bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of antimicrobial stewardship interventions on days of therapy and guideline adherence: A comparative point-prevalence survey assessment
Authors: Shamseddine Jinan , Sadeq Ahmed , Yousuf Khadija , Abukhater Rawan , Yahya Lamia Omer , Espil Maysaa Abdulatif , Hassan Mohamed Elamin , Fadl Rayan Elamin , Ahmed Rami Tag Elsir , Elkonaissi Islam , Abdelsalam Abeer Elmahi , Naqbi Aisha Al , Nuaimi Nora Al , Hosani Maitha Al , Marri Rowdha Al , Abdouli Asma Al , Alakhras Abdullah Mohamad , Masri Neamat Ibrahim Al , O’Sullivan Siobhan , Everett Dean , Babiker Zahir Osman Eltahir
Published: January 2023

Background

Antimicrobial stewardship (AMS) is a crucial tool for rationalizing the use of antimicrobial agents and reducing the burden of antimicrobial resistance. We aimed to assess the impact of AMS interventions on antimicrobial utilization and adherence to antimicrobial guidelines.

Methods

We conducted a prospective quasi-experimental study at a major tertiary hospital in the United Arab Emirates. Using standardized World Health Organization’s methodology, point-prevalence surveys (PPS) were performed in November 2019 and January 2022. Core AMS interventions consisted of proactive bloodstream infection service, proactive and reactive infectious diseases consult service, prospective audit and feedback by clinical pharmacists, development of antimicrobial guidelines based on cumulative antibiograms, and implementation of induction programs for new clinical staff. Days of therapy (DOT) per 1000 patient days present and rate of compliance with antimicrobial guidelines were compared before and after the core interventions. Multiple logistic regression analysis was carried out to adjust for the potential confounding effects of age, gender, hospitalization within 90 days, central or peripheral line insertion, urinary catheterization, and mechanical ventilation. P-value<0.05 was considered statistically significant.

Results

Pre- and post-intervention PPSs included 292 and 370 patients, respectively. Both had similar age and gender distribution. Patients receiving antimicrobials were 51% (149/292) in 2019 and 45% (166/370) in 2022 (p 0.12). Univariate analysis showed a reduced post-intervention DOT per 1000 patients present (6.1 +/- 16.2 vs 2.4 +/-5.1, p<0.01) and an improved post-intervention guideline compliance (59% vs 67%, p 0.23). Following multiple logistic regression, the reduction in post-intervention DOT remained statistically significant (co-efficient -0.17 (95% CI -8.58 to -1.94, p<0.01), and the improvement in guideline adherence became statistically significant (adjusted odds ratio 1.91 (95% CI 1.05 to 3.45, p 0.03).

Conclusion

Coordinated and sustained AMS interventions have a significant impact on improving antimicrobial utilisation and adherence to guidelines.
Dissolved/dispersed polycyclic aromatic hydrocarbon spatial and temporal changes in the Western Gulf of Mexico
Authors: Gold-Bouchot Gerardo , Arcega-Cabrera Flor , Ceja-Moreno Víctor
Published: January 2023

Oil extraction and transport activities in the Gulf of Mexico (GoM), along with major marine oil spills and riverine inputs, are exerting environmental pressure on this system by increasing the concentration of oil-related pollutants such as polycyclic aromatic hydrocarbons (PAHs). To fully identify these changes related to oil activities, current PAH levels should be established. Here, we present the PAH concentration and the low molecular weight/high molecular weight (LMW/HMW) ratios obtained in the Perdido Fold Belt area in surface and bottom water at four cruises from May 2016 to September 2017. The Perdido 1 (P1) cruise was conducted in May 2016, the Perdido 2 (P2) cruise in September–October 2016, the Perdido 3 (P3) cruise in June 2017, and the Perdido 4 (P4) cruise in September 2017. Samples were taken during each cruise at up to 3,500-m depth, the deepest ever recorded for the GoM. Results show that the highest concentrations of PAH, LMW PAHs, and HMW PAHs were found in the P4 cruise (1.15, 1.05, and 0.10 µg/L, respectively), well below the 300 µg/L guideline for acute exposure. LMW/HMW ratios show that only the P1 cruise indicates pyrogenic hydrocarbons, while P2, P3, and P4 were petrogenic. The spatial distribution of total PAH, LMW, and HMW showed higher values in the southern and northeastern areas, except for P4, which showed high values related to riverine inputs. The complex hydrodynamic in the region was found to have a significant effect on PAH seasonal changes, river contributions, eddy circulation, and fronts to promote their dispersion.
Effects of temperature and photoperiod on growth, physiological, and behavioral performance in steelhead trout (Oncorhynchus mykiss) under indoor aquaculture condition
Authors: Ma Zhen , Zhang Jia , Zhang Xu , Li Haixia , Liu Ying , Gao Lei
Published: January 2023

