bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting Neutrophils for Promoting the Resolution of Inflammation
Authors: Filep János G.
Published: March 2022

Acute inflammation is a localized and self-limited innate host-defense mechanism against invading pathogens and tissue injury. Neutrophils, the most abundant immune cells in humans, play pivotal roles in host defense by eradicating invading pathogens and debris. Ideally, elimination of the offending insult prompts repair and return to homeostasis. However, the neutrophils` powerful weaponry to combat microbes can also cause tissue damage and neutrophil-driven inflammation is a unifying mechanism for many diseases. For timely resolution of inflammation, in addition to stopping neutrophil recruitment, emigrated neutrophils need to be disarmed and removed from the affected site. Accumulating evidence documents the phenotypic and functional versatility of neutrophils far beyond their antimicrobial functions. Hence, understanding the receptors that integrate opposing cues and checkpoints that determine the fate of neutrophils in inflamed tissues provides insight into the mechanisms that distinguish protective and dysregulated, excessive inflammation and govern resolution. This review aims to provide a brief overview and update with key points from recent advances on neutrophil heterogeneity, functional versatility and signaling, and discusses challenges and emerging therapeutic approaches that target neutrophils to enhance the resolution of inflammation.
Integrated Social-Economic-Ecological Modeling for Fisheries: The ECOST Model
Authors: Failler Pierre , Pan Haoran , Akbari Negar
Published: March 2022

Marine and coastal areas are complex systems formed by the interaction among the local population, economy, environment and resources and there is an increasing tendency for recent studies in fisheries research to incorporate interdisciplinary methods in their approach. In this paper, the Integrated Social-Economic-Ecological model for Fisheries (ECOST) model is structured with three modules each of which intends to characterize some relevant aspects of social, economic and ecological systems, respectively. At the heart of the model stands a fisheries economic module describing the fisheries economy; within the model the economic module is extended to the areas of fisheries sociology and biology or ecology where social and ecological aspects of fisheries are modeled following appropriate theory and methodology, respectively.
Temperature Effects on Leaf and Epiphyte Photosynthesis, Bicarbonate Use and Diel O2 Budgets of the Seagrass Zostera marina L.
Authors: Hansen Aske Bang , Pedersen Anne Sofie , Kühl Michael , Brodersen Kasper Elgetti
Published: March 2022

Ocean warming along with nutrient enrichment are major stressors causing global seagrass decline. While the effects of global warming on metabolic parameters in seagrasses are well described, the effect of increasing temperature on the epiphytic overgrowth of seagrass leaves and the consequences for the seagrass plant are poorly understood. Here, we investigated the effects of elevating temperature on the photosynthetic efficiency of the seagrass species Zostera marina L. and its associated epiphytes, to explore how ocean warming might affect epiphytism in seagrasses. Gas exchange and final pH measurements on bare seagrass leaves, leaves with epiphytes, and epiphytes separated from seagrass leaves were used to quantify photosynthesis and respiration rates, and the inorganic carbon extraction capacity of leaves and epiphytes as a function of photon scalar irradiance and temperature (12, 17, 22, and 27°C). Seagrass without epiphytic biofilm had a high ability to exploit the incoming irradiance regardless of the light intensity and temperature, shown as continuously high light use efficiency and maximum net photosynthesis rates. The presence of epiphytic biofilm on the seagrass leaves impaired plant photosynthesis by increasing light requirements and reducing the photosynthetic efficiency (especially at 27°C). Epiphytes showed the lowest respiration rates in darkness and had the highest oxygen surplus over diel cycles up to 22°C, whereas bare leaves had the highest diel oxygen surplus at 27°C. Both bare leaves and epiphytes lost the ability to utilize bicarbonate at 27°C, and epiphytes also did not show use of bicarbonate at 12°C. Our results indicate a competitive advantage for epiphytes in cold CO2-rich environments, whereas seagrass with bare leaves could be less affected under elevated seawater temperatures.
Structural and Functional Improvements of Coastal Ecosystem Based on Artificial Oyster Reef Construction in the Bohai Sea, China
Authors: Wang Xu , Feng Jie , Lin Chenggang , Liu Hui , Chen Muyan , Zhang Yunling
Published: March 2022

Oyster reefs are gaining more and more attention in marine ranching and coastal ecosystem restoration, but tremendous knowledge gaps still exist. In this study, we developed trophic models for the established artificial oyster reef (EAOR), newly deployed artificial oyster reef (NAOR), and non-reef bare substratum (NBS) ecosystems located in the Bay of Xiangyun, Bohai Sea, China, to assess the benefits of artificial oyster reef construction and to characterize the unique role of these reefs in coastal management. The analysis showed that the EAOR and NAOR ecosystems were similar to each other, but both were greatly different than the NBS ecosystem. Reefs showed greater “ecological size” and stronger top-down effects compared to the bare area. The ecosystems were not yet mature, but the EAOR and NAOR ecosystems had more complicated trophic relationships, greater potential to withstand perturbations, and higher biological carrying capacities of commercial organisms compared to the NBS ecosystem. These results demonstrated that artificial oyster reef construction resulted in great advantages to the ecosystem. For example, oysters became the structuring functional group and played a critical role in the trophic structure of the reef areas. The phytoplankton/detritus-oysters-carnivorous macrobenthos pathway developed and became dominant in these areas, thereby contributing to highly efficient secondary production. The ratios of total primary production/total respiration were < 1, indicating that the reef ecosystems responded effectively to nutrient inputs from adjacent ecosystems. We speculate that water exchange might be a critical factor influencing the maintenance of the system. Long-term monitoring of the EAOR and NAOR should be implemented for oyster protection and to assess the need to manipulate carnivorous macrobenthos to keep the systems in balance. Results of this study could benefit the restoration, exploitation, and management of oyster reefs. Further studies should take the adjacent ecosystems and anthropogenic activities into account.
Understanding the Evolution of Mitochondrial Genomes in the Green Macroalgal Genus Ulva (Ulvophyceae, Chlorophyta)
Authors: Liu Feng , Melton James T. , Wang Hongshu , Wang Jing , Lopez-Bautista Juan M.
Published: March 2022

