bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep learning-based spinal canal segmentation of computed tomography image for disease diagnosis: A proposed system for spinal stenosis diagnosis
Authors: Zhou Zhiyi , Wang Shenjun , Zhang Shujun , Pan Xiang , Yang Haoxia , Zhuang Yin , Lu Zhengfeng
Published: May 2024

Background:

Lumbar disc herniation was regarded as an age-related degenerative disease. Nevertheless, emerging reports highlight a discernible shift, illustrating the prevalence of these conditions among younger individuals.

Methods:

This study introduces a novel deep learning methodology tailored for spinal canal segmentation and disease diagnosis, emphasizing image processing techniques that delve into essential image attributes such as gray levels, texture, and statistical structures to refine segmentation accuracy.

Results:

Analysis reveals a progressive increase in the size of vertebrae and intervertebral discs from the cervical to lumbar regions. Vertebrae, bearing weight and safeguarding the spinal cord and nerves, are interconnected by intervertebral discs, resilient structures that counteract spinal pressure. Experimental findings demonstrate a lack of pronounced anteroposterior bending during flexion and extension, maintaining displacement and rotation angles consistently approximating zero. This consistency maintains uniform anterior and posterior vertebrae heights, coupled with parallel intervertebral disc heights, aligning with theoretical expectations.

Conclusions:

Accuracy assessment employs 2 methods: IoU and Dice, and the average accuracy of IoU is 88% and that of Dice is 96.4%. The proposed deep learning-based system showcases promising results in spinal canal segmentation, laying a foundation for precise stenosis diagnosis in computed tomography images. This contributes significantly to advancements in spinal pathology understanding and treatment.
A causal analysis of the relationship between exposure to sunlight and colorectal cancer risk: A Mendelian randomization study
Authors: Lin Yuan , Wang Shan-Juan , Fan Zhu-Ping , Xie Jin-Bi , Ding Gang-Yu , Liu Yan-Li , Wang Yi-Fei , Zhang Li-Hang
Published: May 2024

Several observational studies have found that exposure to sunlight reduces the risk of colorectal cancer (CRC). However, sun exposure remains ambiguous in its relationship to CRC. We carried out a Mendelian randomization (MR) study to explore the potential associations between them. We examined the exposure to sunlight summary statistics of the UK Biobank Consortium using a 2-sample MR analysis. Using data from the FinnGen consortium, we derived summary statistics for CRC. We conducted our analysis with various methods, incorporating inverse variance weighted (IVW) along with 4 other approaches. A Cochran Q statistic was used to measure the heterogeneity of instrumental variables (IVs). We screened 133 single nucleotide polymorphisms (SNPs) (time spent outdoors in summer), 41 SNPs (time spent outdoors in winter), and 35 SNPs (frequency of solarium/sunlamp use) representing sunlight exposure for MR analysis. All selected SNPs had an F-statistic >20, indicating that IVs did not weakly bias the results. The summer outdoor activity trait exhibited significant heterogeneity (Cochran Q statistic = 183.795, P = .002 < 0.05), but we found no horizontal polymorphisms or significant heterogeneity for the other exposure traits. According to IVW estimates, no causal association exists between time spent outdoors in summer and CRC (Odds Ratio, OR = 0.735, 95% confidence interval, CI = 0.494–1.017, P = .128 > 0.017). No causal relationship existed between time spent outdoors in winter and CRC, as indicated by Bonferroni-corrected adjusted p-values. The OR was 0.877 with a 95% CI of 0.334–2.299, and the P value was .789, more significant than the significance threshold of 0.017. The solarium/sunlamp use frequency was not associated with CRC (OR = 1.567, 95%CI = 0.243–10.119, P = .637 > .017). Also, an IVW with random effects was applied to determine the causal relationship between summer outdoor time and CRC. No causal association between summer outdoor time and CRC was found (OR = 0.735, 95% CI = 0.494–1.017, P = .128 > .017). Additionally, 4 additional analyses yielded similar results. The findings of our study suggest that exposure to sunlight may reduce CRC risk, but the causal relationship remains unsolved. There is no evidence to suggest that exposure to sunlight prevents CRC. Randomized, controlled trials are needed to determine whether sunlight exposure protects against CRC.
Efficacy and safety of PD-1/PD-L1 immune checkpoint inhibitors in the treatment of recurrent ovarian cancer: A systematic review and meta-analysis
Authors: Chen Yafang , Liu Xiaomei , Hu Ying , Xia Lingling
Published: May 2024

Background:

Recurrent ovarian cancer (OC) presents a significant therapeutic challenge with limited treatment success. Programmed cell death protein 1 (PD-1/PD-L1) immune checkpoint inhibitors have emerged as a potential treatment avenue, necessitating a systematic review and meta-analysis to evaluate their efficacy and safety.

Methods:

Adhering to preferred reporting items for systematic reviews and meta-analyses guidelines, we conducted a comprehensive literature search across PubMed, Embase, Web of Science, and Cochrane Library, culminating in the inclusion of studies focusing on the treatment of recurrent OC with PD-1/PD-L1 inhibitors. Studies were evaluated using the Newcastle-Ottawa Scale and analyzed using fixed or random effects models depending on heterogeneity levels.

Results:

Our search yielded 1215 articles, with 6 meeting the inclusion criteria for final analysis. Studies varied in size and reported median age, overall survival (OS), progression-free survival (PFS), and adverse events. The meta-analysis showed improved Objective Response Rates (ORR), Disease Control Rate (DCR), and PFS in patients treated with PD-1/PD-L1 inhibitors. The overall adverse event rate was 17.9%, indicating a need for careful patient selection and monitoring. No significant publication bias was detected, enhancing the reliability of our findings.