Light and temperature are necessary conditions for migratory fish. The assessment of fish physiology and behavior is important for identifying fish welfare, but also for the assessment of the optimal setting of recirculating aquaculture systems (RASs). This study aimed to explore the interactive effect of photoperiod and temperature on steelhead trout culture. Four treatments were set up with specific settings were as follows: a LP-LT group treated with 16L:8D and 12°C, a LP-HT group treated with 16L:8D and 16°C, a SP-LT group treated with 12L:12D and 12°C, and a SP-HT group treated with 12L:12D and 16°C. Growth performance, behavioral and physiological parameters were measured. Two indexes, locomotor activity and social interaction were used for behavioral analysis, and the results were applied to interpret the behavioral responses to the photoperiod and temperature stimulation in juveniles. The growth performances were significantly lower in treatments LP-LT and SP-LT. The treatment LP-HT had significantly higher growth performance than the other treatments, but no significant differences were noted in survival rate and coefficient of variation. The results of fish behavior indicated that the movement of juveniles should be primarily monitored at high temperatures or long photoperiods, and the state parameters should be primarily monitored at low temperatures or short photoperiods. The results of the physiological parameters showed that the recovery time from stress varied among different treatments. After 60 days of the experiment, superoxide dismutase and alanine aminotransferase dropped back to their initial level. The results of Na+-K+-ATPase showed that although the combined effect of photoperiod and temperature could advance the time of smoltification, it may result in poorer salt tolerance. Our findings underscore the importance of the interaction of photoperiod and temperature on steelhead trout culture. The outcome could provide guidance for the development of effective aquaculture systems.
Effect of thermal cycles on the engineering properties and durability of sustainable fibrous high-strength concrete
Authors: Hakeem Ibrahim Y. , Hosen MD. Akter , Alyami Mana , Qaidi Shaker , Özkılıç Yasin O. , Alhamami Ali , Alharthai Mohammad
Published: January 2023

In this research, the effect of heat–cool cycles (HCCs) on high-strength concrete (HSC) containing steel fibres (SFs), polypropylene fibres (PPFs), and date palm fibres (DPFs), which were named fibrous high-strength concrete (FHSC), was studied. To produce FHSC, three doses of 0.2, 0.6, and 1 percent of each fibre were used. All samples were tested after 28 days of normal water curing and 270 days of exposure to HCCs (continuing the authors’ project and research published at 28 and 180 days). This entails heating for 2 days at 60 C in the oven and cooling for another 2 days at room temperature for 270 days. The experiment’s findings revealed that fibre reinforcement in concrete enhances its strength and durability. By incorporating the three types of fibres into high-strength concrete, with and without HCCs, the modulus of rupture was significantly increased. In both conditions, including with or without the implementation of HCCs, incorporating the three fibre types into the HSC showed a significant increase in toughness. As a result, natural date palm fibres can produce sustainable FHSC that can withstand harsh environmental conditions. Moreover, compared to the previous study conducted by the authors at 180 days, there is a slight severity in both the pattern of decrease and increase of the studied characteristics at 270 days caused by the effect of thermal cycles and fibres.
Extracutaneous features and complications of the Ehlers-Danlos syndromes: A systematic review
Authors: Doolan Brent J. , Lavallee Mark E. , Hausser Ingrid , Schubart Jane R. , Michael Pope F. , Seneviratne Suranjith L. , Winship Ingrid M. , Burrows Nigel P.
Published: January 2023

Introduction

The Ehlers-Danlos syndromes (EDS) comprise a group of inherited connective tissue disorders presenting with variable fragility to skin, soft tissue, and certain internal organs, which can cause significant complications, particularly arterial rupture, bowel perforation and joint difficulties. Currently, there are 14 proposed subtypes of EDS, with all except one subtype (hypermobile EDS) having an identified genetic etiology. An understanding of the extracutaneous features and complications within each subtype is key to maximizing clinical care and reducing the risk of further complications.

Methods

A systematic review of EDS-related extracutaneous features and complications was undertaken.

Results

We identified 839 EDS cases that met the inclusion criteria. We noted a high prevalence of joint hypermobility amongst kyphoscoliotic (39/39, 100%), spondylodysplastic (24/25, 96.0%), and hypermobile (153/160, 95.6%) EDS subtypes. The most common musculoskeletal complications were decreased bone density (39/43, 90.7%), joint pain (217/270, 80.4%), and hypotonia/weakness (79/140, 56.4%). Vascular EDS presented with cerebrovascular events (25/153, 16.3%), aneurysm (77/245, 31.4%), arterial dissection/rupture (89/250, 35.5%), and pneumothorax/hemothorax. Chronic pain was the most common miscellaneous complication, disproportionately affecting hypermobile EDS patients (139/157, 88.5%). Hypermobile EDS cases also presented with chronic fatigue (61/63, 96.8%) and gastrointestinal complications (57/63, 90.5%). Neuropsychiatric complications were noted in almost all subtypes.

Discussion

Understanding the extracutaneous features and complications of each EDS subtype may help diagnose and treat EDS prior to the development of substantial comorbidities and/or additional complications.

