bluuebunny/crossref_metadata_2025 huggingface dataset:
Na + -driven pH regulation by Na+/H+ antiporters promotes photosynthetic efficiency in cyanobacteria
Authors: Tsujii Masaru , Kobayashi Ayumu , Kano Ayaka , Kera Kota , Takagi Tomoko , Nagata Noriko , Kojima Seiji , Hikosaka Kouki , Oguchi Riichi , Sonoike Kintake , Azai Chihiro , Inagaki Tomomi , Ishimaru Yasuhiro , Uozumi Nobuyuki
Published: October 2024

Photosynthetic organisms have developed mechanisms to regulate light reactions in response to varying light conditions. Photosynthetic electron transport leads to the formation of a ΔpH across the thylakoid membrane (TM), which is crucial for regulating electron transport. However, other pH modulators remain to be identified, particularly in cyanobacteria. In this study, we evaluated the potential involvement of six Na+/H+ antiporters (NhaS1 to NhaS6) in control of pH in the cyanobacterium Synechocystis sp. PCC 6803. Synechocystis showed a strong requirement for Na+ at high light intensities, with ΔnhaS1 and ΔnhaS2 strains unable to grow under high-light conditions. We analyzed Na+ efflux-driven H + -uptake activities of NhaS1 to NhaS6 in inverted membranes of Escherichia coli. Biological fractionation and immunoelectron microscopy revealed that NhaS1 localizes to both the plasma and TMs, while NhaS2 localizes to the plasma membrane (PM). Measurement of photosynthesis activity indicated that NhaS2 promotes ATP production and electron transport from PQ to P700. Measurements of pH outside of the cells and in the cytoplasm suggested that both NhaS1 and NhaS2 are involved in PM-mediated light-dependent H+ uptake and cytoplasmic acidification. NhaS1 and NhaS2 were also found to prevent photoinhibition under high-light treatment. These results indicate that H+ transport mediated by NhaS1 and NhaS2 plays a role in regulating intracellular pH and maintaining photosynthetic electron transport.
Metabolic strategies in hypoxic plants
Authors: van Veen Hans , Triozzi Paolo Maria , Loreti Elena
Published: October 2024

Complex multicellular organisms have evolved in an oxygen-enriched atmosphere. Oxygen is therefore essential for all aerobic organisms, including plants, for energy production through cellular respiration. However, plants can experience hypoxia following extreme flooding events and also under aerated conditions in proliferative organs or tissues characterized by high oxygen consumption. When oxygen availability is compromised, plants adopt different strategies to cope with hypoxia and limited aeration. A common feature among different plant species is the activation of an anaerobic fermentative metabolism to provide ATP to maintain cellular homeostasis under hypoxia. Fermentation also requires many sugar substrates, which is not always feasible, and alternative metabolic strategies are thus needed. Recent findings have also shown that the hypoxic metabolism is also active in specific organs or tissues of the plant under aerated conditions. Here, we describe the regulatory mechanisms that control the metabolic strategies of plants and how they enable them to thrive despite challenging conditions. A comprehensive mechanistic understanding of the genetic and physiological components underlying hypoxic metabolism should help to provide opportunities to improve plant resilience under the current climate change scenario.
The transcription factor TaFDL2-1A functions in auxin metabolism mediated by abscisic acid to regulate shoot growth in wheat
Authors: Wang Bingxin , Zhou Ling , Li Liqun , Pang Daqin , Lei Yanhong , Qi Haodong , Chen Birong , Guo Meirui , Zeng Qinghong , Xie Yanzhou , Li Xuejun
Published: October 2024

Genetic strategies can be effective in improving wheat (Triticum aestivum L.) drought stress tolerance, but accumulating evidence suggests that overexpressing drought-resistance genes, especially genes related to the abscisic acid (ABA) signaling pathway, can retard plant growth. We previously characterized the positive roles of the wheat bZIP transcription factor TaFD-Like2-1A (TaFDL2-1A) in drought stress tolerance and ABA biosynthesis and response, whereas a dwarfing shoot exhibited under normal conditions. This study determined the underlying mechanisms that allow TaFDL2-1A to affect shoot growth. Overexpressing TaFDL2-1A decreased cell length, cell width, leaf size, shoot length, and biomass in wheat. The results of RNA-seq showed that multiple differently expressed transcripts are enriched in the auxin signaling pathway. Further analysis indicated higher expression levels of Gretchen Hagen3 (GH3) genes and lower indole-3-acetic acid (IAA) concentrations in the TaFDL2-1A overexpression lines. Exogenous IAA treatment restored the phenotypes of the TaFDL2-1A overexpression lines to wild-type levels. Transcriptional regulation analysis suggested that TaFDL2-1A enhances the expression of auxin metabolism genes, such as TaGH3.2-3A, TaGH3.2-3B, TaGH3.8-2A, and TaGH3.8-2D, by directly binding to ACGT core cis-elements. Furthermore, tafdl2 knockout plants had lower expression levels of these GH3 genes and higher IAA levels than Fielder wheat. These GH3 gene expression and IAA levels were induced and reduced in Fielder wheat and tafdl2 knockout plants treated with exogenous ABA. Our findings elucidate mechanisms underlying the functional redundancy of TaFDL2-1A in the crosstalk between ABA and IAA to affect shoot growth and provide insights into the balance between drought resistance and yield in wheat.
Determination of DNA content as quality control in decellularized tissues: challenges and pitfalls
Authors: Philips Charlot , Terrie Lisanne , Muylle Ewout , Thorrez Lieven
Published: October 2024