To gain more insights into the evolution of mitochondrial genomes (mitogenomes or mtDNAs) in the green macroalgal genus Ulva (Ulvophyceae, Chlorophyta), we sequenced seven Ulva mitogenomes from six species as well as one Percursaria mitogenome as outgroup, and compared them with the available Ulva mtDNA data. Our comparative analyses unveiled many novel findings. First, the Ulva mitogenomes shared a total of 62 core genes including 29 protein-coding genes (PCGs), three ribosomal RNA genes (rRNAs), 26 transfer RNA genes (tRNAs), three conserved free-standing open reading frames (orfs), and one putative RNA subunit of RNase P (rnpB). The rrn5 gene previously unrecognized is present in all sequenced ulvalean mitogenomes, which is situated between trnG(ucc) and trnW(cca). Second, the evolution of tRNAs in Ulva mitogenomes is related to different processes, including duplication, transposition, remolding, degeneration, loss and recruitment of tRNAs. The duplication of three tRNAs, i.e., trnT1(ugu), trnI1(gau), and trnM2(cau), was observed in Ulva mitogenomes. Third, the DNA-directed RNA polymerases (rpos), belonging to single-subunit DNA-dependent RNA polymerase (ssRNAP) family, are common in ulvalean mitogenomes. A total of three full-length and 55 split rpos have been detected in these 33 ulvalean mitogenomes. Fourth, six types of group I/II introns are detected at 29 insertion sites which are related to seven host genes (atp1, cox1, cox2, nad3, nad5, rnl, and rns) in these ulvalean mitogenomes. One group IB intron, i.e., intron cox1-214 which carried a GIY-YIG homing endonuclease (GHE), was observed for the first time in Ulva organelle genomes. Finally, phylogenomic analyses based on mitogenome dataset showed that the Ulva was split into two sister clades, representing Ulva lineage I and II, which was consistent to the results based on plastid genome dataset. Our study provides more important findings to better understand the evolution of mitochondrial genome in green algae.
Case Report: Pure Red Cell Aplasia Caused by Refractory Parvovirus B19 Infection After Pancreas Transplantation Alone
Authors: Lindahl Jørn Petter , Barlinn Regine , Abrahamsen Ingerid Weum , Spetalen Signe , Midtvedt Karsten , Jenssen Trond
Published: March 2022

A multidisciplinary team of doctors is in charge or is involved in the follow-up of patients who undergo solid organ transplantation (SOT). Immunosuppressive drugs are required after SOT, some potential unwanted side effects can be difficult to detect, and physicians must be aware of potential pitfalls. We report a case of a recipient with brittle type 1 diabetes who experienced severe and refractory anemia after pancreas transplantation alone (PTA). Despite a broad diagnostic approach for anemia, the diagnosis was delayed. The patient had normocytic normochromic anemia with severe reticulocytopenia and marked reduction or absence of erythroid precursors in the bone marrow, compatible with pure red cell aplasia (PRCA). Analyses of serological parvovirus B19 anti-IgM and anti-IgG antibodies, including PCR, were initially inconclusive/negative. The diagnosis of parvovirus B19 infection was confirmed after bone marrow biopsy with immunohistochemical staining for parvovirus B19. A retrospective analysis revealed an early post-transplant primary parvovirus B19 infection. The patient was successfully treated with intravenous immunoglobulin (IVIg) therapy. There is a risk of diagnostic delay for the less common types of anemia following SOT. Parvovirus B19 infection-associated PRCA is curable in SOT recipients and should be actively considered in patients with persistent anemia and low reticulocytes.
Prediction of Ventricular Arrhythmias by QRS/QTc - Ratio in Citalopram or Escitalopram Intoxication
Authors: Dietrichs Erik Sveberg , Smith Godfrey L.
Published: March 2022

Background

The U.S. Food and Drug Administration (FDA) has stated that citalopram and escitalopram should not be used at daily doses above 40 mg/20 mg due to risk for development of fatal ventricular arrhythmias like torsade de pointes (TdP). Yet, supratherapeutic serum concentrations of citalopram are common and predicting patients at risk for TdP is of high clinical value. Accordingly, we investigated whether QRS/QTc; developed for predicting TdP in hypothermic patients could be used in citalopram intoxication.

Methods

A total of 16 publications describing patients suffering from complications due to citalopram or escitalopram treatment, or intoxication with the same substances, were included after a systematic search. The main criterion for inclusion was admission ECG, either with given QRS and QTc values or with attached ECG-files that enabled calculation.

Results

QRS/QTc rather that QTc alone emerged as a marker of ventricular arrhythmia in the 16 included case reports, with highly significant (p < 0.0005) lower values in patients displaying ventricular arrhythmias.