Systematic review registration

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022308151, identifier CRD42022308151.
Comparison of photosynthetic responses between haptophyte Phaeocystis globosa and diatom Skeletonema costatum under phosphorus limitation
Authors: Chai Xiaojie , Zheng Lingling , Liu Jin , Zhan Jiao , Song Lirong
Published: January 2023

The diatom Skeletonema costatum and the haptophyte Phaeocystis globosa often form blooms in the coastal waters of the South China Sea. Skeletonemacostatum commonly dominates in nutrient enrichment coastal waters, whereas P. globosa starts flourishing after the diatom blooms when phosphorus (P) is limited. Therefore, P limitation was proposed to be a critical factor affecting diatom–haptophyte transition. To elucidate the tolerance to P limitation in P. globosa compared with S. costatum, the effect of P limitation on their photosystem II (PSII) performance was investigated and their photosynthesis acclimation strategies in response to P limitation were evaluated. P limitation did not affect the growth of P. globosa over 7 days but decreased it for S. costatum. Correspondingly, the PSII activity of S. costatum was significantly inhibited by P limitation. The decline in PSII activity in S. costatum under P limitation was associated with the impairment of the oxygen-evolving complex (the donor side of PSII), the hindrance of electron transport from QA− to QB (the acceptor side of PSII), and the inhibition of electron transport to photosystem I (PSI). The 100% decrease in D1 protein level of S. costatum after P limitation for 6 days and PsbO protein level after 2 days of P limitation were attributed to its enhanced photoinhibition. In contrast, P. globosa maintained its photosynthetic activity with minor impairment of the function of PSII. With accelerated PSII repair and highly increased non-photochemical quenching (NPQ), P. globosa can avoid serious PSII damage under P limitation. On the contrary, S. costatum decreased its D1 restoration under P limitation, and the maximum NPQ value in S. costatum was only one-sixth of that in P. globosa. The present work provides extensive evidence that a close interaction exists between the tolerance to P limitation and photosynthetic responses of S. costatum and P. globosa.
Anammox bacterial abundance and diversity in different temperatures of purple paddy soils by 13C-DNA stable-isotope probing combined with high-throughput sequencing
Authors: Yu Zijie , He Xinhua , Li Zhitong , Zhou Shuang , Guo Dalu , Pu Hao , Luo Hongyan
Published: January 2023

Introduction

Anaerobic ammonium oxidation (anammox) plays a vital role in the global nitrogen cycle by oxidizing ammonium to nitrogen under anaerobic environments. However, the existence, abundance, and diversity of anammox bacteria between different temperatures are less studied, particularly in purple paddy soils.

Methods

13C-DNA stable-isotope probe combined with Illumina MiSeq high-throughput sequencing was employed to explore soil abundance and diversity of anammox bacteria. In doing so, 40–60 cm depth soils from typical purple paddy soils in Chongqing, southwest China, were cultured under 12CO2-labeled and 13CO2-labeled at 35°C, 25°C, 15°C, and 5°C for 56 days.

Results and Discussion

Anammox bacteria were not labeled at all by 13CO2 at 5°C. The highest abundance of anammox bacteria was found at 25°C (3.52 × 106~3.66 × 106 copies·g−1 dry soil), followed by 35°C and 15°C (2.01 × 106~2.37 × 106 copies·g−1 dry soil) and almost no increase at 5°C. The relative abundance of Candidatus Jettenia sp. was higher at 25°C and 15°C, while Candidatus Brocadia sp. was higher at 35°C and 5°C. Our results revealed differences in anammox bacteria at different temperatures in purple paddy soils, which could provide a better understanding of soil N cycling regulated by anammox bacteria.
Research progress on rheumatoid arthritis-associated depression
Authors: Liu Nian , Yan Weitian , Su Rong , Zhang Lin , Wang Xingqiang , Li Zhaofu , Qin Dongdong , Peng Jiangyun
Published: January 2023

Depression is an independent mood disorder and one of the most common comorbidities of rheumatoid arthritis (RA). Growing evidence suggests that there is two-way regulation between RA and depression, resulting in a vicious cycle of RA, depression, poor outcomes, and disease burden. The rising prevalence of RA-associated depression warrants a re-examination of the relationships between them. Here we provide an overview of the etiology and pathological mechanisms of RA-associated depression, and recent advances in treatment with biologics, which will facilitate the development of new and effective prevention and treatment strategies.
Effect of transcranial direct current stimulation for patients with disorders of consciousness: A systematic review and meta-analysis
Authors: Ma Hui , Zhao Kehong , Jia Chengsen , You Jiuhong , Zhou Mei , Wang Tingting , Huang Cheng
Published: January 2023

Introduction

Transcranial direct current stimulation (tDCS) could potentially facilitate consciousness improvement in patients with disorders of consciousness (DOC). The aim of this study was to investigate the therapeutic efficacy of tDCS on consciousness recovery for patients with DOC.

Methods

Eight databases were systematically searched from their inception to June 2022. Quality of included studies were assessed using PEDro score and Cochrane’s risk of bias assessment. All statistical analyses were performed using RevMan software. Seventeen studies with 618 patients were identified eligible for this study, and fifteen studies with sufficient data were pooled in the meta-analysis.

Results

The results of meta-analysis showed a significant effect on increasing GCS scores (MD = 1.73; 95% CI, 1.28–2.18; P < 0.01) and CRS-R scores (MD = 1.28; 95% CI = 0.56–2.00; P < 0.01) in favor of the real stimulation group as compared to sham. The results of subgroup analysis demonstrated that only more than 20 sessions of stimulation could significantly enhance the improvement of GCS scores and the CRS-R scores. Moreover, the effect of tDCS on CRS-R score improvement was predominant in patients with minimal conscious state (MCS) (MD = 1.84; 95% CI = 0.74–2.93; P < 0.01).

Conclusion

Anodal tDCS with sufficient stimulation doses appears to be an effective approach for patients with MCS, in terms of CRS-R scores.