Conclusions:

PD-1/PD-L1 inhibitors offer a promising treatment option for recurrent OC, improving ORR, DCR, and PFS. However, the higher incidence of adverse events necessitates a cautious approach to their use. Future research should focus on long-term outcomes, biomarker identification, and optimal combination therapies.
MYC and NCAPG2 as molecular targets of colorectal cancer and gastric cancer in nursing
Authors: Mi Xihua , Shan Haifeng , Kang Chunbo , Zhang Jie , Hou Shiyang , Gao Yanfang , Hao Lingli , Gao Xiaoli , Gao Qiang , Chi Xiaoqian , Zhang Qijun
Published: May 2024

Colorectal cancer is a common malignant tumor in intestinal tract, the early symptoms are not obvious. Gastric cancer is a malignant tumor originating from the gastric mucosal epithelium. However, the role of MYC and non-SMC condensin II complex subunit G2 (NCAPG2) in colorectal cancer and gastric cancer remains unclear. The colorectal cancer datasets GSE49355 and gastric cancer datasets GSE19826 were downloaded from gene expression omnibus database. Differentially expressed genes (DEGs) were screened and weighted gene co-expression network analysis (WGCNA) was performed. Functional enrichment analysis, gene set enrichment analysis (GSEA) and immune infiltration analysis was performed. Construction and analysis of protein-protein interactions (PPI) network. Survival analysis and comparative toxicogenomics database (CTD) were performed. A heat map of gene expression was drawn. A total of 751 DEGs were obtained. According to the gene ontology (GO) analysis, in Biological process (BP) analysis, they are mainly enriched in cell differentiation, cartilage development, and skeletal development. In cellular component (CC) analysis, they are mainly enriched in the cytoskeleton of muscle cells and actin filaments. In molecular function (MF) analysis, they are mainly concentrated in Rho GTPase binding, DNA binding, and fibronectin binding. In Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis, they are mainly enriched in the MAPK signaling pathway, apoptosis, and cancer pathways. The soft threshold power for WGCNA analysis was set to 9, resulting in the generation of 40 modules. Ultimately, 2 core genes (MYC and NCAPG2) were identified. The heatmap of core gene expression showed high expression of MYC and NCAPG2 in colorectal cancer tissue samples and low expression in normal tissue samples, while they were core molecules in gastric cancer. Survival analysis indicated that MYC and NCAPG2 were risk factors, showing an upregulation trend with increasing risk scores. CTD analysis revealed associations of MYC and NCAPG2 with colorectal cancer, gastric cancer, inflammation, and immune system diseases. MYC and NCAPG2 are highly expressed in colorectal cancer. The higher the expression of MYC and NCAPG2, the worse the prognosis. MYC and NCAPG2 are core molecules in gastric cancer.
Predictive potential of preoperative Naples prognostic score-based nomogram model for the prognosis in surgical resected thoracic esophageal squamous cell carcinoma patients: A retrospective cohort study
Authors: Guo Xin-Wei , Ji Lei , Xi Xiao-Xiang , Zhao Wei-Wei , Liu Yang-Chen , Zhou Shao-Bing , Ji Sheng-Jun
Published: May 2024

The present study aimed to establish an effective prognostic nomogram model based on the Naples prognostic score (NPS) for resectable thoracic esophageal squamous cell carcinoma (ESCC). A total of 277 patients with ESCC, who underwent standard curative esophagectomy and designated as study cohort, were retrospectively analyzed. The patients were divided into different groups, including NPS 0, NPS 1, NPS 2, and NPS 3 or 4 groups, for further analysis, and the results were validated in an external cohort of 122 ESCC patients, who underwent surgery at another cancer center. In our multivariate analysis of the study cohort showed that the tumor-node-metastasis (TNM) stage, systemic inflammation score, and NPS were the independent prognostic factors for the overall survival (OS) and progression-free survival (PFS) durations. In addition, the differential grade was also an independent prognostic factor for the OS in the patients with ESCC after surgery (all P < .05). The area under the curve of receiver operator characteristics for the PFS and OS prediction with systemic inflammation score and NPS were 0.735 (95% confidence interval [CI] 0.676–0.795, P < .001) and 0.835 (95% CI 0.786–0.884, P < .001), and 0.734 (95% CI 0.675–0.793, P < .001) and 0.851 (95% CI 0.805–0.896, P < .001), respectively. The above independent predictors for OS or PFS were all selected in the nomogram model. The concordance indices (C-indices) of the nomogram models for predicting OS and PFS were 0.718 (95% CI 0.681–0.755) and 0.669 (95% CI 0.633–0.705), respectively, which were higher than that of the 7th edition of American Joint Committee on Cancer TNM staging system [C-index 0.598 (95% CI 0.558–0.638) for OS and 0.586 (95% CI 0.546–0.626) for PFS]. The calibration curves for predicting the 5-year OS or PFS showed a good agreement between the prediction by nomogram and actual observation. In the external validation cohort, the nomogram discrimination for OS was better than that of the 7th edition of TNM staging systems [C-index: 0.697 (95% CI 0.639–0.755) vs 0.644 (95% CI 0.589–0.699)]. The calibration curves showed good consistency in predicting the 5-year survival between the actual observation and nomogram predictions. The decision curve also showed a higher potential of the clinical application of predicting the 5-years OS of the proposed nomogram model as compared to that of the 7th edition of TNM staging systems. The preoperative NPS-based nomogram model had a certain potential role for predicting the prognosis of ESCC patients.
Management of open fracture and related complications: the Japanese way
Authors: Minehara Hiroaki , Zenke Yukichi , Maruo Akihiro , Matsushita Takashi , Miclau Theodore
Published: May 2024