Decellularized organs and tissues are emerging within the field of regenerative medicine to meet the growing demand for organ and tissue transplantation. Quality control of these acellular matrices prior to transplantation is of paramount importance to ensure the absence of an adverse reaction. In particular, thorough evaluation of the DNA content is essential but also poses technical challenges. Therefore, in this study, we compared different methods for quantitative and qualitative evaluation of DNA content in native and decellularized skeletal muscle tissue to identify strengths and weaknesses for each. Histological analysis revealed that Feulgen staining is more sensitive and robust than the commonly used hematoxylin–eosin and 4′,6-diamidino-2-phenylindole staining for detection of remaining nuclear material. Furthermore, gel electrophoresis allowed to identify the quality and length of remaining DNA fragments. The results of the quantitative analysis indicated that direct measurement of DNA content in tissue lysates is preferred over silica-based extraction methods, since the latter resulted in the loss of small DNA fragments during extraction. Moreover, a weight loss correction factor should be implemented to take into account the impact of the decellularization on the extracellular matrix. With regard to the detection method, the results revealed that a fluorescence-based approach is more accurate than the use of UV/VIS absorbance. Through combination of the proposed methods, it should be possible to achieve a more standardized evaluation of novel acellular matrices in terms of DNA content and to enhance the predictability of clinical success.
Injectable drug-loaded thermosensitive hydrogel delivery system for protecting retina ganglion cells in traumatic optic neuropathy
Authors: Wang Lei , Jiang Yan , Yao Yili , Deng Yudan , Liu Zhiqiang , Ding Jiangtao , Wang Wenwen , Chen Hao , Nan Kaihui , Li Lingli
Published: October 2024

Currently, generalized therapy for traumatic optic neuropathy (TON) is lacking. Various strategies have been developed to protect and regenerate retinal ganglion cells (RGCs) after TON. Intravitreal injection of supplements has been approved as a promising approach, although serious concerns, such as low delivery efficacy and pain due to frequent injections, remain. In this study, we tested an injectable thermosensitive hydrogel drug delivery system engineered to deliver ciliary neurotrophic factor (CNTF) and triamcinolone acetonide (TA). The results of rheological studies showed that the prepared drug-loaded hydrogel possessed a suitable mechanical modulus of ∼300 Pa, consistent with that of vitreum. The hydrogel exhibited thermosensitive with sustained drug release performance. In vitro co-culture of the CNTF-loaded hydrogel system with primary RGCs also induced significant axon regeneration, with 38.5% increase in neurite length, indicating the regenerative response of the thermosensitive hydrogel drug delivery system. A Sprague-Dawley rat optic nerve crush model was constructed and applied to determine the neuroprotective and regenerative capacities of the system. The results demonstrated that a single intravitreal injection of the drug-loaded hydrogel (PLGA-PEG-PLGA + TA or PLGA-PEG-PLGA + CNTF) significantly increased RGC survival at both 14 and 28 days. The RGC survival rate was 31.05 ± 1.41% for the drug-loaded hydrogel system (the control group was 16.79 ± 1.50%) at Day 28. These findings suggest that the injectable drug-loaded thermosensitive hydrogel delivery system is a promising therapeutic tool for treating optic nerve degeneration.
Impact of baseline proteinuria level on long-term outcomes in lupus nephritis
Authors: Kharouf Fadi , Li Qixuan , Whittall Garcia Laura P , Gladman Dafna D , Touma Zahi
Published: October 2024

Objectives

Proteinuria is a marker of lupus nephritis (LN) activity and damage. We aimed to explore the impact of baseline proteinuria level on long-term outcomes.

Methods

We included 249 patients diagnosed with their first biopsy-proven LN. We divided patients based on baseline proteinuria into low-level (≤1 g/day, group 1; 62 patients), moderate-level (>1 and <3 g/day, group 2; 90 patients) and high-level proteinuria (≥3 g/day, group 3; 97 patients). Outcomes included complete proteinuria recovery (CPR) at 1 year, an adverse composite outcome (ESKD, a sustained ≥40% decline in eGFR, or death) and LN flares. Cox proportional hazard models were used to examine the association between baseline characteristics and long-term outcomes.

Results

At baseline, the median [IQR] age was 33.2 [26.4, 42.4] years; median proteinuria level was 2.2 [1.0, 3.8] g/day. A total of 177 (71%) patients had proliferative lesions on biopsy; 59.7% in group 1, 78.9% in group 2 and 71.4% in group 3. The rate of achievement of CPR at 1 year was highest for group 1 and lowest for group 3. For long-term outcomes (median follow-up 8.4 years), the frequency of the adverse composite outcome was 27.4%, 26.7% and 48.5% in groups 1, 2 and 3, respectively; P = 0.003. The corresponding frequency of flares was 27.4%, 38.2% and 61.9%, respectively; P < 0.001. In the multivariable model for factors associated with long-term outcomes, there was no significant difference between groups 1 and 2; group 3 was associated with the worst prognosis.