Systematic review registration

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022336958.
High-resolution synthesis of high-density breast mammograms: Application to improved fairness in deep learning based mass detection
Authors: Garrucho Lidia , Kushibar Kaisar , Osuala Richard , Diaz Oliver , Catanese Alessandro , del Riego Javier , Bobowicz Maciej , Strand Fredrik , Igual Laura , Lekadir Karim
Published: January 2023

Computer-aided detection systems based on deep learning have shown good performance in breast cancer detection. However, high-density breasts show poorer detection performance since dense tissues can mask or even simulate masses. Therefore, the sensitivity of mammography for breast cancer detection can be reduced by more than 20% in dense breasts. Additionally, extremely dense cases reported an increased risk of cancer compared to low-density breasts. This study aims to improve the mass detection performance in high-density breasts using synthetic high-density full-field digital mammograms (FFDM) as data augmentation during breast mass detection model training. To this end, a total of five cycle-consistent GAN (CycleGAN) models using three FFDM datasets were trained for low-to-high-density image translation in high-resolution mammograms. The training images were split by breast density BI-RADS categories, being BI-RADS A almost entirely fatty and BI-RADS D extremely dense breasts. Our results showed that the proposed data augmentation technique improved the sensitivity and precision of mass detection in models trained with small datasets and improved the domain generalization of the models trained with large databases. In addition, the clinical realism of the synthetic images was evaluated in a reader study involving two expert radiologists and one surgical oncologist.
Strategies for five tumour markers in the screening and diagnosis of female breast cancer
Authors: Luo Jun , Xiao Jianbo , Yang Yuwei , Chen Gang , Hu Dong , Zeng Jiawei
Published: January 2023

Objective

This study evaluated the diagnostic value of different combinations of five commonly used tumour markers and screened the best combination of tumour markers.

Methods

Regression analysis was used to evaluate 185 patients with suspected breast cancer admitted to Mianyang Central Hospital from January 2020 to December 2021. The differences of five tumour markers between a breast cancer group and a benign lesion group were analysed. The sensitivity and specificity of five tumour markers were compared.

Results

Of 185 patients with suspected breast cancer, 108 patients had breast cancer and 77 patients had benign breast tumours. The detection results of carcinoembryonic antigen (CEA), alpha fetoprotein (AFP), carbohydrate antigen 125 (CA125), carbohydrate antigen 199 (CA199) and carbohydrate antigen 153 (CA153) in patients with breast cancer were significantly higher than those in patients with benign breast tumours. In the analysis of the single-detection results of tumour markers, CEA had the highest sensitivity (23.94%), CA153 had the highest specificity (96.43%), AFP had the highest accuracy (47.66%) and CA153 had the highest area under the curve (AUC) value (0.727). With the increase of parallel indicators, the sensitivity, accuracy and AUC value increased in turn, and the increase was obvious in the front. The increase began to slow down after the three parallel indicators. Among the different combinations of three parallel detections of breast cancer tumour markers, the highest sensitivity was AFP + CEA + CA153 (83.46%), the highest accuracy was AFP + CEA + CA153 and AFP + CA153 + CA125 (80.25%), and the highest AUC was CEA + CA125 + CA199 (0.922).

Conclusion

AFP, CA153 and CA199 are recommended for clinical diagnosis of breast cancer. In routine physical examination and early breast cancer screening, the optimal combination of AFP + CEA + CA153 three parallel tests is recommended.
Reconstructive types effect the prognosis of patients with tumors in the central and nipple portion of breast cancer? An analysis based on SEER database
Authors: Wang Ping , Wang Le , Liang Xiaming , Si Erran , Yang Yongguang , Kong Lingfei , Dong Yonghui
Published: January 2023

Introduction

The impact of different types of reconstruction, including tissue reconstruction, implant reconstruction and combined reconstruction, on patient survival were not illustrated completely. We tried to investigate the impact of patient survival between different types of reconstruction.

Methods

We enrolled 6271 patients with tumors in the central and nipple portion of breast cancer from the Surveillance, Epidemiology, and End Results database. Factors associated with survival were identified by Cox regression analyses. The mortality rates per 1,000 person-years were calculated and compared. Survival curves were produced by Kaplan-Meier analyses using log-rank tests and cox proportional hazards regression quantified the risk of survival.

Results

Reconstructive types, region, insurance, race, marial status, grade, stage, ER status, PR status, HER-2 status and chemotherapy were significant prognostic factors associated with breast cancer-specific survival. The breast cancer mortality rates per 1,000 person-years for patients with tissue, implant and combined group were 26.01,21.54 and 19.83 which showed a downward trend. The HR of implant and combined reconstruction adjusted for demographic, pathological, and therapeutic data was 0.82 (95% CI: 0.67-1.00, p=0.052) and 0.73(95% CI:0.55-0.97, p=0.03) compared with tissue reconstruction.