Open fractures continue to be a challenging clinical problem throughout the world, and Japan is no exception. Surgeons are faced with critical decisions throughout the care of these injuries that can have significant effects in clinical outcome, ranging from the type and timing of antibiotic administration, fixation, soft-tissue management, and interventions for postfracture complications. In October 2022, the Japanese Society for Fracture Repair (JSFR) was invited to represent Japan as the Guest Nation society at the 38th Annual Meeting of the Orthopaedic Trauma Society held in Tampa, Florida. The JSFR organized a symposium, entitled “Management of Open Fracture and related complications—the Japanese way,” that featured cutting-edge approaches to open fractures in their country, including presentations on the “fix-and-flap” approach, local antibiotics perfusion delivery, and a “chipping” method for the stimulation of bone healing. This article summarizes the content of these 3 presentations from that symposium.
The HIV Care Cascade for Older Adults in Rural South Africa: A Longitudinal Cohort Study (2014–2019)
Authors: Rohr Julia K. , Manne-Goehler Jennifer , Gómez-Olivé F. Xavier , Kahn Kathleen , Bärnighausen Till W.
Published: May 2024

Background:

As people with HIV grow older, stable engagement in care is essential for healthy aging. We evaluate the HIV care cascade for older adults in rural South Africa at 2 time points cross-sectionally and assess movement in the cascade over time.

Setting:

We evaluated the cascade stage at waves 1 (2014–2015) and 2 (2018–2019) of Health and Aging in Africa: A Longitudinal Study of an INDPETH Community in South Africa, a population-based longitudinal cohort study in Mpumalanga Province, South Africa.

Methods:

Biomarker screening defined cascade stages [HIV+/no antiretroviral therapy (ART); ART+/unsuppressed viral load; ART+/suppressed viral load]. Between-wave probability of death, cascade progression, regression, cascade transitions, and sociodemographic predictors were assessed with Poisson regression. The impact of death was considered using the Fine and Gray competing risk model.

Results:

We observed a higher prevalence of antiretroviral therapy with viral suppression over time (50% in wave 1 vs. 70% in wave 2). Among those alive, the oldest age group (70+ years old) was most likely to have cascade progression [adjusted risk ratio for treatment initiation vs. 40–49 years old: 1.38 (95% confidence interval: 1.02 to 1.86)]. However, there was a significant risk of death and cascade regression. Death between waves reached 40% for 70+-year-olds who were ART+/unsuppressed. In competing risk models, older age was associated with equivalent or less cascade progression.

Conclusion:

Older age groups who were unsuppressed on treatment and men had poorer cascade outcomes. Improvements observed in HIV treatment coverage over time for older adults must be interpreted in the context of the high risk of death for older HIV-positive adults, especially among those failing treatment.
Prevalence of Anal Human Papillomavirus Infection and Anal High-Grade Squamous Intraepithelial Lesions Among Men Who Have Sex With Men 50 Years and Older Living With or Without HIV
Authors: Hernandez Alexandra L. , Hilton Joan F. , Weatherly Christopher Scott , Berry-Lawhorn J. Michael , Jay Naomi , Brickman Cristina , Wang Chia-ching J. , Kauffman Jason , Calderon Joanne , Farhat Sepideh , Da Costa Maria , Akha Arezou Sadighi , Darragh Teresa , Palefsky Joel M.
Published: May 2024

Background:

Anal cancer is caused by human papillomavirus (HPV), particularly HPV-16, and is preceded by anal high-grade squamous intraepithelial lesions (HSILs). The incidence of anal cancer is highest among men who have sex with men (MSM) living with HIV (MSMLWH) and increases with age. However, most previous studies of anal HPV infection and anal HSIL were performed on men under 50 years old, and relatively little is known about HSIL among older MSMLWH or MSM not living with HIV (MSM-Not-LWH).

Setting:

We enrolled MSM who were aged 50+ during 2018–2022 in San Francisco, CA.

Methods:

One hundred twenty-nine MSMLWH and 109 MSM-not-LWH participated. All participants had anal HPV DNA testing (Atila Biosystems) and high-resolution anoscopy with a biopsy of visible lesions.

Results:

Among MSMLWH, 47% had anal HSIL, 19% had HPV-16, and 51% had other oncogenic anal HPV types (excluding HPV-16). Among MSM-not-LWH, 37% had anal HSIL, 22% had HPV-16, and 34% had other oncogenic anal HPV types. Increasing age was not statistically associated with prevalent HSIL, HPV-16, or other oncogenic HPV infections in MSMLWH or MSM-not-LWH. HPV-16 (odds ratio: 45.1, 95% confidence interval: 15.8–129); other oncogenic HPV types (odds ratio: 5.95, 95% confidence interval: 2.74–12.9) were associated with increased odds of anal HSIL, adjusted for age, income, education, and HIV status.