Conclusions

Low-level proteinuria is commonly associated with proliferative LN and adverse long-term outcomes.
Age-inclusive leadership and intrinsic work motivation: the moderating role of the leader–member age difference
Authors: De Boom Laura , De Meulenaere Kim
Published: October 2024

As workforces become more age-diverse, organizations and their leaders encounter the challenge of nurturing intrinsic work motivation across employees of varying ages. Integrating self-determination theory (SDT) with relational demography theory, we propose a link between age-inclusive leadership (AIL) and employees’ intrinsic work motivation, with a focus on how the leader–member’s age difference moderates this relationship. A study with 100 Belgian employee–leader dyads reveals that employees’ perceived level of their leaders’ AIL positively affects their intrinsic work motivation, especially with a great leader–member age difference (Study 1). An online experiment with 360 U.S. participants further supports the moderated mediation relationship via the SDT-related needs (Study 2): AIL helps stimulate employees’ intrinsic work motivation through the satisfaction of their need for relatedness and autonomy (and to a lesser extent, competence), especially when employees differ greatly from their leader in terms of age. Our research yields both valuable theoretical insights and practical implications for organizational management.
The desulfinylation enzyme sulfiredoxin-1 attenuates HSC activation and liver fibrosis by modulating the PTPN12-NLRP3 axis
Authors: Kim Jong-Won , Tung Hung-Chun , Ke Mengyun , Xu Pengfei , Cai Xinran , Xi Yue , Xu Meishu , Ren Songrong , Huang Yixian , Bhowmik Amit , Carroll Kate S. , Bae Yun Soo , Li Song , Xie Wen
Published: October 2024

Background and Aims:

Liver fibrosis is characterized by the progressive scarring of liver tissue. Oxidative stress is a critical causal factor of HSC activation and subsequent liver fibrogenesis, but the mechanism is not fully understood. Cysteine sulfinic acid (Cys-SO2H), a modification of reactive cysteine residues, is a unique form of oxidative response that alters the structure and function of proteins. Sulfiredoxin-1 (SRXN1) is responsible for the ATP-dependent reduction of the Cys-SO2H to sulfenic acid (Cys-SOH).

Approach and Results:

We found that the expression of SRXN1 was increased in activated HSCs and in human and mouse fibrotic livers. HSC-specific ablation of Srxn1 or pharmacological inhibition of Srxn1 exacerbated HSC activation and sensitized mice to liver fibrosis. Mechanistically, SRXN1 inhibited HSC activation by desulfinylating the phosphatase protein tyrosine phosphatase nonreceptor type 12 (PTPN12), which enhanced its phosphatase activity and protein stability, leading to decreased tyrosine phosphorylation and reduced activation of the profibrotic inflammasome protein NLRP3 (nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3). The antifibrotic effect of SRXN1 was abolished when NLRP3 was inhibited. In contrast, overexpression of PTPN12 attenuated NLRP3 activation, and this effect was further amplified by the C164A S-sulfinylation–resistant mutant of PTPN12.

Conclusions:

Our findings have uncovered an important role of SRXN1 and protein S-sulfinylation in HSC activation and liver fibrosis. The SRXN1-PTPN12-NLRP3 axis represents potential therapeutic targets for liver fibrosis.
Revolutionizing LVH detection using artificial intelligence: the AI heartbeat project
Authors: Suchal Zafar Aleem , Ain Noor ul , Mahmud Azra
Published: October 2024

Many studies have shown the utility and promise of artificial intelligence (AI), for the diagnosis of left ventricular hypertrophy (LVH). The aim of the present study was to conduct a meta-analysis to compare the accuracy of AI tools to electrocardiographic criteria, including Sokolow–Lyon and the Cornell, most commonly used for the detection of LVH in clinical practice.

Nine studies meeting the inclusion criteria were selected, comprising a sample size of 31 657 patients in the testing and 100 271 in the training datasets. Meta-analysis was performed using a hierarchal model, calculating the pooled sensitivity, specificity, accuracy, along with the 95% confidence intervals (95% CIs). To ensure that the results were not skewed by one particular study, a sensitivity analysis using the ‘leave-out-one approach’ was adopted for all three outcomes.

AI was associated with greater pooled estimates; accuracy, 80.50 (95% CI: 80.4–80.60), sensitivity, 89.29 (95% CI: 89.25–89.33) and specificity, 93.32 (95% CI: 93.26–93.38). Adjusting for weightage of individual studies on the outcomes, the results showed that while accuracy and specificity were unchanged, the adjusted pooled sensitivity was 53.16 (95% CI: 52.92–53.40).

AI demonstrates higher diagnostic accuracy and sensitivity compared with conventional ECG criteria for LVH detection. AI holds promise as a reliable and efficient tool for the accurate detection of LVH in diverse populations. Further studies are needed to test AI models in hypertensive populations, particularly in low resource settings.
Clinical indications associated with new opioid use for pain management in the United Kingdom: using national primary care data
Authors: Ramirez Medina Carlos Raul , Lyon Max , Davies Elinor , McCarthy David , Reid Vanessa , Khanna Ashwin , Jani Meghna
Published: October 2024