Conclusion

Breast cancer-related mortality between implant reconstruction and autologous tissue reconstruction showed no significantly different, but the risk of BCSS of compound reconstruction was lower than tissue reconstruction.
Cancel cancer: The immunotherapeutic potential of CD200/CD200R blockade
Authors: Choe Deborah , Choi Dongwon
Published: January 2023

Immune checkpoint molecules function to inhibit and regulate immune response pathways to prevent hyperactive immune activity from damaging healthy tissues. In cancer patients, targeting these key molecules may serve as a valuable therapeutic mechanism to bolster immune function and restore the body’s natural defenses against tumors. CD200, an immune checkpoint molecule, is a surface glycoprotein that is widely but not ubiquitously expressed throughout the body. By interacting with its inhibitory receptor CD200R, CD200 suppresses immune cell activity within the tumor microenvironment, creating conditions that foster tumor growth. Targeting the CD200/CD200R pathway, either through the use of monoclonal antibodies or peptide inhibitors, has shown to be effective in boosting anti-tumor immune activity. This review will explore CD200 and the protein’s expression and role within the tumor microenvironment, blood endothelial cells, and lymph nodes. This paper will also discuss the advantages and challenges of current strategies used to target CD200 and briefly summarize relevant preclinical/clinical studies investigating the immunotherapeutic efficacy of CD200/CD200R blockade.
Knowledge, attitudes, and behaviors toward fertility preservation in patients with breast cancer: A cross-sectional survey of physicians
Authors: Baek Soo Yeon , Lee Kyung-Hun , Kim Sung-Bae , Gomez Henry , Vidaurre Tatiana , Park Yeon Hee , Ahn Hee Kyung , Kim Yoo Seok , Park In Hae , Ahn Sung Gwe , Lee Jeeyeon , Jeong Jae Ho , Kim Seonok , Kim Hee Jeong
Published: January 2023

Background

Fertility is an important issue for young women with breast cancer, but studies about physicians’ knowledge, attitudes, and practices toward fertility preservation (FP) are largely based on Western populations and do not reflect recent international guidelines for FP. In this international study, we aimed to assess the knowledge, attitudes, and practices of physicians from South Korea, other Asian countries, and Latin America toward FP in young women with breast cancer, and identify the related barriers.

Methods

The survey was conducted anonymously among physicians from South Korea, other Asian countries, and Latin America involved in breast cancer care between November 2020 and July 2021. Topics included knowledge, attitudes, and perceptions toward FP; practice behaviors; barriers; and participant demographics. We grouped related questions around two main themes—discussion with patients about FP, and consultation and referral to a reproductive endocrinologist. We analyzed the relationships between main questions and other survey items.

Results

A total of 151 physicians completed the survey. Most participants’ overall knowledge about FP was good. More than half of the participants answered that they discussed FP with their patients in most cases, but that personnel to facilitate discussions about FP and the provision of educational materials were limited. A major barrier was time constraints in the clinic (52.6%). Discussion, consultations, and referrals were more likely to be performed by surgeons who primarily treated patients with operable breast cancer (FP discussion odds ratio [OR]: 2.90; 95% confidence interval [CI]: 1.24–6.79; FP consultation and referral OR: 2.98; 95% CI: 1.14–7.74). Participants’ knowledge and attitudes about FP were significantly associated with discussion, consultations, and referrals.

Conclusion

Physicians from South Korea, other Asian countries, and Latin America are knowledgeable about FP and most perform practice behaviors toward FP well. Physicians’ knowledge and favorable attitudes are significantly related to discussion with patients, as well as consultation with and referral to reproductive endocrinologists. However, there are also barriers, such as limitations to human resources and materials, suggesting a need for a systematic approach to improve FP for young women with breast cancer.
Elucidating the molecular determinants in the process of gastrin C-terminal pentapeptide amide end activating cholecystokinin 2 receptor by Gaussian accelerated molecular dynamics simulations
Authors: Yang Kecheng , Jin Huiyuan , Gao Xu , Wang Gang-Cheng , Zhang Guo-Qiang
Published: January 2023

Gastrin plays important role in stimulating the initiation and development of many gastrointestinal diseases through interacting with the cholecystokinin 2 receptor (CCK2R). The smallest bioactive unit of gastrin activating CCK2R is the C-terminal tetrapeptide capped with an indispensable amide end. Understanding the mechanism of this smallest bioactive unit interacting with CCK2R on a molecular basis could provide significant insights for designing CCK2R antagonists, which can be used to treat gastrin-related diseases. To this end, we performed extensive Gaussian accelerated molecular dynamics simulations to investigate the interaction between gastrin C-terminal pentapeptide capped with/without amide end and CCK2R. The amide cap influences the binding modes of the pentapeptide with CCK2R by weakening the electrostatic attractions between the C-terminus of the pentapeptide and basic residues near the extracellular domain in CCK2R. The C-terminus with the amide cap penetrates into the transmembrane domain of CCK2R while floating at the extracellular domain without the amide cap. Different binding modes induced different conformational dynamics of CCK2R. Residue pairs in CCK2R had stronger correlated motions when binding with the amidated pentapeptide. Key residues and interactions important for CCK2R binding with the amidated pentagastrin were also identified. Our results provide molecular insights into the determinants of the bioactive unit of gastrin activating CCK2R, which would be of great help for the design of CCK2R antagonists.
Successful treatment discontinuation in CML patients with full-dose and low-dose TKI: Results from real-world practice
Authors: Chen Yilin , Zhao Huifang , Guo Jingming , Zou Jing , He Wenjuan , Han Danlei , Cheng Fanjun , Zhang Yanli , Li Weiming
Published: January 2023

Background: In clinical studies, some patients who achieve deep molecular response (DMR) can successfully discontinue tyrosine kinase inhibitor (TKI). TKI dose reduction is also an important aspect of alleviating adverse effects and improving quality of life. This study aimed to explore the outcome after drug withdrawal in Chinese CML patients.