Conclusion:

The prevalence of oncogenic anal HPV, anal HPV-16, and anal HSIL remains very high in older MSMLWH and MSM-not-LWH. With recent evidence showing that treating anal HSIL prevents anal cancer, MSM aged 50+ should be considered for anal cancer screening.
Rhodoferax potami sp. nov. and Rhodoferax mekongensis sp. nov., isolated from the Mekong River in Thailand
Authors: Kitikhun Supattra , Charoenyingcharoen Piyanat , Siriarchawatana Paopit , Likhitrattanapisal Somsak , Nilsakha Thanyakorn , Chanpet Amonwan , Jeennor Sukanya , Yukphan Pattaraporn , Ingsriswang Supawadee
Published: May 2024

Four newly discovered Gram-stain-negative bacteria, designated as BL00010T, BL00058, D8-11T and BL00200, were isolated from water samples collected at three hydrological monitoring stations (namely Chiang Saen, Chiang Khan and Nong Khai) located along the Mekong River in Thailand. An investigation encompassing phenotypic, chemotaxonomic and genomic traits was conducted. The results of phylogenetic analysis based on 16S rRNA gene sequences indicated that all four isolates represented members of the genus Rhodoferax. These isolates were closely related to Rhodoferax bucti KCTC 62564T with a similarity of 99.59%. The major fatty acids of the four novel isolates included C16:0 and C16:1ω7c and/or C16 : 1ω6c, whereas the major respiratory quinone was identified as ubiquinone Q-8. In addition, phosphatidylethanolamine was identified as a major polar lipid in these bacteria. The genomes of BL00010T, BL00058, D8-11T and BL00200 were similar in size (3.88–4.01 Mbp) and DNA G+C contents (59.5, 59.3, 59.5 and 59.3 mol%, respectively). In contrast to R. bucti KCTC 62564T and Rhodoferax aquaticus KCTC 32394T, the newly discovered species possessed several genes involved in nitrite and nitrile metabolism, which may be related to their unique adaptation to nitrile-rich environments. From the results of the pairwise analysis of average nucleotide identity of the whole genome and digital DNA–DNA hybridisation, it was evident that BL00010T and D8-11T represented two novel species, for which we propose the nomenclature Rhodoferax potami sp. nov., with the type strain BL00010T (TBRC 17198T = NBRC 116413T), and Rhodoferax mekongensis sp. nov., with the type strain D8-11T (TBRC 17307T = NBRC 116415T).
Marinomonas rhodophyticola sp. nov. and Marinomonas phaeophyticola sp. nov., isolated from marine algae
Authors: Butt Mahrukh , Choi Dae Gyu , Kim Jeong Min , Lee Jae Kyeong , Baek Ju Hye , Jeon Che Ok
Published: May 2024

Two Gram-stain-negative, facultatively aerobic, and motile rod bacteria, designated as strains KJ51-3T and 15G1-11T, were isolated from marine algae collected in the Republic of Korea. Both strains exhibited catalase- and oxidase-positive activities. Optimum growth conditions for strain KJ51-3T were observed at 30 °C and pH 6.0–8.0, with 1.0–7.0 % (w/v) NaCl, whereas strain 15G1-11T exhibited optimal growth at 30 °C, pH 7.0, and 1.0–5.0 % NaCl. Major fatty acids detected in both strains included C16 : 0, C10 : 0 3-OH and summed features 3 (C16 : 1
 ω7c and/or C16 : 1
 ω6c) and 8 (C18 : 1
 ω7c and/or C18 : 1
 ω6c). As for polar lipids, strain KJ51-3T contained phosphatidylethanolamine (PE), phosphatidylglycerol (PG), diphosphatidylglycerol, and two unidentified phospholipids, whereas strain 15G1-11T had PE, PG, and an unidentified aminolipid. Ubiquinone-8 was the predominant respiratory quinone in both strains, with minor detection of ubiquinone-9 in strain KJ51-3T. The genomic DNA G+C contents were 44.0 mol% for strain KJ51-3T and 40.5 mol% for strain 15G1-11T. Phylogenetic analyses based on both 16S rRNA gene and genome sequences placed strains KJ51-3T and 15G1-11T into distinct lineages within the genus Marinomonas, most closely related to Marinomonas arctica 328T (98.6 %) and Marinomonas algicola SM1966T (98.3 %), respectively. Strains KJ51-3T and 15G1-11T exhibited a 94.6 % 16S rRNA gene sequence similarity and a 70.7 % average nucleotide identity (ANI), with ANI values of 91.9 and 79.3 % between them and M. arctica 328T and M. algicola SM1966T, respectively, indicating that they represent novel species. In summary, based on their phenotypic, chemotaxonomic, and phylogenetic properties, strains KJ51-3T and 15G1-11T are proposed to represent novel species within the genus Marinomonas, for which the names Marinomonas rhodophyticola sp. nov. (KJ51-3T=KACC 22756T=JCM 35591T) and Marinomonas phaeophyticola sp. nov. (15G1-11T=KACC 22593T=JCM 35412T) are respectively proposed.
Attaching artificial Achilles and tibialis cranialis tendons to bone using suture anchors in a rabbit model: assessment of outcomes
Authors: Fidelis Obinna P. , Stubbs Caleb , Easton Katrina L. , Billings Caroline , Pedersen Alisha P. , Anderson David E. , Crouch Dustin L.
Published: May 2024

Objective

The purpose of this study was to investigate the factors associated with outcomes of attaching artificial tendons to bone using suture anchors for replacement of biological tendons in rabbits.