Conclusion

Citalopram and escitalopram are extensively used in treatment of depressive disorders, and a large proportion of patients have supratherapeutic serum concentrations. Calculation of QRS/QTc in available case reports show that this novel ECG-marker has potential to predict patients at risk for developing ventricular arrhythmias.
Unsupervised Facial Action Representation Learning by Temporal Prediction
Authors: Wang Chongwen , Wang Zicheng
Published: March 2022

Due to the cumbersome and expensive data collection process, facial action unit (AU) datasets are generally much smaller in scale than those in other computer vision fields, resulting in overfitting AU detection models trained on insufficient AU images. Despite the recent progress in AU detection, deployment of these models has been impeded due to their limited generalization to unseen subjects and facial poses. In this paper, we propose to learn the discriminative facial AU representation in a self-supervised manner. Considering that facial AUs show temporal consistency and evolution in consecutive facial frames, we develop a self-supervised pseudo signal based on temporally predictive coding (TPC) to capture the temporal characteristics. To further learn the per-frame discriminativeness between the sibling facial frames, we incorporate the frame-wisely temporal contrastive learning into the self-supervised paradigm naturally. The proposed TPC can be trained without AU annotations, which facilitates us using a large number of unlabeled facial videos to learn the AU representations that are robust to undesired nuisances such as facial identities, poses. Contrary to previous AU detection works, our method does not require manually selecting key facial regions or explicitly modeling the AU relations manually. Experimental results show that TPC improves the AU detection precision on several popular AU benchmark datasets compared with other self-supervised AU detection methods.
Total Sleep Deprivation Triggers Greater Activation in the Parietal Brain in the Visual Working Memory Updating Processes: An Event-Related Potentials Study
Authors: Song Tao , Yu Ke , Wang Letong , Xu Lin , Xu Mengmeng , Peng Ziyi , Dai Cimin , Wang Haiteng , Yang Tianyi , Shao Yongcong , Wang Xiaoming , Lv Jing
Published: March 2022

Working memory functions are known to be altered after total sleep deprivation (TSD). However, few studies have explored the deficits of working memory updating (WMU) after TSD, or the underlying electrophysiological mechanisms of these alterations. In the current exploratory study, we enrolled 14 young male volunteers who performed two kinds of WMU tasks—spatial and object two-back tasks—with simultaneous electroencephalography recordings under two sleep conditions: a normal sleep baseline condition and after 36 h of TSD. Repeated-measures analysis of variance showed that compared with those at baseline, the rates of correct responses in the WMU tasks decreased significantly after TSD. Analysis of event-related potentials revealed that the average amplitude of P3 components decreased significantly in the frontal and central brain regions and increased significantly in the parietal brain regions. Our findings suggest that TSD damages WMU behavior, impairs cognitive functions in the frontal and central brain regions, and triggers greater activation in the parietal brain regions. This is the first study to report the existence of event-related compensatory neural activity. This event-related compensatory effect may provide a new perspective for understanding the mechanisms underlying the influences triggered by sleep loss.
Visuomotor Adaptation Modulates the Clustering of Sleep Spindles Into Trains
Authors: Solano Agustín , Riquelme Luis A. , Perez-Chada Daniel , Della-Maggiore Valeria
Published: March 2022

Sleep spindles are thought to promote memory consolidation. Recently, we have shown that visuomotor adaptation (VMA) learning increases the density of spindles and promotes the coupling between spindles and slow oscillations, locally, with the level of spindle-SO synchrony predicting overnight memory retention. Yet, growing evidence suggests that the rhythmicity in spindle occurrence may also influence the stabilization of declarative and procedural memories. Here, we examined if VMA learning promotes the temporal organization of sleep spindles into trains. We found that VMA increased the proportion of spindles and spindle-SO couplings in trains. In agreement with our previous work, this modulation was observed over the contralateral hemisphere to the trained hand, and predicted overnight memory retention. Interestingly, spindles grouped in a cluster showed greater amplitude and duration than isolated spindles. The fact that these features increased as a function of train length, provides evidence supporting a biological advantage of this temporal arrangement. Our work opens the possibility that the periodicity of NREM oscillations may be relevant in the stabilization of procedural memories.
The Diurnal Profile of Human Basal Pain Sensitivity and Skin Sympathetic Nerve Activity: A Healthy Volunteer Study
Authors: Zhu Ying , Yan Ai , Shu Bin , Chen Xuehan , Chen Yupei , Duan Guangyou , Huang He
Published: March 2022

Objective

The diurnal rhythm profile of human basal pain sensitivity and its association with sympathetic nerve activity are not fully understood. This study aimed to examine rhythmic changes in experimental pain sensitivity and skin sympathetic nerve activity in healthy volunteers.

Methods

Thirty healthy volunteers were included in the study. Experimental pain sensitivity, including pressure pain threshold and tolerance, cold pain threshold (CPT) and tolerance, skin sympathetic nerve activity, and cardiovascular parameters (including heart rate, cardiac output, and peripheral vascular resistance) at six time points throughout the day (08:00, 12:00, 16:00, 20:00, 00:00, and 04:00) were sequentially measured. Circadian rhythm analysis was performed on the mean values of the different measurements and individual subjects.

Results

Significant differences were found in experimental pain sensitivity, skin sympathetic nerve activity, and non-invasive cardiovascular parameters at different time points (P < 0.05). The minimum measured values of all four types of experimental pain sensitivity were consistently observed at 04:00. Rhythmical analysis showed that the mean values of pressure pain threshold (meta2d P = 0.016) and skin sympathetic nerve activity (meta2d P = 0.039) were significant. Significant diurnal rhythms in pain sensitivity and skin sympathetic nerve activity existed in some individuals but not in others. No significant correlation between experimental pain sensitivity and skin sympathetic nerve activity was found at any time point (P > 0.05).