Prescription opioids for noncancer pain in the United Kingdom have increased over the past 2 decades, alongside associated harms. Policies addressing opioid prescribing must be tailored to individual patient needs with specific disease systems. The aim of this study was to evaluate clinical conditions associated with new opioid initiation in noncancer pain using nationally representative UK data. Primary care electronic health records from January 1, 2006, to September 31, 2021, were used from the Clinical Research Practice Datalink to identify incident opioid prescriptions. Patient histories were reviewed using code lists for opioid-related conditions with a 5-year look-back for chronic conditions and a 1-year look-back for surgical indications before opioid initiation. In total, 3,030,077 new opioid use episodes in 2,027,402 patients were identified, with 61% being women, 77% aged 45 years and older, and 48% from the highest deprivation quintile. Ten systems associated with opioid initiation were identified, which were not mutually exclusive, as patients could have opioids prescribed for multiple indications. The most common were musculoskeletal (80.8%), respiratory (57.6%), infections (30.4%), trauma/injury (20.4%), neurology (19.9%), and postsurgical indications (5.5%). Osteoarthritis (60.7%) and low back pain (41.0%) were the most frequent musculoskeletal conditions. Orthopedic surgeries accounted for 41.2% of all postsurgical indications. This is the first study in the United Kingdom evaluating large-scale national data to assess indications associated with opioid initiation. Nearly 3 quarters of new opioid prescriptions for noncancer pain were in patients with musculoskeletal conditions, often for conditions with limited evidence for opioid efficacy. These findings could inform targeted interventions and future policies to support nonpharmacological interventions in the most common conditions where opioid harms outweigh benefits.
Is the combination of two automated rapid assays for diagnosis of heparin-induced thrombocytopenia necessary?
Authors: Jani Erika , Bozzola Margherita , Zagler Elmar Marco , Daves Massimo
Published: October 2024

Heparin-induced thrombocytopenia (HIT) is an immune-mediated condition characterized by a decrease in platelet count and an increased thrombotic risk. HIT event is caused by antiplatelet factor/heparin (PF4/H) antibodies that can activate the platelets. The diagnosis of HIT is based on a clinical evaluation and laboratory results. Aim of our study was to evaluate whether the combined use of two rapid assays for diagnosis of HIT provides a diagnostic advantage over the use of a single automate assay.

We extracted from the laboratory informatic system all the determinations requested for the detection of antibodies against heparin/PF4 complexes from July 2020 to June 2024 (n. 229). In our laboratory, total antibodies against heparin/PF4 complex [HemosIL HIT-Ab-(PF4-H), Instrumentation Laboratory] and IgG Ab (HemosIL AcuStar HIT-IgG, Instrumentation Laboratory) are measured simultaneously with two different instruments.

Two hundred six samples tested negative for both methods, 23 samples tested positive for at least one method and nine samples tested positive for both methods. The grade of concordance between the two assays shows a weighted Kappa of 0.536 (moderate agreement). No sample tested positive only for IgG-Ab. The sensitivity of HIT-Ab-(PF4-H) was 1, whereas the specificity was 0.95. For the HIT-IgG (PF4-H) method, sensibility and specificity were 0.77 and 1, respectively.

Our results suggest that performing these two tests simultaneously does not provide additional useful information in patients with suspicion of HIT. The total Ab assay seems to be sufficient, as it shows higher sensitivity although at the expense of lower specificity.
Nephrocalcinosis, distal renal tubular acidosis and skeletal abnormality in two siblings with ROGDI-related Kohlschütter-Tönz syndrome
Authors: Nerakh Gayatri , Koneru Swetha , Dhareneni Prashanth Rao
Published: October 2024

Introduction

Kohlschütter-Tönz (KTS) is a rare autosomal recessive, genetically heterogeneous disorder characterized by a triad of early-onset seizures, global developmental delay or regression, and amelogenesis imperfecta of both temporary and permanent teeth. To date, 66 cases have been reported in the literature, of which 44 with genetic confirmation.

Case report

Here we report the observation of sibling pairs in a family from a small village in India who presented with nephrocalcinosis, distal renal tubular acidosis, and skeletal abnormality. Nephrocalcinosis has only been reported once before in an individual affected with KTS.

Results

Trio exome sequencing revealed a novel, homozygous, likely pathogenic variant, c.646-2_649del, in exon 9 of the ROGDI gene (NM_024589.3) in the first child. Sanger sequencing confirmed homozygosity in both children. Both parents are heterozygous carriers of the same variant.

Conclusion

Further research needs to be done to identify the exact mechanism by which ROGDI-encoded protein deficiency leads to nephrocalcinosis and distal renal tubular acidosis.
Comparing the Sensitivity of HER2 Epitope Detection of HercepTest mAb pharmDx (Dako Omnis, GE001) and Ventana PATHWAY Anti-HER-2/neu (4B5) Using IHC Calibrators
Authors: Aidt Frederik , Sierra Maria , Salomon Karin , Noumsi Ghislain
Published: October 2024

Accurate assessment of HER2 expression levels is paramount for determining eligibility for targeted therapies. HER2 immunohistochemistry provides a semiquantitative measurement of HER2 protein overexpression. Historically, little focus has been on the lower end of the HER2 expression range. The advent of novel therapeutic molecules that require fewer membrane epitopes to be effective has prompted a reevaluation of the current immunohistochemistry testing protocols, with special emphasis on the detection limit. Here, we have used Boston Cell Standards technology to determine the sensitivity of 2 commercially available HER2 immunohistochemistry assays, including a lower limit of detection.
Planetary Health in Rehabilitation
Authors: Bateman Emma A. , Fortin Christian D. , Ghuman Arjun , Neferu Ramona , Guo Meiqi
Published: October 2024