Study Design

Metal suture anchors with braided composite sutures of varying sizes (USP #1, #2, or #5) were used to secure artificial tendons replacing both the Achilles and tibialis cranialis tendons in 12 New Zealand White rabbits. Artificial tendons were implanted either at the time of (immediate replacement, n=8), or four weeks after (delayed replacement, n=4) resection of the biological tendon. Hindlimb radiographs of the rabbits were obtained immediately after surgery and approximately every other week until the study endpoint (16 weeks post-surgery).

Results

All suture anchors used for the tibialis cranialis artificial tendons remained secure and did not fail during the study. The suture linkage between the Achilles artificial tendon and anchor failed in 9 of 12 rabbits. In all cases, the mode of failure was suture breakage distant from the knot. Based on radiographic analysis, the mean estimated failure timepoint was 5.3±2.3 weeks post-surgery, with a range of 2-10 weeks. Analysis of variance (ANOVA) tests revealed no significant effect of tendon implantation timing or suture size on either the timing or frequency of suture anchor failure.

Conclusion

Based on the mode of failure, suture mechanical properties, and suture anchor design, we suspect that the cause of failure was wear of the suture against the edges of the eyelet in the suture anchor post, which reduced the suture strength below in vivo loads. Suture anchor designs differed for the tibialis cranialis and did not fail during the period of study. Future studies are needed to optimize suture anchor mechanical performance under different loading conditions and suture anchor design features.
A novel VCP modulator, KUS121, attenuates atherosclerosis progression by maintaining intracellular ATP and mitigating ER stress in endothelial cells
Authors: Zou Fuquan , Baba Osamu , Horie Takahiro , Nakashima Yasuhiro , Tsuji Shuhei , Yamasaki Tomohiro , Otani Chiharu , Xu Sijia , Imanaka Miyako , Matsushita Kazuki , Suzuki Keita , Kume Eitaro , Kojima Hidenori , Qian Qiuxian , Kimura Kayo , Sowa Naoya , Kakizuka Akira , Ono Koh
Published: May 2024

Background

Endoplasmic reticulum (ER) stress signaling pathways have pivotal roles in atherosclerosis progression. Recently, we have developed Kyoto University Substance (KUS) 121, which selectively inhibits ATPase activities of valosin-containing protein (VCP) and consequently saves intracellular ATP consumption and mitigates ER stress.

Methods and Results

We assessed the efficacy of KUS121 against atherosclerosis by its daily injection intoApoe−/−mice fed with Western Diet (WD) for 8 weeks. Consequently, KUS121 treatment reduced atherosclerosis progression by approximately 40% in atherosclerotic plaques. Interestingly, we found that C/EBP homologous protein (CHOP), an established ER stress marker, was mainly expressed in plaque endothelium. Therefore, we assessed the action of KUS121 in endothelial cells using the human endothelial cell line (EA.hy926 cells). As a result, KUS121 prevented ER stress-induced apoptosis and downregulated the IRE1 (Inositol-requiring enzyme) α-associated inflammatory pathways. Consistent with these in vitro findings, KUS121 treatment also significantly reduced endothelial apoptosis assessed by TUNEL staining and inflammation examined by immunostaining of Nuclear factor kappa B (NF-κB) and Intercellular adhesion molecule (ICAM) 1 at plaque endothelium. We also demonstrated that KUS121 maintained ATP levels in EA.hy926 cells and atherosclerotic plaque lesions using the single-wavelength or the FRET-based fluorescent ATP sensor. Supplementation of intracellular ATP by Methyl pyruvate (MePyr) attenuated ER stress-induced apoptotic and inflammatory pathways in endothelial cells, which could be the main mechanism how KUS121 reduces ER stress.

Conclusions

KUS121 can be a new therapeutic option for atherosclerotic diseases by maintaining intracellular ATP levels and attenuating ER stress-induced apoptosis and inflammation in plaque endothelium.
Impact of PIK3CA gain and PTEN loss on mantle cell lymphoma biology and sensitivity to targeted therapies
Authors: Bettazova Nardjas , Senavova Jana , Kupcova Kristyna , Sovilj Dana , Rajmonova Anezka , Andera Ladislav , Svobodova Karla , Berkova Adéla , Herman Vaclav , Zemanova Zuzana , Daumova Lenka , Dolníkova Alexandra , Davis R. Eric , Trneny Marek , Klener Pavel , Havranek Ondrej
Published: May 2024

Besides many other mutations in known cancer driver genes, mantle cell lymphoma (MCL) is characterized by recurrent genetic alterations of important regulators of the phosphoinositol-3-kinase (PI3K) cascade includingPIK3CAgains andPTENlosses. To evaluate the biological and functional consequences of these aberrations in MCL, we have introduced transgenic expression ofPIK3CA(PIK3CA UP) and performed knockout ofPTENgene (PTEN KO) in 5 MCL cell lines. The modified cell lines were tested for associated phenotypes including dependence on upstream B-cell receptor (BCR) signaling (by an additionalBCRknockout). PIK3CA overexpression decreased the dependence of the tested MCL on prosurvival signaling from BCR, decreased levels of oxidative phosphorylation, and increased resistance to 2-deoxy-glucose, a glycolysis inhibitor. Unchanged AKT phosphorylation status and unchanged sensitivity to a battery of PI3K inhibitors suggested thatPIK3CAgain might impact MCL cells in AKT independent manner.PTENKO was associated with a more distinct phenotype: AKT hyperphosphorylation and overactivation, increased resistance to multiple inhibitors (most of the tested PI3K inhibitors, BTK inhibitor ibrutinib, and BCL2 inhibitor venetoclax), increased glycolytic rates with resistance to 2-deoxy-glucose, and significantly decreased dependence on prosurvival BCR signaling. Our results suggest that the frequent aberrations of the PI3K pathway may rewire associated signaling with lower dependence on BCR signaling, better metabolic and hypoxic adaptation, and targeted therapy resistance in MCL.