Methods: We conducted a retrospective analysis of the outcome of 190 patients who stopped TKI. 27 patients experienced dose reduction before TKI discontinuation. The median duration of TKI treatment and MR4 before discontinuation was 82 months and 61 months.

Results: With median follow-up after stopping TKI treatment of 17 months, the estimated TFR (Treatment Free Remission) were 76.9% (95%CI, 70.2%–82.4%), 68.8% (95%CI, 61.3%–75.2%), and 65.5% (95%CI, 57.4%–72.5%) at 6, 12 and 24 months. For full-dose and low-dose TKI groups, the TFR at 24 months was 66.7% and 55.8% (p = 0.320, log-rank). Most patients (56/57) quickly achieved MMR after restarting TKI treatment. Multivariable analysis showed that patients with TKI resistance had a higher risk of molecular relapse than patients without TKI resistance (p < 0.001).

Conclusion: TFR rates were not impaired in patients experiencing dose reduction before TKI discontinuation compared to patients with full-dose TKI. Our data on Chinese population may provide a basis for the safety and feasibility of TKI discontinuation, including discontinuation after dose reduction, in clinical practice.
Uncovering the effects and molecular mechanism of Astragalus membranaceus (Fisch.) Bunge and its bioactive ingredients formononetin and calycosin against colon cancer: An integrated approach based on network pharmacology analysis coupled with experimental validation and molecular docking
Authors: Hu Yu , Zhai Wenjuan , Tan Duanling , Chen Haipeng , Zhang Guiyu , Tan Xuanjing , Zheng Yuting , Gao Wenhui , Wei Yijie , Wu Jinjun , Yang Xin
Published: January 2023

Colon cancer is a highly malignant cancer with poor prognosis. Astragalus membranaceus (Fisch.) Bunge (Huang Qi in Chinese, HQ), a well-known Chinese herbal medicine and a popular food additive, possesses various biological functions and has been frequently used for clinical treatment of colon cancer. However, the underlying mechanism is not fully understood. Isoflavonoids, including formononetin (FMNT) and calycosin (CS), are the main bioactive ingredients isolated from HQ. Thus, this study aimed to explore the inhibitory effects and mechanism of HQ, FMNT and CS against colon cancer by using network pharmacology coupled with experimental validation and molecular docking. The network pharmacology analysis revealed that FMNT and CS exerted their anticarcinogenic actions against colon cancer by regulating multiple signaling molecules and pathways, including MAPK and PI3K-Akt signaling pathways. The experimental validation data showed that HQ, FMNT and CS significantly suppressed the viability and proliferation, and promoted the apoptosis in colon cancer Caco2 and HT-29 cells. HQ, FMNT and CS also markedly inhibited the migration of Caco2 and HT-29 cells, accompanied by a marked increase in E-cadherin expression, and a notable decrease in N-cadherin and Vimentin expression. In addition, HQ, FMNT and CS strikingly decreased the expression of ERK1/2 phosphorylation (p-ERK1/2) without marked change in total ERK1/2 expression. They also slightly downregulated the p-Akt expression without significant alteration in total Akt expression. Pearson correlation analysis showed a significant positive correlation between the inactivation of ERK1/2 signaling pathway and the HQ, FMNT and CS-induced suppression of colon cancer. The molecular docking results indicated that FMNT and CS had a strong binding affinity for the key molecules of ERK1/2 signaling pathway. Conclusively, HQ, FMNT and CS exerted good therapeutic effects against colon cancer by mainly inhibiting the ERK1/2 signaling pathway, suggesting that HQ, FMNT and CS could be useful supplements that may enhance chemotherapeutic outcomes and benefit colon cancer patients.
Heart rate variability during mindful breathing meditation
Authors: Natarajan Aravind
Published: January 2023

We discuss Heart Rate Variability (HRV) measured during mindful breathing meditation. We provide a pedagogical computation of two commonly used heart rate variability metrics, i.e. the root mean square of successive differences (RMSSD) and the standard deviation of RR intervals (SDRR), in terms of Fourier components. It is shown that the root mean square of successive differences preferentially weights higher frequency Fourier modes, making it unsuitable as a biosignal for mindful breathing meditation which encourages slow breathing. We propose a new metric called the autonomic balance index (ABI) which uses Respiratory Sinus Arrhythmia to quantify the fraction of heart rate variability contributed by the parasympathetic nervous system. We apply this metric to heart rate variability data collected during two different meditation techniques, and show that the autonomic balance index is significantly elevated during mindful breathing, making it a good signal for biofeedback during meditation sessions.
Prolonged repolarization in the early phase of ischemia is associated with ventricular fibrillation development in a porcine model
Authors: Bernikova Olesya G. , Tsvetkova Alena S. , Gonotkov Mikhail A. , Ovechkin Alexey O. , Demidova Marina M. , Azarov Jan E. , Platonov Pyotr G.
Published: January 2023

Background: Repolarization prolongation can be the earliest electrophysiological change in ischemia, but its role in arrhythmogenesis is unclear. The aim of the present study was to evaluate the early ischemic action potential duration (APD) prolongation concerning its causes, expression in ECG and association with early ischemic ventricular fibrillation (phase 1A VF).