Sometimes out of necessity and sometimes out of convenience, medicine is wasteful. Resource stewardship is a critical and expanding field for reducing wasteful practices. Numerous international organizations are driving resource stewardship globally, including >20 countries worldwide participating in Choosing Wisely initiatives. However, opportunities for environmental stewardship have been long overlooked. Planetary health, climate action, and environmental stewardship in medicine consider opportunities which offer a co-benefit to the planet while improving or maintaining appropriate patient care across the healthcare continuum, including acute care, transitions in care, and postacute care, as well as in primary, secondary, and tertiary care settings. As rehabilitation is necessary across all healthcare settings, developing a culture among rehabilitation care providers that is conscientious about planetary health is imperative for sustainability of rehabilitation medicine and the health of our planet. We devised a recommendation for Choosing Wisely Canada’s planetary health focus: don’t dispose of adaptive equipment, mobility devices, orthoses, and prostheses that could be reused or recycled. This brief report discusses 1) why rehabilitation providers should engage with planetary health and climate action; 2) the rationale for the Choosing Wisely Canada Physical Medicine & Rehabilitation planetary health recommendation; and 3) existing avenues and novel opportunities for rehabilitation care providers worldwide to reduce waste in rehabilitation.
TARGETING S100A9-TLR2 AXIS CONTROLS MACROPHAGE NLRP3 INFLAMMASOME ACTIVATION IN FATTY LIVER ISCHEMIA REPERFUSION INJURY
Authors: Sheng Mingwei , Liu Weihua , Cao Yingli , Wang Shixuan , Lin Yuanbang , Yu Wenli
Published: October 2024

Liver ischemia reperfusion (IR) injury significantly impacts clinical outcomes by increasing the risk of hepatic dysfunction after liver surgery. Fatty livers are more susceptible to IR stress. Recent studies have demonstrated that S100A9 plays a crucial role in both IR injury and the progression of liver steatosis. Nevertheless, the precise mechanisms underlying these effects remain unclear. In our study, transcriptome analysis of fatty livers subjected to IR insult in mice identified S100A9 as an important mediator. Employing loss-of-function approaches, we investigated the immune regulatory function of S100A9 and its downstream signaling in fatty liver IR injury. As expected, S100A9 emerged as one of the most significantly upregulated genes during the reperfusion stage in fatty livers. Genetic knockdown of S100A9 markedly ameliorated liver pathological damage, evidenced by reduced macrophage/neutrophil infiltration as well as the decreased expression of proinflammatory factors. Transcriptome/functional studies revealed that S100A9 triggered liver inflammatory response via regulating toll-like receptor 2 (TLR2)/activating transcription factor 4 (ATF4) signaling. Additionally, TLR2 expression was notably increased in macrophages from ischemic fatty livers. In vitro, recombinant S100A9-stimulated macrophages exhibited the elevated production of proinflammatory factors and TLR2/ATF4 pathway activation. Intriguingly, S100A9 facilitated ATF4 nuclear translocation and enhanced NEK7/NLRP3 inflammasome activation in macrophages. In conclusion, our study identified S100A9 as a key regulator responsible for macrophage NLRP3 inflammasome activation and subsequent inflammatory injury in fatty liver IR process. Targeting TLR2/ATF4 signaling may offer a novel therapeutic strategy for mitigating S100A9-mediated liver injury.
COMPARISON OF CONTINUOUS VITAL SIGNS DATA ANALYSIS VERSUS VENOUS LACTATE FOR THE PREDICTION OF LIFESAVING INTERVENTIONS IN PATIENTS WITH TRAUMATIC SHOCK
Authors: Yang Shiming , Hu Peter , Teeter William , Floccare Douglas J. , Hu Howard , Galvagno Samuel M.
Published: October 2024

Introduction: The prehospital environment is fraught with operational constraints, making it difficult to assess the need for resources such as lifesaving interventions (LSI) for adults with traumatic injuries. While invasive methods such as lactate have been found to be highly predictive for estimating injury severity and resource requirements, noninvasive methods, to include continuous vital signs (VS), have the potential to provide prognostic information that can be quickly acquired, interpreted, and incorporated into decision making. In this work, we hypothesized that an analysis of continuous VS would have predictive capacity comparable to lactate and other laboratory tests for the prediction of injury severity, need for LSIs and intensive care unit admission. Methods: In this preplanned secondary analysis of 300 prospectively enrolled patients, venous blood samples were collected in the prehospital environment aboard a helicopter and analyzed with a portable lab device. Patients were transported to the primary adult resource center for trauma in the state of Maryland. Continuous VS were simultaneously collected. Descriptive statistics were used to describe the cohort and predictive models were constructed using a regularized gradient boosting framework with 10-fold cross-validation with additional analyses using Shapley additive explanations (SHAP). Results: Complete VS and laboratory data from 166 patients were available for analysis. The continuous VS models had better performance for prediction of receiving LSIs and intensive care unit length of stay compared to single (initial) VS measurements. The continuous VS models had comparable performance to models using only laboratory tests in predicting discharge within 24 h (continuous VS model: area under the receiver operating curve [AUROC] 0.71; 95% CI, 0.68–0.75 vs. lactate model: AUROC, 0.65; 95% CI, 0.68; 95% CI, 0.66–0.71). The model using all laboratory data yielded the highest sensitivity and sensitivity (AUROC, 0.77; 95% CI, 0.74–0.81). Discussion: The results from this study suggest that continuous VS obtained from autonomous monitors in an aeromedical environment may be helpful for predicting LSIs and the critical care requirements for traumatically injured adults. The collection and use of noninvasively obtained physiological data during the early stages of prehospital care may be useful for in developing user-friendly early warning systems for identifying potentially unstable trauma patients.
Different dorsolateral prefrontal activation during an emotionalautobiographical memory task between male and female depressed individuals: a fNIRS study
Authors: Zheng Minxiao , Xiang Nian , Qiu Min , Da Hui , Xiao Qiang , Wei Qiang , Zhu Dongmei , Ke Shanzhi , Shi Hui , Zhang Yan , Su Lufang , Zhong Jiayi
Published: October 2024