Key point 1

PIK3CA gain and PTEN loss decrease the dependence of MCL cells on B-Cell Receptor Signaling and anti-apoptotic BCL2.

Key point 2

PIK3CA gain and PTEN loss lead to complex metabolic rewiring and increased survival of MCL cells under hypoxia.
ChatNT: A Multimodal Conversational Agent for DNA, RNA and Protein Tasks
Authors: Richard Guillaume , de Almeida Bernardo P , Dalla-Torre Hugo , Blum Christopher , Hexemer Lorenz , Pandey Priyanka , Laurent Stefan , Lopez Marie P , Laterre Alexander , Lang Maren , Sahin Ugur , Beguir Karim , Pierrot Thomas
Published: May 2024

Language models are thriving, powering conversational agents that assist and empower humans to solve a number of tasks. Recently, these models were extended to support additional modalities including vision, audio and video, demonstrating impressive capabilities across multiple domains including healthcare. Still, conversational agents remain limited in biology as they cannot yet fully comprehend biological sequences. On the other hand, high-performance foundation models for biological sequences have been built through self-supervision over sequencing data, but these need to be fine-tuned for each specific application, preventing transfer and generalization between tasks. In addition, these models are not conversational which limits their utility to users with coding capabilities. In this paper, we propose to bridge the gap between biology foundation models and conversational agents by introducing ChatNT, the first multimodal conversational agent with an advanced understanding of biological sequences. ChatNT achieves new state-of-the-art results on the Nucleotide Transformer benchmark while being able to solve all tasks at once, in English, and to generalize to unseen questions. In addition, we have curated a new set of more biologically relevant instructions tasks from DNA, RNA and proteins, spanning multiple species, tissues and biological processes. ChatNT reaches performance on par with state-of-the-art specialized methods on those tasks. We also present a novel perplexity-based technique to help calibrate the confidence of our model predictions. Our framework for genomics instruction-tuning can be easily extended to more tasks and biological data modalities (e.g. structure, imaging), making it a widely applicable tool for biology. ChatNT is the first model of its kind and constitutes an initial step towards building generally capable agents that understand biology from first principles while being accessible to users with no coding background.
Favorable histo-molecular remodeling of pancreatic ductal adenocarcinoma after Total Neoadjuvant Therapy including Stereotactic Body Radiotherapy
Authors: Bouchart Christelle , Senar Oier Azurmendi , Navez Julie , Verset Laurine , Boisson Anais , Hein Matthieu , Stosic Kosta , Quertinmont Eric , Tafciu Vjola , Zhao Shulin , Mas Leo , D'Haene Nicky , Van Gestel Dirk , Moretti Luigi , Rooman Ilse , Detours Vincent , Bachet Jean-Baptiste , Demetter Pieter , Willard-Gallo Karen , Nicolle Remy , Arsenijevic Tatjana , Van Laethem Jean-Luc
Published: May 2024

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest tumors with slow progress in systemic therapies due to its peculiar and resistant tumor microenvironment. Inclusion of isotoxic high-dose stereotactic body radiation therapy (iHD-SBRT) into a total neoadjuvant strategy (TNT) is promising for the treatment of localized PDAC. However, the histo-molecular effects of iHD-SBRT are still poorly explored. In this study, we have shown that TNT, associating FOLFIRINOX [FFX] followed by iHD-SBRT, leads to significant and long-lasting remodeling of PDAC, affecting its stromal, metabolic, and molecular features. Contrary to FFX alone, TNT is able to enrich tumors with Classical and Inactive stromal signatures associated with better prognosis. Furthermore, iHD-SBRT seems capable to counteract several of the detrimental modulatory effects induced by FFX such as Epithelial-to-Mesenchymal Transition or angiogenesis. Additionally, we identified inflammatory cancer-associated fibroblasts signatures as an important prognostic factor. This work provides new rationale to sequentially combine FFX with iHD-SBRT and suggests new pathways that can be targeted in combination with a TNT.
Flexible reproductive seasonality in Africa-dwelling papionins is associated with low environmental productivity and high climatic unpredictability
Authors: Dezeure Jules , Dagorrette Julie , Burtschell Lugdiwine , Chowdhury Shahrina , Lukas Dieter , Swedell Larissa , Huchard Elise
Published: May 2024

At a time when seasonal cycles are increasingly disrupted, the ecology and evolution of reproductive seasonality in tropical vertebrates remains poorly understood. In order to predict how changes in seasonality might affect these animals, it is important to understand which aspects of their diverse patterns of reproductive phenology are linked to either the equally diverse patterns of rainfall seasonality (within-year variations) or instead the marked climatic unpredictability (year-to-year variations) occurring across the intertropical belt. Here, we gather birth and climatic seasonality data from 21 populations of 11 Africa-dwelling primate species from the papionin tribe, occupying a wide range of environments, including equatorial, tropical, temperate and arid climates. We investigate (1) the environmental variations that influence the intensity of reproductive seasonality, and (2) the reproductive stage that is synchronized with increased resource availability. Our results demonstrate wide variation in the intensity of birth seasonality between and within species. Across multiple measures of climatic variation, we found rainfall unpredictability to be the only clear predictor of the intensity of reproductive seasonality across populations, i.e., greater year-to-year variation in the amount of rainfall was associated with lower to no reproductive seasonality. Finally, we identified diverse patterns of reproductive phenology, with the most seasonal breeders generally aligning lactation with the peak in resource availability while other populations show more diverse patterns, where conception, lactation or weaning can all be synchronized with maximal food availability. This study sheds new light on the extent and ecological drivers of flexible reproductive phenology in long-lived tropical mammals, and may even contribute to our understanding of why humans give birth year-round.
Degradation determinants are abundant in human noncanonical proteins
Authors: Casola Claudio , Owoyemi Adekola , Vakirlis Nikolaos
Published: May 2024