Methods: Coronary occlusion was induced in 18 anesthetized pigs, and standard 12 lead ECG along with epicardial electrograms were recorded. Local activation time (AT), end of repolarization time (RT), and activation-repolarization interval (ARIc) were determined as dV/dt minimum during QRS-complex, dV/dt maximum during T-wave, and rate-corrected RT–AT differences, respectively. Patch-clamp studies were done in enzymatically isolated porcine cardiomyocytes. IK(ATP) activation and Ito1 inhibition were tested as possible causes of the APD change.

Results: During the initial period of ischemia, a total of 11 pigs demonstrated maximal ARIc prolongation >10 ms at 1 and/or 2.5 min of occlusion (8 and 6 cases at 1 and 2.5 min, respectively) followed by typical ischemic ARIc shortening. The maximal ARIc across all leads was associated with VF development (OR 1.024 95% CI 1.003–1.046, p = 0.025) and maximal rate-corrected QT interval (QTc) (B 0.562 95% CI 0.346–0.775, p < 0.001) in logistic and linear regression analyses, respectively. Phase 1A VF incidence was associated with maximal QTc at the 2.5 min of occlusion in ROC curve analysis (AUC 0.867, p = 0.028) with optimal cut-off 456 ms (sensitivity 1.00, specificity 0.778). The pigs having maximal QTc at 2.5 min more and less than 450 ms significantly differed in phase 1A VF incidence in Kaplan-Meier analysis (log-rank p = 0.007). In the patch-clamp experiments, 4-aminopyridine did not produce any effects on the APD; however, pinacidil activated IK(ATP) and caused a biphasic change in the APD with initial prolongation and subsequent shortening.

Conclusion: The transiently prolonged repolarization during the initial period of acute ischemia was expressed in the prolongation of the maximal QTc interval in the body surface ECG and was associated with phase 1A VF. IK(ATP) activation in the isolated cardiomyocytes reproduced the biphasic repolarization dynamics observed in vivo, which suggests the probable role of IK(ATP) in early ischemic arrhythmogenesis.
Effects of physical exercise associated with a diet enriched with natural antioxidants on cerebral hypoperfusion and reperfusion injury in spontaneously hypertensive rats
Authors: Lapi Dominga , Federighi Giuseppe , Lonardo Maria Serena , Chiurazzi Martina , Muscariello Espedita , Tenore Giancarlo , Colantuoni Antonio , Novellino Ettore , Scuri Rossana
Published: January 2023

Oxidative stress is implicated in the pathogenesis of arterial hypertension. The reduction in the bioavailability of nitric oxide (NO) causes endothelial dysfunction, altering the functions of cerebral blood vessels. Physical exercise and intake of antioxidants improve the redox state, increasing the vascular NO production and/or the decrease in NO scavenging by reactive oxygen species (ROS). The present study was aimed at assessing the effects of physical exercise associated with a diet enriched with antioxidants from the Annurca apple in preventing the microvascular damage due to cerebral hypoperfusion and reperfusion injury in spontaneously hypertensive rats (SHRs). The rat pial microcirculation was investigated by intravital fluorescence microscopy through a parietal closed cranial window. As expected, SHRs subjected to physical exercise or an antioxidants-enriched diet showed a reduction of microvascular permeability, ROS formation, and leukocyte adhesion to venular walls, with a major effect of the antioxidants-enriched diet, when compared to untreated SHRs. Moreover, capillary perfusion was preserved by both treatments in comparison with untreated SHRs. Unexpectedly, the combined treatments did not induce higher effects than the single treatment. In conclusion, our results support the efficacy of physical activity or antioxidant supplement in reducing the microvascular alterations due to hypertension and ascribe to an antioxidants-enriched diet effective microvascular protection in SHRs.
High spatial and temporal resolution cerebrovascular reactivity for humans and large mammals: A technological description of integrated fNIRS and niABP mapping system
Authors: Sainbhi Amanjyot Singh , Froese Logan , Gomez Alwyn , Marquez Izzy , Amenta Fiorella , Batson Carleen , Stein Kevin Y. , Zeiler Frederick A.
Published: January 2023

Introduction: The process of cerebral vessels maintaining cerebral blood flow (CBF) fairly constant over a wide range of arterial blood pressure is referred to as cerebral autoregulation (CA). Cerebrovascular reactivity is the mechanism behind this process, which maintains CBF through constriction and dilation of cerebral vessels. Traditionally CA has been assessed statistically, limited by large, immobile, and costly neuroimaging platforms. However, with recent technology advancement, dynamic autoregulation assessment is able to provide more detailed information on the evolution of CA over long periods of time with continuous assessment. Yet, to date, such continuous assessments have been hampered by low temporal and spatial resolution systems, that are typically reliant on invasive point estimations of pulsatile CBF or cerebral blood volume using commercially available technology.

Methods: Using a combination of multi-channel functional near-infrared spectroscopy and non-invasive arterial blood pressure devices, we were able to create a system that visualizes CA metrics by converting them to heat maps drawn on a template of human brain.

Results: The custom Python heat map module works in “offline” mode to visually portray the CA index per channel with the use of colourmap. The module was tested on two different mapping grids, 8 channel and 24 channel, using data from two separate recordings and the Python heat map module was able read the CA indices file and represent the data visually at a preselected rate of 10 s.