Conclusion

Significant diurnal fluctuations were observed in different pain sensitivities and skin sympathetic nerve activity. No significant correlation between experimental pain sensitivity and sympathetic excitability at different times was found; the reasons for these phenomena remain to be further studied.

Clinical Trial Registration

[www.ClinicalTrials.gov], identifier [ChiCTR2000039709].
Acupuncture and Traditional Chinese Herbal Medicine Integrated With Conventional Rehabilitation for Post-stroke Functional Recovery: A Retrospective Cohort Study
Authors: Tseng Cheng-Yu , Hsu Pei-Shan , Lee Chang-Ti , Huang Hui-Fen , Lan Chou-Chin , Hsieh Tsung-Han , Liu Guan-Ting , Kuo Chan-Yen , Wang Ming-Chieh , Hsieh Po-Chun
Published: March 2022

Background

Stroke leads to tremendous impacts on patients and the healthcare system. It is crucial to explore the potential management of rehabilitation. Acupuncture and traditional Chinese herbal medicine (TCHM) integrated with conventional rehabilitation benefit post-stroke functional recovery.

Methods

We retrospectively reviewed the medical records of all patients included in the Integrated Traditional Chinese-Western Medicine care program for stroke (ITCWM-stroke care program) in 2019 in Taipei Tzu Chi Hospital to investigate the effects of acupuncture and TCHM integrated with conventional rehabilitation on National Institutes of Health Stroke Scale (NIHSS) and Barthel Index (BI) scores before and after the program.

Results

A total of 255 stroke inpatients were retrieved and divided into acupuncture and acupuncture + TCHM group by hemorrhagic and ischemic stroke types, respectively. All the patients were recruited in the program at the early subacute phase after stroke onset. Of the hemorrhagic and ischemic stroke subjects, the NIHSS and BI total scores were significantly improved in the acupuncture and acupuncture + TCHM groups. The subgroup analysis results showed that in subjects with a baseline BI score ≤ 40, the acupuncture + TCHM group significantly improved BI total score better than the acupuncture group in both hemorrhagic (p < 0.05) and ischemic (p < 0.05) stroke subjects.

Conclusion

Acupuncture and TCHM integrated with conventional rehabilitation significantly improve stroke patients’ functional recovery at the early subacute phase. Acupuncture + TCHM contributes to better activities of daily living (ADL) improvements in stroke patients with a baseline BI score ≤ 40. We suggest integrating acupuncture and TCHM into the post-stroke rehabilitation strategy, especially for stroke patients with poor ADL function.
Embryonic Valproate Exposure Alters Mesencephalic Dopaminergic Neurons Distribution and Septal Dopaminergic Gene Expression in Domestic Chicks
Authors: Adiletta Alice , Pross Alessandra , Taricco Nicolò , Sgadò Paola
Published: March 2022

In recent years, the role of the dopaminergic system in the regulation of social behavior is being progressively outlined, and dysfunctions of the dopaminergic system are increasingly associated with neurodevelopmental disorders, including autism spectrum disorder (ASD). To study the role of the dopaminergic (DA) system in an animal model of ASD, we investigated the effects of embryonic exposure to valproic acid (VPA) on the postnatal development of the mesencephalic DA system in the domestic chick. We found that VPA affected the rostro-caudal distribution of DA neurons, without changing the expression levels of several dopaminergic markers in the mesencephalon. We also investigated a potential consequence of this altered DA neuronal distribution in the septum, a social brain area previously associated to social behavior in several vertebrate species, describing alterations in the expression of genes linked to DA neurotransmission. These findings support the emerging hypothesis of a role of DA dysfunction in ASD pathogenesis. Together with previous studies showing impairments of early social orienting behavior, these data also support the use of the domestic chick model to investigate the neurobiological mechanisms potentially involved in early ASD symptoms.
Motor Rhythm Dissection From the Backward Circuit in C. elegans
Authors: Yu Bin , Wang Ya , Gao Shangbang
Published: March 2022

Motor rhythm is initiated and sustained by oscillatory neuronal activity. We recently discovered that the A-class excitatory motor neurons (MNs) (A-MNs) function as intrinsic oscillators. They drive backward locomotion by generating rhythmic postsynaptic currents (rPSCs) in body wall muscles. Molecular underpinning of the rPSCs, however, is not fully elucidated. We report here that there are three types of the rPSC patterns, namely the phasic, tonic, and long-lasting, each with distinct kinetics and channel-dependence. The Na+ leak channel is required for all rPSC patterns. The tonic rPSCs exhibit strong dependence on the high-voltage-gated Ca2+ channels. Three K+ channels, the BK-type Ca2+-activated K+ channel, Na+-activated K+ channel, and voltage-gated K+ channel (Kv4), primarily inhibit tonic and long-lasting rPSCs with varying degrees and preferences. The elaborate regulation of rPSCs by different channels, through increasing or decreasing the rPSCs frequency and/or charge, correlates with the changes in the reversal velocity for respective channel mutants. The molecular dissection of different A-MNs-rPSC components therefore reveals different mechanisms for multiplex motor rhythm.
Identification of Germline Mutations in Upper Tract Urothelial Carcinoma With Suspected Lynch Syndrome
Authors: Guan Bao , Wang Jie , Li Xuesong , Lin Lin , Fang Dong , Kong Wenwen , Tian Chuangyu , Li Juan , Yang Kunlin , Han Guanpeng , Wu Yucai , He Yuhui , Peng Yiji , Yu Yanfei , He Qun , He Shiming , Gong Yanqing , Zhou Liqun , Tang Qi
Published: March 2022

Objective

Whole-exon sequencing (WES) is a commercially available tool for hereditary disease testing. However, little is known about hereditary upper-tract urothelial carcinoma (UTUC) in the Chinese population. This study aims to investigate the prevalence of Lynch syndrome (LS) in UTUC patients with high-risk features and identify the germline mutations of genetic predisposition gene mutations in those patients.

