. Furthermore, these chloroindoles potently inhibited biofilm formation in other nosocomial pathogens and polymicrobial consortia.
The Gut Microbiome of 54 Mammalian Species
Authors: de Jonge Nadieh , Carlsen Benjamin , Christensen Mikkel Hostrup , Pertoldi Cino , Nielsen Jeppe Lund
Published: June 2022

The gut microbiome plays a critical role in many aspects of host life, and the microbial community composition is heavily influenced by the prevailing conditions in the gut environment. Community composition has been suggested to have large implications for conservation efforts, and gut health has become of interest for optimizing animal care in captivity. In this study, we explore the gut microbiome of a wide range of animals in the context of conservation biology. The composition of the gut microbial community of 54 mammalian animal species was investigated using 16S rRNA gene amplicon sequencing. The composition of the gut microbiota clearly reflects diet and the structure of the gastrointestinal system, and it is to a certain degree more similar between closely related animals. Specific clusters of taxa were observed across animals of the same species, diet, and gut morphology. The microbiota retained regardless of captivity status is hypothesized to cover important symbiotic relationships with the host, while the remaining part reflects the artificial living conditions and can therefore be used as a future tool for conservation biologists. For five animal species (giraffes, horses, baboons, elephants, and zebras), it was possible to compare the microbiota of wild and captive individuals. Differences were observed in the proportion of microbiota detected between wild and captive specimens of the same animal species. We propose that the gut microbiota harbours important species, which can potentially serve as indicators for the well-being of the animal and the effect of living in captivity.
Novel Promising Antifungal Target Proteins for Conquering Invasive Fungal Infections
Authors: Zhen Cheng , Lu Hui , Jiang Yuanying
Published: June 2022

Invasive fungal infections (IFIs) pose a serious clinical problem, but the antifungal arsenal is limited and has many disadvantages, such as drug resistance and toxicity. Hence, there is an urgent need to develop antifungal compounds that target novel target proteins of pathogenic fungi for treating IFIs. This review provides a comprehensive summary of the biological functions of novel promising target proteins for treating IFIs in pathogenic fungi and their inhibitors. Inhibitors of inositol phosphoramide (IPC) synthases (such as Aureobasidin A, Khafrefungin, Galbonolide A, and Pleofungin A) have potent antifungal activities by inhibiting sphingolipid synthesis. Disrupting glycosylphosphatidylinositol (GPI) biosynthesis by Jawsamycin (an inhibitor of Spt14), M720 (an inhibitor of Mcd4), and APX001A (an inhibitor of Gwt1) is a promising strategy for treating IFIs. Turbinmicin is a natural-compound inhibitor of Sec14 and has extraordinary antifungal efficacy, broad-antifungal spectrum, low toxicity, and is a promising new compound for treating IFIs. CMLD013075 targets fungal heat shock protein 90 (Hsp90) and has remarkable antifungal efficacy. Olorofim, as an inhibitor of dihydrolactate dehydrogenase, is a breakthrough drug treatment for IFIs. These novel target proteins and their inhibitors may overcome the limitations of currently available antifungal drugs and improve patient outcomes in the treatment of IFIs.
Network-Based Analysis Reveals Novel Biomarkers in Peripheral Blood of Patients With Preeclampsia
Authors: Lin Jing , Meng Yu , Song Meng-Fan , Gu Wei
Published: June 2022

WGCNA is a potent systems biology approach that explains the connection of gene expression based on a microarray database, which facilitates the discovery of disease therapy targets or potential biomarkers. Preeclampsia is a kind of pregnancy-induced hypertension caused by complex factors. The disease’s pathophysiology, however, remains unknown. The focus of this research is to utilize WGCNA to identify susceptible modules and genes in the peripheral blood of preeclampsia patients. Obtain the whole gene expression data of GSE48424 preeclampsia patients and normal pregnant women from NCBI’s GEO database. WGCNA is used to construct a gene co-expression network by calculating correlation coefficients between modules and phenotypic traits, screening important modules, and filtering central genes. To identify hub genes, we performed functional enrichment analysis, pathway analysis, and protein-protein interaction (PPI) network construction on key genes in critical modules. Then, the genetic data file GSE149437 and clinical peripheral blood samples were used as a validation cohort to determine the diagnostic value of these key genes. Nine gene co-expression modules were constructed through WGCNA analysis. Among them, the blue module is significantly related to preeclampsia and is related to its clinical severity. Thirty genes have been discovered by using the intersection of the genes in the blue module and the DEGs genes as the hub genes. It was found that HDC, MS4A2, and SLC18A2 scored higher in the PPI network and were identified as hub genes. These three genes were also differentially expressed in peripheral blood validation samples. Based on the above three genes, we established the prediction model of peripheral blood markers of preeclampsia and drew the nomogram and calibration curve. The ROC curves were used in the training cohort GSE48424 and the validation cohort GSE149437 to verify the predictive value of the above model. Finally, it was confirmed in the collected clinical peripheral blood samples that MS4A2 was differentially expressed in the peripheral blood of early-onset and late-onset preeclampsia, which is of great significance. This study provides a new biomarker and prediction model for preeclampsia.
PON-All: Amino Acid Substitution Tolerance Predictor for All Organisms
Authors: Yang Yang , Shao Aibin , Vihinen Mauno
Published: June 2022