The comprehensive characterization of human proteins, a key objective in contemporary biology, has been revolutionized by the identification of thousands of potential novel proteins through ribosome profiling and proteomics. Determining the physiological activity of these noncanonical proteins has proven difficult, because they are encoded by different types of coding regions and tend to share no sequence similarity with canonical polypeptides. Evidence from immunopeptidomic assays combined with a better understanding of the quality control of protein synthesis suggest that many noncanonical proteins may possess low stability in the cellular environment. Here, we tested this hypothesis by analyzing the frequency of multiple sequence features eliciting either proteasomal degradation or autophagy across 91,003 canonical (annotated) protein isoforms and 232,460 noncanonical proteins. Overall, noncanonical proteins were enriched for degradation-related features compared to all canonical proteins. Notably, degradation determinants were also enriched in canonical protein isoforms starting with a non-methionine amino acid. Analyses of original and shuffled sequences showed evidence of selective pressure either against or towards the accumulation of specific degradation signatures only in major isoforms of canonical proteins. However, stability was significantly higher in noncanonical proteins with evidence of phenotypic effects when knocked-out in cell lines. Notably, we found that the C-terminal tail hydrophobicity represents a reliable proxy for degradation propensity with potential applications in identifying functional noncanonical proteins. These findings underscore the critical role of degradation processes in regulating the half-life of noncanonical proteins and demonstrate the power of degradation-associated signatures in discriminating noncanonical genes likely to encode for biologically functional molecules.
Disentangling neural correlates of tinnitus and hyperacusis following noise exposure in auditory cortex of rats
Authors: Wake Naoki , Shiramatsu Tomoyo I. , Takahashi Hirokazu
Published: May 2024

Both tinnitus and hyperacusis, likely triggered by hearing loss, can be attributed to maladaptive plasticity in auditory perception. However, owing to their co-occurrence, disentangling their neural mechanisms proves difficult. We hypothesized that the neural correlates of tinnitus are associated with neural activities triggered by low-intensity tones, while hyperacusis is linked to responses to moderate- and high-intensity tones. To test these hypotheses, we conducted behavioral and electrophysiological experiments in rats 2 to 8 days after traumatic tone exposure. In the behavioral experiments, prepulse and gap inhibition tended to exhibit different frequency characteristics (although not reaching sufficient statistical levels), suggesting that exposure to traumatic tones resulted in hyperacusis and tinnitus symptoms at different frequency ranges. When examining the auditory cortex at the thalamocortical recipient layer, we observed that tinnitus symptoms correlated with a disorganized tonotopic map, typically characterized by responses to low-intensity tones. Neural correlates of hyperacusis were found in the cortical recruitment function at the multi-unit activity (MUA) level, but not at the local field potential (LFP) level, in response to moderate- and high-intensity tones. This shift from LFP to MUA was associated with a loss of monotonicity, suggesting a crucial role for inhibitory synapses. Thus, in acute symptoms of traumatic tone exposure, our experiments successfully disentangled the neural correlates of tinnitus and hyperacusis at the thalamocortical recipient layer of the auditory cortex. They also suggested that tinnitus is linked to central noise, whereas hyperacusis is associated with aberrant gain control. Further interactions between animal experiments and clinical studies will offer insights into neural mechanisms, diagnosis and treatments of tinnitus and hyperacusis, specifically in terms of long-term plasticity of chronic symptoms.
Insights into the representativeness of biodiversity assessment in large reservoir through eDNA metabarcoding
Authors: Cortez Thainá , Torres André LQ , Guimarães Murilo , Pinheiro Henrique B , Cabral Marcelo , Zielinsky Gabriel , Pereira Camila M , de Castro Giovanni M , Guerreiro Luana TA , Americo Juliana A , do Amaral Danielle LAS , Rebelo Mauro F
Published: May 2024

Monitoring biodiversity on a large scale, such as in hydropower reservoirs, poses scientific challenges. Conventional methods such as passive fishing gear are prone to various biases, while the utilization of environmental DNA (eDNA) metabarcoding has been restricted. Most eDNA studies have primarily focused on replicating results from traditional methods, which themselves have limitations regarding representativeness and bias. In our study, we employed eDNA metabarcoding with three markers (12SrRNA, COI, and 16SrRNA) to evaluate the biodiversity of an 800 km² reservoir. We utilized hydrodynamic modeling to determine water flow velocity and the water renewal ratio throughout the study area. Additionally, we conducted statistical comparisons – rarefaction curves and multivariate methods – among samples as an alternative approach to assess biodiversity representation. The eDNA identified taxa previously documented in the reservoir by traditional monitoring methods, as well as revealed 29 – nine fishes and 20 non-fish – previously unreported species. These results highlight the robustness of eDNA as a biodiversity monitoring technique. Our findings also indicated that by randomly sampling 30% of the original number of samples, we could effectively capture the same biodiversity. This approach enabled us to comprehend the reservoir’s biodiversity profile and propose a straightforward, cost-effective monitoring protocol for the future based on eDNA.
Causal and stable first-order chiral hydrodynamics
Authors: Abboud Nick , Speranza Enrico , Noronha Jorge
Published: May 2024