Depression in male and female are commonly associated with different prevalence, severity, and, in some cases, distinct syndromes or subtypes. However, only a small amount of research has been conducted to completely understand the underlying neuroanatomical mechanisms. The goal of the current study was to provide neural markers for specific depression therapies by demonstrating the differences in aberrant prefrontal activity between male and female depressed subjects during an emotional autobiographical memory test. The study included 127 young adults who were randomly assigned to one of two groups: male depression (62 participants) or female depression (65 participants). The average oxyhemoglobin levels in the dorsolateral prefrontal cortex throughout the emotional autobiographical memory task were assessed utilizing 53-channel functional near-infrared spectroscopy imaging equipment. The oxy-Hb activation in the left dorsolateral prefrontal cortex (lDLPFC) and right dorsolateral prefrontal cortex (rDLPFC) had no significant interaction between groups and emotional valences. A significant main effect was found between male and female, with female depression groups showing lower oxy-Hb activity in lDLPFC and rDLPFC than male depression groups. Male and female depression patients showed distinct brain activation in the DLPFC during an emotional autobiographical memory test, suggesting potential specific neurological indicators for varied somatic symptoms in male and female depression patients. These distinctions should be taken into account while creating preventive measures.
Natural variation in chalcone isomerase defines a major locus controlling radial stem growth variation amongPopulus nigrapopulations
Authors: Duruflé Harold , Déjardin Annabelle , Jorge Véronique , Pégard Marie , Pilate Gilles , Rogier Odile , Sanchez Leopoldo , Segura Vincent
Published: October 2024

Abstract

Poplar is a promising resource for wood production and the development of lignocel-lulosic biomass, but currently available varieties have not been optimized for these purposes. Therefore, it is critical to investigate the genetic variability and mechanisms underlying traits that affect biomass yield. Previous studies have shown that target traits in different poplar species are complex, with a small number of genetic factors having relatively low effects compared to medium to high heritability. In this study, a systems biology approach was implemented, combining genomic, transcriptomic, and phenotypic information from a large collection of individuals from natural populations of black poplar from Western Europe. Such an approach identified a QTL and a gene, coding for chalcone isomerase (CHI), as a candidate for controlling radial growth. Additionally, analysis of the structure and diversity of traits as well as CHI gene expression revealed a high allelic fixation index, linked to the geographical origin of the natural populations under study. These findings provide insights into how adaptive traits arise, are selected, and maintained in the populations. Overall, this study contributes to enhancing the use of poplar as a valuable resource for sustainable biomass production.
Temporal placement of RNA modifications under 5-fluorouracil treatment in human cell culture
Authors: Berg Maximilian , Li Chengkang , Kaiser Stefanie
Published: October 2024

Recent studies have explored the dynamic changes in RNA modification across various organisms, often in response to stressors like chemical agents or drugs. Among these, the anticancer drug 5-fluorouracil (5-FU) has been evaluated regarding its impact on RNA and DNA. Although different alterations in RNA modification have been associated with 5-FU, a mechanistic insight into the dynamic effects on RNA modification is missing. In this study, we provide a detailed insight into the dynamic modification changes for tRNA and rRNA of HEK293T cells exposed to 5-FU using Nucleic Acid Isotope Labeling coupled Mass Spectrometry (NAIL-MS). Consistent with existing literature, we observed a constant loss of m5U in newly transcribed tRNA during 5-FU exposure. In addition to m5U, we identified a loss of m5Um and an increase of Um within tRNALysUUU. While cells recover from a 24-hour 5-FU treatment, we found changed abundances of modifications like an increase of mcm5U and m5C and a decrease of m7G and m1A in total tRNA. Moreover, we demonstrate that 5-FU affects various rRNA subtypes, altering both their modification stoichiometry and abundance. Taken together, we use NAIL-MS to deconvolute RNA modification abundance changes caused by drug treatment and we uncover patterns of RNA modification adaptation.
The E3 ligase NEDD4L prevents colorectal cancer liver metastasis via degradation of PRMT5 to inhibit the AKT/mTOR signaling pathway
Authors: Dong Zhewen , She Xiaofei , Ma Junxian , Chen Qian , Gao Yaqun , Chen Ruiyan , Qin Huanlong , Gao Hua
Published: October 2024