Conclusion: The generation of the heat maps are entirely non-invasive, with high temporal and spatial resolution by leveraging the recent advances in NIRS technology along with niABP. The CA mapping system is in its initial stage and development plans are ready to transform it from “offline” to real-time heat map generation.
A comprehensive framework for evaluation of high pacing frequency and arrhythmic optical mapping signals
Authors: Ramlugun Girish S. , Kulkarni Kanchan , Pallares-Lupon Nestor , Boukens Bastiaan J. , Efimov Igor R. , Vigmond Edward J. , Bernus Olivier , Walton Richard D.
Published: January 2023

Introduction: High pacing frequency or irregular activity due to arrhythmia produces complex optical mapping signals and challenges for processing. The objective is to establish an automated activation time-based analytical framework applicable to optical mapping images of complex electrical behavior.

Methods: Optical mapping signals with varying complexity from sheep (N = 7) ventricular preparations were examined. Windows of activation centered on each action potential upstroke were derived using Hilbert transform phase. Upstroke morphology was evaluated for potential multiple activation components and peaks of upstroke signal derivatives defined activation time. Spatially and temporally clustered activation time points were grouped in to wave fronts for individual processing. Each activation time point was evaluated for corresponding repolarization times. Each wave front was subsequently classified based on repetitive or non-repetitive events. Wave fronts were evaluated for activation time minima defining sites of wave front origin. A visualization tool was further developed to probe dynamically the ensemble activation sequence.

Results: Our framework facilitated activation time mapping during complex dynamic events including transitions to rotor-like reentry and ventricular fibrillation. We showed that using fixed AT windows to extract AT maps can impair interpretation of the activation sequence. However, the phase windowing of action potential upstrokes enabled accurate recapitulation of repetitive behavior, providing spatially coherent activation patterns. We further demonstrate that grouping the spatio-temporal distribution of AT points in to coherent wave fronts, facilitated interpretation of isolated conduction events, such as conduction slowing, and to derive dynamic changes in repolarization properties. Focal origins precisely detected sites of stimulation origin and breakthrough for individual wave fronts. Furthermore, a visualization tool to dynamically probe activation time windows during reentry revealed a critical single static line of conduction slowing associated with the rotation core.

Conclusion: This comprehensive analytical framework enables detailed quantitative assessment and visualization of complex electrical behavior.
Leaf-size control beyond transcription factors: Compensatory mechanisms
Authors: Tabeta Hiromitsu , Gunji Shizuka , Kawade Kensuke , Ferjani Ali
Published: January 2023

Plant leaves display abundant morphological richness yet grow to characteristic sizes and shapes. Beginning with a small number of undifferentiated founder cells, leaves evolve via a complex interplay of regulatory factors that ultimately influence cell proliferation and subsequent post-mitotic cell enlargement. During their development, a sequence of key events that shape leaves is both robustly executed spatiotemporally following a genomic molecular network and flexibly tuned by a variety of environmental stimuli. Decades of work on Arabidopsis thaliana have revisited the compensatory phenomena that might reflect a general and primary size-regulatory mechanism in leaves. This review focuses on key molecular and cellular events behind the organ-wide scale regulation of compensatory mechanisms. Lastly, emerging novel mechanisms of metabolic and hormonal regulation are discussed, based on recent advances in the field that have provided insights into, among other phenomena, leaf-size regulation.
Genome-wide analysis of LysM gene family members and their expression in response to Colletotrichum fructicola infection in Octoploid strawberry(Fragaria × ananassa)
Authors: Zhang Liqing , Li Shuigen , Fang Xianping , An Haishan , Zhang Xueying
Published: January 2023

The cultivated octoploid strawberry (Fragaria × ananassa) is an economically important fruit that is planted worldwide. The lysin motif (LysM) protein family is composed of the major class of plant pattern recognition receptors, which play important roles in sensing pathogen-associated molecular patterns (PAMPs), and subsequently triggers downstream plant immunity. In the present study, a comprehensive, genome-wide analysis of F. × ananassa LysM (FaLysM) genes was performed to investigate gene structures, phylogenic relationships, chromosome location, collinear relationships, transcription factor binding sites, and protein model analysis. We aimed to identify the LysM genes involved in the defense against plant pathogens. A total of 14 FaLysM genes were identified in the F. × ananassa genome and divided into 2 subgroups (LYP and LYK) on the basis of the phylogenetic analysis. The Ka/Ks ratio for the duplicated pair of most FaLysM genes was less than 1, which indicates that the selection pressure was mostly subject to the purifying selection during evolution. The protein model analysis revealed that FaLysM2-10 contain conserved mode of chitin binding, which suggest the potential role of FaLysM2-10 in pathogen perception and plant immunity. The RNA-Seq results showed the differential regulation of 14 FaLysM genes in response to Colletotrichum fructicola infection, implying the complex interaction between C. fructicola and strawberry. Knockout of candidate effector gene CfLysM2, which was previously proved to be highly expressed during C. fructicola infection, resulted in the up-regulation of six FaLysM genes (FaLysM1, FaLysM2, FaLysM3, FaLysM7, FaLysM8, and FaLysM12), indicating the competitive relations between CfLysM2 and FaLysM genes. Overall, this study provides fundamental information on the roles of LysM proteins in octoploid strawberry and its interaction with C. fructicola, laying useful information for further investigation on the C. fructicola-strawberry interaction and strawberry resistance breeding.