Methods

In total, 354 consecutive UTUC patients undergoing surgery were universally recruited, of whom 108 patients under 60 years old or with a personal/family history of cancer underwent universal immunohistochemistry staining to detect the expression of mismatch repair (MMR) proteins (MLH1, MSH2, MSH6 and PMS2). Patients with deficient or weak MMR protein staining or meeting the Amsterdam II criterion were defined as suspected LS patients, who further experienced microsatellite instability (MSI) (BAT25, BAT26, BAT40, D2S123, D5S346, D17S250) detection and performed WES analysis to explore germline pathogenic/likely pathogenic (P/LP) alterations.

Results

Of 108 patients, 90 (83.3%) cases were included due to younger than 60 years, and 18 cases due to personal/family history. IHC staining identified 21 patients with deficient MMR protein staining and 15 cases with weak MMR protein staining. Three cases met the Amsterdam II criterion but with proficient MMR protein staining. Finally, WES analysis was performed in 38 suspected LS patients and P/LP germline mutations were identified in 22 individuals. Genetic testing confirmed 5 LS cases, including 3 cases with novel mutations. MSI-harboring tumor was discovered in 4 LS cases, one of whom had weak MMR protein staining. Germline P/LP variants in DNA damage repair genes were found in 11 cases. In addition, we found that 11 patients had high- or moderate- penetrance P/LP mutations other than MMR genes. The common P/LP variants in high- or moderate-penetrance genes were 4 in ATM, 3 in MSH6 and KIT, and 2 in APC, NF1 and DICER.

Conclusions

We identified approximately 11% of UTUC cases as suspected LS and at least 1.4% patients with confirmed LS-associated UTUC. In addition, broader germline genetic testing could be considered to screen for cancer severity in hereditary UTUC patients.
Considerations for Germline Testing in Melanoma: Updates in Behavioral Change and Pancreatic Surveillance for Carriers of CDKN2A Pathogenic Variants
Authors: Pauley Kristen , Khan Ambreen , Kohlmann Wendy , Jeter Joanne
Published: March 2022

The largest proportion of hereditary melanoma cases are due to pathogenic variants (PVs) in the CDKN2A/p16 gene, which account for 20%-40% of familial melanomas and confer up to a 30%-70% lifetime risk for melanoma in individuals with these variants. In addition, PVs in the CDKN2A gene also increase risk for pancreatic cancer (~5–24% lifetime risk). Individuals with PVs in the CDKN2A gene also tend to have an earlier onset of cancer. Despite these known risks, uptake of germline testing has been limited in the past, largely due to perceptions of limited benefit for patients. Prevention recommendations have been developed for individuals with CDKN2A PVs as well the providers who care for them. On the patient level, behavioral modifications regarding melanoma prevention such as wearing sunscreen, limiting prolonged sun exposure and practicing general sun safety can help reduce risks. Germline testing can provide motivation for some individuals to adhere to these lifestyle changes. On the provider level, pancreatic cancer surveillance for individuals with CDKN2A PVs has been increasingly endorsed by expert consensus, although the efficacy of these surveillance methods remains under study. This review summarizes the updated surveillance guidelines for individuals with CDKN2A PVs and explores the impact of genetic counseling and testing in influencing behavioral changes in these individuals.
Nuclear Receptor PXR Confers Irradiation Resistance by Promoting DNA Damage Response Through Stabilization of ATF3
Authors: Niu Xiaxia , Cui Hongmei , Gu Xinsheng , Wu Ting , Sun Min , Zhou Changlong , Ma Mei
Published: March 2022

Low response rate to radiotherapy remains a problem for liver and colorectal cancer patients due to inappropriate DNA damage response in tumors. Here, we report that pregnane X receptor (PXR) contributes to irradiation (IR) resistance by promoting activating transcription factor 3 (ATF3)-mediated ataxia-telangiectasia-mutated protein (ATM) activation. PXR stabilized ATF3 protein by blocking its ubiquitination. PXR–ATF3 interaction is required for regulating ATF3, as one mutant of lysine (K) 42R of ATF3 lost binding with PXR and abolished PXR-reduced ubiquitination of ATF3. On the other hand, threonine (T) 432A of PXR lost binding with ATF3 and further compromised ATM activation. Moreover, the PXR–ATF3 interaction increases ATF3 stabilization through disrupting ATF3–murine double minute 2 (MDM2) interaction and negatively regulating MDM2 protein expression. PXR enhanced MDM2 auto-ubiquitination and shortened its half-life, therefore compromising the MDM2-mediated degradation of ATF3 protein. Structurally, both ATF3 and PXR bind to the RING domain of MDM2, and on the other hand, MDM2 binds with PXR on the DNA-binding domain (DBD), which contains zinc finger sequence. Zinc finger sequence is well known for nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) playing E3 ligase activity to degrade nuclear factor κB (NFκB)/p65. However, whether zinc-RING sequence grants E3 ligase activity to PXR remains elusive. Taken together, these results provide a novel mechanism that PXR contributes to IR resistance by promoting ATF3-mediated ATM activation through stabilization of ATF3. Our result suggests that targeting PXR may sensitize liver and colon cancer cells to IR therapy.
Effects of H2O2 Treatment Combined With PI3K Inhibitor and MEK Inhibitor in AGS Cells: Oxidative Stress Outcomes in a Model of Gastric Cancer
Authors: Savino Luca , Di Marcantonio Maria Carmela , Moscatello Carmelo , Cotellese Roberto , Centurione Lucia , Muraro Raffaella , Aceto Gitana Maria , Mincione Gabriella
Published: March 2022