Colorectal cancer is the second most common cause of cancer mortality worldwide, and liver metastasis is the major cause of death in patients with colorectal cancer. Dysfunctional E3 ligase activity has recently been shown to be associated with colorectal cancer. However, the key E3 ligase affecting colorectal cancer liver metastasis remains unknown. Therefore, we used an shRNA library targeting 156 E3 ubiquitin ligases to perform anin vivoloss-of-function screen of a human colorectal cancer cell line in a mouse model of colorectal cancer liver metastasis. The screen revealed that NEDD4L knockdown promoted colorectal cancer liver metastasis. Moreover, overexpression of NEDD4L prevented colorectal cancer liver metastasis. Mechanistic studies revealed that NEDD4L bound to the PPNAY motif in PRMT5 and ubiquitinated PRMT5 to promote its degradation. PRMT5 degradation attenuated the methylation of an arginine residue in AKT1 to inhibit the AKT/mTOR signaling pathway, consequently decreasing colorectal cancer cell proliferation. We are the first to show that PRMT5 is a substrate protein of the E3 ligase NEDD4L and reveals not only the metastasis-inhibiting function of NEDD4L but also a novel mechanism by which NEDD4L suppresses colorectal cancer liver metastasis. These findings may provide a new preventive strategy for liver metastasis.
Hydroxy polyethylene glycol: a solution to evade human pre-existing anti-PEG antibodies for efficient delivery
Authors: Ding Tianhao , Fu Jiaru , Yang Min , Zhang Zui , Ma Yinyu , Wu Ercan , Guo Zhiwei , Lin Shiqi , Wang Songli , Liu Xiaohua , Wang Bin , Li Guanghui , Zhan Changyou
Published: October 2024

Polyethylene glycol (PEG) has been extensively utilized in food, cosmetics, and pharmaceutical fields, especially in the realm of nanomedicines, where it serves as a pivotal excipient for extending the nanoparticles circulation half-life. Contrary to its historical perception as non-immunogenic, pre-existing anti-PEG antibodies have been widely detected in human who even have never been exposed to PEGylated therapeutics, which considered to be associated with serious side effects of PEGylated nanomedicines including infusion reactions and other hypersensitive reactions. Herein, we elucidated the prevalence and distribution characteristics of pre-existing anti-PEG antibodies in 2074 human blood samples, and investigated its binding with PEG. Pre-existing anti-PEG antibodies were found to primarily recognize the PEG terminus, especially methoxy, which is the only PEG terminus contained in currently marketed PEGylated nanomedicines. While hydroxy PEG (OH-PEG) significantly evaded binding with pre-existing anti-PEG antibodies among most clinical samples. Noteworthily, substituting OH-PEG for MeO-PEG significantly mitigated complement activation of lipid nanoparticle (LNP) caused by pre-existing anti-PEG antibodies, thereby markedly enhancing stability and reducing mRNA leakage in human serum. Additionally, LNP modified with OH-PEG exhibited reduced immunogenicity, which was crucial for repeated drug administrations. The present work elucidated the crucial role of OH-PEG in evading human pre-existing anti-PEG antibodies, and discovered that the current pre-clinical studies inadequately simulated the biological effects of clinical pre-existing anti-PEG antibodies on such formulations through interspecies study, which had a profound impact on clinical translation of PEGylated nanomedicines.
The fourspine stickleback (Apeltes quadracus) has an XY sex chromosome system with polymorphic inversions on both X and Y chromosomes
Authors: Liu Zuyao , Herbert Amy L. , Chan Yingguang Frank , Kučka Marek , Kingsley David M. , Peichel Catherine L.
Published: October 2024

Teleost fish are well-known for possessing a diversity of sex chromosomes and for undergoing frequent turnovers of these sex chromosomes. However, previous studies have mainly focused on variation between species, while comparatively little attention has been given to sex chromosome polymorphisms within species, which may capture early stages of sex chromosome changes. To better understand the evolution of sex chromosomes, we used the fourspine stickleback (Apeltes quadracus) as a model organism. Previously, it was believed that females of this species possessed a ZW heteromorphic sex chromosome system. However, genetic crosses and our whole-genome sequencing of wild populations revealed thatA. quadracushas an XY sex chromosome on chromosome 23. This chromosome has not previously been identified as a sex chromosome in other stickleback species, indicating a recent sex chromosome turnover. We also identified two genes -rxfp2aandzar1l- as novel candidate sex determination genes. Notably, we observed inversions on both the X and Y chromosomes in different populations, resulting in distinctive patterns of differentiation between the X and Y chromosomes across populations. We propose that the inversion on the X chromosome may have been favored by sexually antagonistic selection. The new sex chromosome and intraspecies inversion polymorphisms observed inA. quadracusprovide an excellent system for studying the evolution of sex chromosomes and their turnovers.