We derive the set of inequalities that is necessary and sufficient for nonlinear causality and linear stability of first-order relativistic hydrodynamics with either a U(1)V conserved current or a U(1)A current with a chiral anomaly or both. Our results apply to generic hydrodynamic frames in which no relations among the transport parameters are imposed. Furthermore, our analysis yields, to the best of our knowledge, the first theory of viscous chiral hydrodynamics proven to be causal and stable. We find that causality demands the absence of vorticity-induced heat flux, forcing a departure from the thermodynamic frame in the chiral case. The inequalities for causality and stability define a hypervolume in the space of transport parameters, wherein each point corresponds to a consistent formulation. Notably, causality is determined by just three combinations of transport parameters. We present our results in a form amenable to numerical hydrodynamic simulations.

Published by the American Physical Society
2024
Recognizing dominant cultures around assessment and educational change in physics programs
Authors: Sachmpazidi Diana , Turpen Chandra , Petrella Jayna , Dalka Robert P. , Abdurrahman Fatima N.
Published: May 2024

Leaders, policymakers, and researchers have called attention to the need to improve critical aspects of physics programs, from teaching and pedagogy to making physics more diverse and equitable. As such programmatic changes are challenging and require a second-order change to be effective, many physics faculty responsible for carrying them out are not equipped with the necessary experience and support to do so. This can result in a significant waste of resources and time. Moreover, while there is a robust body of literature in higher education focusing on institutional and cultural change, there is a limited understanding of the baseline of the culture of physics programs (where physics programs are starting from), a critical aspect that shapes the change effort. Dr. David Craig and Dr. Joel Corbo with the support of the American Physical Society and the American Association of Physics Teachers developed the Departmental Action Leadership Institutes (DALIs) to meet the needs of the physics community by supporting physics faculty to effectively design and implement departmental change focusing on areas needing improvement. In this research project, we developed case studies of five DALI-active physics programs from two DALI cohorts. We use a cultural dynamics lens to document facets of the dominant culture around how physics faculty approach and pursue change work. We see evidence of DALI participants’ growing awareness of taken-for-granted assumptions about educational change processes and assessment practices within their departmental cultures and coming to recognize and value alternative ways of collaborating and enacting change in their local contexts. We found that physics faculty typically approach change work in a rushed and way ignoring the use of formal evidence. In particular, we found that any data collection efforts are the primary responsibility of a single person, rarely becoming the focus of joint attention. Whenever data did receive joint attention, it was approached in a cursory way without meaningfully informing collective change efforts. This study lays the foundation to explore critical aspects of the dominant physics culture that may constrain enacting particular forms of programmatic change. In future work, we document the cultural shifts made by these DALI-active departments around change work.

Published by the American Physical Society
2024
In situ
coherent x-ray scattering reveals polycrystalline structure and discrete annealing events in strongly coupled nanocrystal superlattices
Authors: Hurley Matthew J. , Tanner Christian P. N. , Portner Joshua , Utterback James K. , Coropceanu Igor , Das Avishek , Slivka Joseph D. , Fluerasu Andrei , Sun Yanwen , Song Sanghoon , Hamerlynck Leo M. , Miller Alexander H. , Bhattacharyya Priyadarshini , Talapin Dmitri V. , Williams Garth J. , Ginsberg Naomi S. , Teitelbaum Samuel W.
Published: May 2024

Solution-phase bottom up self-assembly of nanocrystals into superstructures such as ordered superlattices is an attractive strategy to generate functional materials of increasing complexity, including very recent advances that incorporate strong interparticle electronic coupling. While the self-assembly kinetics in these systems have been elucidated and related to the product characteristics, the weak interparticle bonding interactions suggest the superstructures formed could continue to order within the solution long after the primary nucleation and growth have occurred, even though the mechanism of annealing remains to be elucidated. Here, we use a combination of Bragg coherent diffractive imaging and x-ray photon correlation spectroscopy to create real-space maps of supercrystalline order along with a real-time view of the strain fluctuations in aging strongly coupled nanocrystal superlattices while they remain suspended and immobilized in solution. By combining the results, we deduce that the self-assembled superstructures are polycrystalline, initially comprising multiple nucleation sites, and that shear avalanches at grain boundaries continue to increase crystallinity long after growth has substantially slowed. This multimodal approach should be generalizable to characterize a breadth of materials in their native chemical environments, thus extending the reach of high-resolution coherent x-ray characterization to the benefit of a much wider range of physical systems.

Published by the American Physical Society
2024
Quantum recurrences in the kicked top
Authors: Anand Amit , Davis Jack , Ghose Shohini
Published: May 2024

The emergence of classical chaos from an underlying quantum mechanics remains a challenging question due to the differences between dynamics driven by Schrödinger's equation versus Newton's equations. We present an infinite family of purely quantum recurrences that are not present in the classical limit of a chaotic system. They take the form of stroboscopic unitary evolutions in the quantum kicked top that act as the identity after a finite number of kicks. These state-independent recurrences are present in all finite dimensions and depend on the strength of the chaoticity parameter of the top. We further discuss the relationship of these periodicities to the quantum kicked rotor dynamics and the phenomenon of quantum antiresonance.

Published by the American Physical Society
2024