Gastric cancer is worldwide the fifth and third cancer for incidence and mortality, respectively. Stomach wall is daily exposed to oxidative stress and BER system has a key role in the defense from oxidation-induced DNA damage, whilst ErbB receptors have important roles in the pathogenesis of cancer. We used AGS cells as an aggressive gastric carcinoma cell model, treated with H2O2 alone or combined with ErbB signaling pathway inhibitors, to evaluate the effects of oxidative stress in gastric cancer, focusing on the modulation of ErbB signaling pathways and their eventual cross-talk with BER system. We showed that treatment with H2O2 combined with PI3K/AKT and MEK inhibitors influenced cell morphology and resulted in a reduction of cancer cell viability. Migration ability was reduced after H2O2 treatment alone or combined with MEK inhibitor and after PI3K/AKT inhibitor alone. Western blotting analysis showed that oxidative stress stimulated EGFR pathway favoring the MAPKs activation at the expense of PI3K/AKT pathway. Gene expression analysis by RT-qPCR showed ErbB2 and OGG1 increase under oxidative stress conditions. Therefore, we suggest that in AGS cells a pro-oxidant treatment can reduce gastric cancer cell growth and migration via a different modulation of PI3K and MAPKs pathways. Moreover, the observed ErbB2 and OGG1 induction is a cellular response to protect the cells from H2O2-induced cell death. In conclusion, to tailor specific combinations of therapies and to decide which strategy to use, administration of a chemotherapy that increases intracellular ROS to toxic levels, might not only be dependent on the tumor type, but also on the molecular targeting therapy used.
The Relationship Between Short-Term Surrogate Endpoint Indicators and mPFS and mOS in Clinical Trials of Malignant Tumors: A Case Study of Approved Molecular Targeted Drugs for Non-Small-Cell Lung Cancer in China
Authors: Rui Mingjun , Wang Zijing , Fei Zhengyang , Wu Yao , Wang Yingcheng , Sun Lei , Shang Ye , Li Hongchao
Published: March 2022

Objective: Due to the initiation of the priority review program in China, many antitumor drugs have been approved for marketing based on phase II clinical trials and short-term surrogate endpoint indicators. This study used approved targeted drugs for the treatment of non-small-cell lung cancer (NSCLC) in China as an example to evaluate the association between short-term surrogate endpoints [objective response rate (ORR) and disease control rate (DCR)] and median progression-free survival (mPFS) and median overall survival (mOS).

Methods: Five databases, i.e., MEDLINE, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang Data were searched, for phase II or phase III clinical trials of all molecular targeted drugs that have been marketed in China for the treatment of NSCLC. After screening the literature and extracting information, both univariate and multivariate linear regression were performed on the short-term surrogate indicators and mPFS and mOS to explore the relationship.

Results: A total of 63 studies were included (25 studies with only ORR, DCR, and mPFS and 39 studies with ORR, DCR, mPFS, and mOS). In terms of the targeted drugs for the treatment of NSCLC, in addition to the good but not excellent linear relationship between DCR and mOS (0.4 < R2adj = 0.5653 < 0.6), all other short-term surrogate endpoint indicators had excellent linear relationships with mPFS and mOS (R2adj≥0.6), while mPFS and mOS had the most excellent linear relationships (R2adj = 0.8036).

Conclusion: For targeted drugs for the treatment of NSCLC, short-term surrogate endpoint indicators such as ORR and DCR may be reliable surrogate indicators for mPFS and mOS. However, whether short-term surrogate endpoint indicators can be used to predict final endpoints remains to be verified.
A Mammary Organoid Model to Study Branching Morphogenesis
Authors: Caruso Marika , Huang Sjanie , Mourao Larissa , Scheele Colinda L. G. J.
Published: March 2022

Branching morphogenesis is the process that gives rise to branched structures in several organs, such as the lung, the kidney, and the mammary gland. Although morphologically well described, the exact mechanisms driving branch elongation and bifurcation are still poorly understood. Signaling cues from the stroma and extracellular matrix have an important role in driving branching morphogenesis. Organoid models derived from primary mammary epithelial cells have emerged as a powerful tool to gain insight into branching morphogenesis of the mammary gland. However, current available mammary organoid culture protocols result in morphologically simple structures which do not resemble the complex branched structure of the in vivo mammary gland. Supplementation of growth factors to mammary organoids cultured in basement membrane extract or collagen I were shown to induce bud formation and elongation but are not sufficient to drive true branching events. Here, we present an improved culture approach based on 3D primary mammary epithelial cell culture to develop branched organoids with a complex morphology. By alternating the addition of fibroblast growth factor 2 and epidermal growth factor to mammary organoids cultured in a basement membrane extract matrix enriched with collagen type I fibers, we obtain complex mammary organoid structures with primary, secondary, and tertiary branches over a period of 15–20 days. Mammary organoid structures grow >1 mm in size and show an elongated and branched shape which resembles in vivo mammary gland morphology. This novel branched mammary organoid model offers many possibilities to study the mechanisms of branching in the developing mammary gland.
Simultaneous Whole-Chamber Non-contact Mapping of Highest Dominant Frequency Sites During Persistent Atrial Fibrillation: A Prospective Ablation Study
Authors: Chu Gavin S. , Li Xin , Stafford Peter J. , Vanheusden Frederique J. , Salinet João L. , Almeida Tiago P. , Dastagir Nawshin , Sandilands Alastair J. , Kirchhof Paulus , Schlindwein Fernando S. , Ng G. André
Published: March 2022