Author Summary

As compared to mammals and birds, teleost fish exhibit a very high level of diversity in their sex chromosomes, even among closely related species. Thus far, little attention has been paid to variation within species, although it offers a valuable opportunity to advance our understanding of the mechanisms underlying the formation and turnover of sex chromosomes. Through a quantitative trait locus (QTL) cross and sequencing diverse populations, we determined that instead of the previously reported ZW system,A. quadracushas an XY sex determination system on chromosome 23. Within the sex determining region, we identifiedrxfp2aandzar1las putative sex determining genes. Notably, we also observed polymorphic inversions present on both the X and Y chromosomes that differ among populations. Based on our findings, we hypothesize that the X-linked inversions are favored by selection that differs between males and females. These observations represent a rare situation in which sex chromosomes are still polymorphic for sex-linked inversions, which offers important insights into the early stages of sex chromosome evolution.
Effect of p-benzoquinone, a cigarette smoke-derived component, on the architecture and function of human RBC
Authors: Yadav Neha , Mondal Santosh Kumar , Mandal Amit Kumar
Published: October 2024

p-benzoquinone (pBQ), a cigarette smoke-derived component, stands as one of the lethal oxidants of cigarette smoke. Health hazards caused by cigarette smoking are a profound global health concern. It has been reported to contribute significantly to several health disorders, such as lung cancer, chronic obstructive pulmonary disease (COPD), cardiovascular diseases, etc. These adverse health effects might be attributed to the complex mixture of approximately 4,000 chemicals present in cigarette smoke, such as nicotine, tar, nitric oxide, and p-benzosemiquinone (pBSQ). pBSQ, ranging from 100-200 µg per cigarette, gets oxidized to pBQ in the lungs of smokers and subsequently enters into the bloodstream. In the present study, we investigated the detrimental effect of pBQ on the architecture of human RBCs. Previously, we showed that the covalent modification of human hemoglobin with pBQ results in an alteration in its structure and function. In addition, we explored the potential neutralizing role of N-acetyl cysteine (NAC) in the reactivity of pBQ. Our results demonstrated that pBQ exposure to human red blood cells (RBCs),ex vivo, significantly decreases the reduced glutathione (GSH) content of RBCs, leading to the elevation of reactive oxygen species (ROS) and consequently causing oxidative damage to cellular components. pBQ exposure resulted in increased RBC sedimentation, altered membrane fluidity, enhanced lipid peroxidation, and significant morphological changes, such as bulging and distortion on the surface of RBCs, which eventually compromise membrane integrity. In addition, the coexistence of NAC with pBQ was found to be effective in neutralizing pBQ, thereby restoring GSH levels and RBC membrane architecture. These findings highlight the potential of NAC in mitigating the harmful effects of cigarette smoke on RBCs.

Graphical abstract
Kernel Filter-Based Adaptive Controllers For Cybergenetics Applications
Authors: Smart Benjamin , Marucci Lucia , Renson Ludovic
Published: October 2024

Cybergenetics is an advancing field seeking to implement control theory within biological systems. When applying feedback control for the regulation of gene expression or cell proliferation, model-based control strategies can be applied; in this context, online adaptive mathematical models can be used to keep models in tune with the current behaviour of the biological system. Controllers are often constrained by their sampling rate, which is usually relatively low when using microfluidics/microscopy platforms. Current adaptive filters can lead to an inaccurate predictive model when operating with a low sampling rate, leading to sub-optimal control. Here, we propose a kernel filter that can adapt model parameters online to produce a more accurate predictive model that can be included within an adaptive model predictive control scheme. The use of the kernel filter is demonstrated inin silicoexperiments, where we control a synthetic gene network oscillator and a P53 oscillator. Results show that the kernel filter outperforms a particle filter when used for parameter estimation in both the predictive model accuracy and when included within an adaptive model-based controller.
Systemic effects of oral tolerance improve the healing of several and concomitant wounds in different body parts
Authors: Nobrega Isabela Beatriz Cabacinha , Souza Andrade Angélica Vitória , Nyetem Bikat Thomson Junior , Quintão Gustavo Motta , Azevedo Junior Geraldo Magela , Valência Karen Franco , Costa Raquel Alves , Carvalho Claudia Rocha
Published: October 2024

Throughout our lives, we are continually subjected to different situations that can result in several and concomitant wounds to different parts of our body. The healing of these wounds is essential to maintaining health. Inflammation is an important step in wound healing, but in cases of intense or prolonged inflammation, pathological scarring or non-closure of the wound may occur. Assuming that leukocytes participate in wound healing and that it is possible to intervene systemically with inflammation, we investigated a way to promote better repair of multiple wounds that may occur at the same time. Oral tolerance is an immunological phenomenon that result from protein intake and that have systemic effects on inflammation. Previous works have shown that parenteral injection of tolerated proteins reduces the inflammatory infiltrate and improves skin wound healing. Herein we tested whether the injection of tolerated proteins improves the healing of several wounds in different body parts, such as on the skin of the back and in the external ear (the auricle). To induce oral tolerance to ovalbumin (OVA), eight weeks old C57BL/6 mice drank egg white diluted 1:5 in water for 3 consecutive days. Control mice drank water. Seven days after oral treatment, mice were submitted to excisional injuries in the skin of the back (6 mm) and in the ears (4 mm). Minutes before the injuries, the mice received an intraperitoneal injection of OVA + Al(OH)3. Seven and 40 days after injuries, tissue samples were collected and processed for histological analysis of the wounds. The results show that the injection of OVA in animals that drank OVA reduced the inflammatory infiltrate in all lesions. Besides, injection of OVA in animals that drank OVA promoted better organization of the extracellular matrix, with thicker and intertwined collagen fibers in the neodermis, resulting in smaller scars in the skin. Furthermore, the healing area of the ears of OVA-tolerant animals showed chondrocyte aggregates and less obvious fibrous scar tissue compared with control animals. In conclusion, systemic effects of oral tolerance positively influenced the healing of several lesions in different body parts.