Genetic variations are investigated in human and many other organisms for many purposes (e.g., to aid in clinical diagnosis). Interpretation of the identified variations can be challenging. Although some dedicated prediction methods have been developed and some tools for human variants can also be used for other organisms, the performance and species range have been limited. We developed a novel variant pathogenicity/tolerance predictor for amino acid substitutions in any organism. The method, PON-All, is a machine learning tool trained on human, animal, and plant variants. Two versions are provided, one with Gene Ontology (GO) annotations and another without these details. GO annotations are not available or are partial for many organisms of interest. The methods provide predictions for three classes: pathogenic, benign, and variants of unknown significance. On the blind test, when using GO annotations, accuracy was 0.913 and MCC 0.827. When GO features were not used, accuracy was 0.856 and MCC 0.712. The performance is the best for human and plant variants and somewhat lower for animal variants because the number of known disease-causing variants in animals is rather small. The method was compared to several other tools and was found to have superior performance. PON-All is freely available at http://structure.bmc.lu.se/PON-All and http://8.133.174.28:8999/.
How Do Pollen Allergens Sensitize?
Authors: Guryanova Svetlana V. , Finkina Ekaterina I. , Melnikova Daria N. , Bogdanov Ivan V. , Bohle Barbara , Ovchinnikova Tatiana V.
Published: June 2022

Plant pollen is one of the main sources of allergens causing allergic diseases such as allergic rhinitis and asthma. Several allergens in plant pollen are panallergens which are also present in other allergen sources. As a result, sensitized individuals may also experience food allergies. The mechanism of sensitization and development of allergic inflammation is a consequence of the interaction of allergens with a large number of molecular factors that often are acting in a complex with other compounds, for example low-molecular-mass ligands, which contribute to the induction a type 2-driven response of immune system. In this review, special attention is paid not only to properties of allergens but also to an important role of their interaction with lipids and other hydrophobic molecules in pollen sensitization. The reactions of epithelial cells lining the nasal and bronchial mucosa and of other immunocompetent cells will also be considered, in particular the mechanisms of the activation of B and T lymphocytes and the formation of allergen-specific antibody responses.
Bridging Glycomics and Genomics: New Uses of Functional Genetics in the Study of Cellular Glycosylation
Authors: Stewart Natalie , Wisnovsky Simon
Published: June 2022

All living cells are coated with a diverse collection of carbohydrate molecules called glycans. Glycans are key regulators of cell behavior and important therapeutic targets for human disease. Unlike proteins, glycans are not directly templated by discrete genes. Instead, they are produced through multi-gene pathways that generate a heterogenous array of glycoprotein and glycolipid antigens on the cell surface. This genetic complexity has sometimes made it challenging to understand how glycosylation is regulated and how it becomes altered in disease. Recent years, however, have seen the emergence of powerful new functional genomics technologies that allow high-throughput characterization of genetically complex cellular phenotypes. In this review, we discuss how these techniques are now being applied to achieve a deeper understanding of glyco-genomic regulation. We highlight specifically how methods like ChIP-seq, RNA-seq, CRISPR genomic screening and scRNA-seq are being used to map the genomic basis for various cell-surface glycosylation states in normal and diseased cell types. We also offer a perspective on how emerging functional genomics technologies are likely to create further opportunities for studying cellular glycobiology in the future. Taken together, we hope this review serves as a primer to recent developments at the glycomics-genomics interface.
GABA System Modifications During Periods of Hormonal Flux Across the Female Lifespan
Authors: Gilfarb Rachel A. , Leuner Benedetta
Published: June 2022

The female lifespan is marked by periods of dramatic hormonal fluctuation. Changes in the ovarian hormones estradiol and progesterone, in addition to the progesterone metabolite allopregnanolone, are among the most significant and have been shown to have widespread effects on the brain. This review summarizes current understanding of alterations that occur within the GABA system during the major hormonal transition periods of puberty, the ovarian cycle, pregnancy and the postpartum period, as well as reproductive aging. The functional impacts of altered inhibitory activity during these times are also discussed. Lastly, avenues for future research are identified, which, if pursued, can broaden understanding of the GABA system in the female brain and potentially lead to better treatments for women experiencing changes in brain function at each of these hormonal transition periods.