Purpose

Sites of highest dominant frequency (HDF) are implicated by many proposed mechanisms underlying persistent atrial fibrillation (persAF). We hypothesized that prospectively identifying and ablating dynamic left atrial HDF sites would favorably impact the electrophysiological substrate of persAF. We aim to assess the feasibility of prospectively identifying HDF sites by global simultaneous left atrial mapping.

Methods

PersAF patients with no prior ablation history underwent global simultaneous left atrial non-contact mapping. 30 s of electrograms recorded during AF were exported into a bespoke MATLAB interface to identify HDF regions, which were then targeted for ablation, prior to pulmonary vein isolation. Following ablation of each region, change in AF cycle length (AFCL) was documented (≥ 10 ms considered significant). Baseline isopotential maps of ablated regions were retrospectively analyzed looking for rotors and focal activation or extinction events.

Results

A total of 51 HDF regions were identified and ablated in 10 patients (median DF 5.8Hz, range 4.4–7.1Hz). An increase in AFCL of was seen in 20 of the 51 regions (39%), including AF termination in 4 patients. 5 out of 10 patients (including the 4 patients where AF termination occurred with HDF-guided ablation) were free from AF recurrence at 1 year. The proportion of HDF occurrences in an ablated region was not associated with change in AFCL (τ = 0.11, p = 0.24). Regions where AFCL decreased by 10 ms or more (i.e., AF disorganization) after ablation also showed lowest baseline spectral organization (p < 0.033 for any comparison). Considering all ablated regions, the average proportion of HDF events which were also HRI events was 8.0 ± 13%. Focal activations predominated (537/1253 events) in the ablated regions on isopotential maps, were modestly associated with the proportion of HDF occurrences represented by the ablated region (Kendall’s τ = 0.40, p < 0.0001), and very strongly associated with focal extinction events (τ = 0.79, p < 0.0001). Rotors were rare (4/1253 events).

Conclusion

Targeting dynamic HDF sites is feasible and can be efficacious, but lacks specificity in identifying relevant human persAF substrate. Spectral organization may have an adjunctive role in preventing unnecessary substrate ablation. Dynamic HDF sites are not associated with observable rotational activity on isopotential mapping, but epi-endocardial breakthroughs could be contributory.
Impact of Lhcx2 on Acclimation to Low Iron Conditions in the Diatom Phaeodactylum tricornutum
Authors: Buck Jochen M. , Wünsch Marie , Schober Alexander F. , Kroth Peter G. , Lepetit Bernard
Published: March 2022

Iron is a cofactor of photosystems and electron carriers in the photosynthetic electron transport chain. Low concentrations of dissolved iron are, therefore, the predominant factor that limits the growth of phototrophs in large parts of the open sea like the Southern Ocean and the North Pacific, resulting in “high nutrient–low chlorophyll” (HNLC) areas. Diatoms are among the most abundant microalgae in HNLC zones. Besides efficient iron uptake mechanisms, efficient photoprotection might be one of the key traits enabling them to outcompete other algae in HNLC regions. In diatoms, Lhcx proteins play a crucial role in one of the main photoprotective mechanisms, the energy-dependent fluorescence quenching (qE). The expression of Lhcx proteins is strongly influenced by various environmental triggers. We show that Lhcx2 responds specifically and in a very sensitive manner to iron limitation in the diatom Phaeodactylum tricornutum on the same timescale as the known iron-regulated genes ISIP1 and CCHH11. By comparing Lhcx2 knockout lines with wild type cells, we reveal that a strongly increased qE under iron limitation is based on the upregulation of Lhcx2. Other observed iron acclimation phenotypes in P. tricornutum include a massively reduced chlorophyll a content/cell, a changed ratio of light harvesting and photoprotective pigments per chlorophyll a, a decreased amount of photosystem II and photosystem I cores, an increased functional photosystem II absorption cross section, and decoupled antenna complexes. H2O2 formation at photosystem I induced by high light is lowered in iron-limited cells, while the amount of total reactive oxygen species is rather increased. Our data indicate a possible reduction in singlet oxygen by Lhcx2-based qE, while the other iron acclimation phenotype parameters monitored are not affected by the amount of Lhcx2 and qE.
High Ambient Temperature Regulated the Plant Systemic Response to the Beneficial Endophytic Fungus Serendipita indica
Authors: Chen Xiao-Jie , Yin Yue-Qing , Zhu Xin-Meng , Xia Xue , Han Jia-Jia
Published: March 2022

Most plants in nature establish symbiotic associations with endophytic fungi in soil. Beneficial endophytic fungi induce a systemic response in the aboveground parts of the host plant, thus promoting the growth and fitness of host plants. Meanwhile, temperature elevation from climate change widely affects global plant biodiversity as well as crop quality and yield. Over the past decades, great progresses have been made in the response of plants to high ambient temperature and to symbiosis with endophytic fungi. However, little is known about their synergistic effect on host plants. The endophytic fungus Serendipita indica colonizes the roots of a wide range of plants, including Arabidopsis. Based on the Arabidopsis-S. indica symbiosis experimental system, we analyzed the synergistic effect of high ambient temperature and endophytic fungal symbiosis on host plants. By transcriptome analysis, we found that DNA replication-related genes were significantly upregulated during the systemic response of Arabidopsis aboveground parts to S. indica colonization. Plant hormones, such as jasmonic acid (JA) and ethylene (ET), play important roles in plant growth and systemic responses. We found that high ambient temperature repressed the JA and ET signaling pathways of Arabidopsis aboveground parts during the systemic response to S. indica colonization in roots. Meanwhile, PIF4 is the central hub transcription factor controlling plant thermosensory growth under high ambient temperature in Arabidopsis. PIF4 is also involving JA and/or ET signaling pathway. We found that PIF4 target genes overlapped with many differentially expressed genes (DEGs) during the systemic response, and further showed that the growth promotion efficiency of S. indica on the pif4 mutant was higher than that on the wild-type plants. In short, our data showed that high ambient temperature strengthened the growth promotion effect of S. indica fungi on the aboveground parts of the host plant Arabidopsis, and the growth promotion effect of the systemic response under high ambient temperature was regulated by PIF4.
Shade-Tolerant Soybean Reduces Yield Loss by Regulating Its Canopy Structure and Stem Characteristics in the Maize–Soybean Strip Intercropping System
Authors: Cheng Bin , Wang Li , Liu Ranjin , Wang Weibing , Yu Renwei , Zhou Tao , Ahmad Irshan , Raza Ali , Jiang Shengjun , Xu Mei , Liu Chunyan , Yu Liang , Wang Wenyan , Jing Shuzhong , Liu Weiguo , Yang Wenyu
Published: March 2022

The shading of maize is an important factor, which leads to lodging and yield loss of soybean in the maize–soybean strip intercropping system, especially in areas with low solar radiation. This study was designed to explore how shade-tolerant soybean reduces yield loss by regulating its canopy structure and stem characteristics in the maize–soybean strip intercropping system. The soybean cultivars Tianlong No.1 (TL-1, representative of shade-tolerant plants) and Chuandou-16 (CD-16, representative of shade-intolerant plants) were grown in monocropping and intercropping systems from 2020 to 2021 in Chongzhou, Sichuan, China. Regardless of shade-intolerant or shade-tolerant soybean, the canopy and stem of soybean in strip intercropping were weaker than those of the corresponding monoculture. But compared with shade-intolerant soybean, the shade-tolerant soybean slightly changed its spatial structure of canopy and stem morphology and physiology in maize–soybean strip intercropping system, especially in the later growth stages. On the one hand, the canopy of shade-tolerant soybean showed relatively high transmission coefficient (TC) and relatively low leaf area index (LAI) and mean leaf angle (MLA). On the other hand, the stem of shade-tolerant soybean was obviously stronger than that of shade-intolerant soybean in terms of external morphology, internal structure, and physiological characteristics. Additionally, compared with shade-intolerant soybean, shade-tolerant soybean showed higher APnWP (the average net photosynthetic rate of the whole plant) and seed yield in the strip intercropping. The results showed that shade-tolerant soybean increased light energy capture and photosynthesis in the different canopy levels to promote the morphological and physiological development of the stem and ultimately reduce the yield loss of the strip intercropping system. However, the molecular mechanism of low radiation regulating soybean canopy structure (LAI, TC, and MLA) needs further in-depth research to provide theoretical guidance for cultivating plants with ideal canopy shape that can adapt to changing light environment in intercropping system.
MAG2 and MAL Regulate Vesicle Trafficking and Auxin Homeostasis With Functional Redundancy
Authors: Ma Xiaohui , Zhao Xiaonan , Zhang Hailong , Zhang Yiming , Sun Shanwen , Li Ying , Long Zhengbiao , Liu Yuqi , Zhang Xiaomeng , Li Rongxia , Tan Li , Jiang Lixi , Zhu Jian-Kang , Li Lixin
Published: March 2022

Auxin is a central phytohormone and controls almost all aspects of plant development and stress response. Auxin homeostasis is coordinately regulated by biosynthesis, catabolism, transport, conjugation, and deposition. Endoplasmic reticulum (ER)-localized MAIGO2 (MAG2) complex mediates tethering of arriving vesicles to the ER membrane, and it is crucial for ER export trafficking. Despite important regulatory roles of MAG2 in vesicle trafficking, the mag2 mutant had mild developmental abnormalities. MAG2 has one homolog protein, MAG2-Like (MAL), and the mal-1 mutant also had slight developmental phenotypes. In order to investigate MAG2 and MAL regulatory function in plant development, we generated the mag2-1 mal-1 double mutant. As expected, the double mutant exhibited serious developmental defects and more alteration in stress response compared with single mutants and wild type. Proteomic analysis revealed that signaling, metabolism, and stress response in mag2-1 mal-1 were affected, especially membrane trafficking and auxin biosynthesis, signaling, and transport. Biochemical and cell biological analysis indicated that the mag2-1 mal-1 double mutant had more serious defects in vesicle transport than the mag2-1 and mal-1 single mutants. The auxin distribution and abundance of auxin transporters were altered significantly in the mag2-1 and mal-1 single mutants and mag2-1 mal-1 double mutant. Our findings suggest that MAG2 and MAL regulate plant development and auxin homeostasis by controlling membrane trafficking, with functional redundancy.