bluuebunny/crossref_metadata_2025 huggingface dataset:
Dual inhibition of P38 MAPK and JNK pathways preserves stemness markers and alleviates premature activation of muscle stem cells during isolation
Authors: Ozturk Teoman , Mignot Julien , Gattazzo Francesca , Gervais Marianne , Relaix Frédéric , Rouard Hélène , Didier Nathalie
Published: June 2024

Background

Adult skeletal muscle contains resident muscle stem cells (MuSC) with high myogenic and engraftment potentials, making them suitable for cell therapy and regenerative medicine approaches. However, purification process of MuSC remains a major hurdle to their use in the clinic. Indeed, muscle tissue enzymatic dissociation triggers a massive activation of stress signaling pathways, among which P38 and JNK MAPK, associated with a premature loss of MuSC quiescence. While the role of these pathways in the myogenic progression of MuSC is well established, the extent to which their dissociation-induced activation affects the functionality of these cells remains unexplored.

Methods

We assessed the effect of P38 and JNK MAPK induction on stemness marker expression and MuSC activation state during isolation by pharmacological approaches. MuSC functionality was evaluated by in vitro assays and in vivo transplantation experiments. We performed a comparative analysis of the transcriptome of human MuSC purified with pharmacological inhibitors of P38 and JNK MAPK (SB202190 and SP600125, respectively) versus available RNAseq resources.

Results

We monitored PAX7 protein levels in murine MuSC during muscle dissociation and demonstrated a two-step decline partly dependent on P38 and JNK MAPK activities. We showed that simultaneous inhibition of these pathways throughout the MuSC isolation process preserves the expression of stemness markers and limits their premature activation, leading to improved survival and amplification in vitro as well as increased engraftment in vivo. Through a comparative RNAseq analysis of freshly isolated human MuSC, we provide evidence that our findings in murine MuSC could be relevant to human MuSC. Based on these findings, we implemented a purification strategy, significantly improving the recovery yields of human MuSC.

Conclusion

Our study highlights the pharmacological limitation of P38 and JNK MAPK activities as a suitable strategy to qualitatively and quantitatively ameliorate human MuSC purification process, which could be of great interest for cell-based therapies.
Improvement of multilineage hematopoiesis in hematopoietic stem cell-transferred c-kit mutant NOG-EXL humanized mice
Authors: Ito Ryoji , Ohno Yusuke , Mu Yunmei , Ka Yuyo , Ito Shuko , Emi-Sugie Maiko , Mochizuki Misa , Kawai Kenji , Goto Motohito , Ogura Tomoyuki , Takahashi Riichi , Niwa Akira , Nakahata Tatsutoshi , Ito Mamoru
Published: June 2024

Human hematopoietic stem cell (HSC)-transferred humanized mice are valuable models for exploring human hematology and immunology. However, sufficient recapitulation of human hematopoiesis in mice requires large quantities of enriched human CD34+ HSCs and total-body irradiation for adequate engraftment. Recently, we generated a NOG mouse strain with a point mutation in the c-kit tyrosine kinase domain (W41 mutant; NOGW mice). In this study, we examined the ability of NOGW mice to reconstitute human hematopoietic cells. Irradiated NOGW mice exhibited high engraftment levels of human CD45+ cells in the peripheral blood, even when only 5,000–10,000 CD34+ HSCs were transferred. Efficient engraftment of human CD45+ cells was also observed in non-irradiated NOGW mice transferred with 20,000–40,000 HSCs. The bone marrow (BM) of NOGW mice exhibited significantly more engrafted human HSCs or progenitor cells (CD34+CD38− or CD34+CD38+ cells) than the BM of NOG mice. Furthermore, we generated a human cytokine (interleukin-3 and granulocyte-macrophage colony-stimulating factor) transgenic NOG-W41 (NOGW-EXL) mouse to achieve multilineage reconstitution with sufficient engraftment of human hematopoietic cells. Non-irradiated NOGW-EXL mice showed significantly higher engraftment levels of human CD45+ and myeloid lineage cells, particularly granulocytes and platelets/megakaryocytes, than non-irradiated NOGW or irradiated NOG-EXL mice after human CD34+ cell transplantation. Serial BM transplantation experiments revealed that NOGW mice exhibited the highest potential for long-term HSC compared with other strains. Consequently, c-kit mutant NOGW-EXL humanized mice represent an advanced model for HSC-transferred humanized mice and hold promise for widespread applications owing to their high versatility.
Llamol: a dynamic multi-conditional generative transformer for de novo molecular design
Authors: Dobberstein Niklas , Maass Astrid , Hamaekers Jan
Published: June 2024

Generative models have demonstrated substantial promise in Natural Language Processing (NLP) and have found application in designing molecules, as seen in General Pretrained Transformer (GPT) models. In our efforts to develop such a tool for exploring the organic chemical space in search of potentially electro-active compounds, we present Llamol, a single novel generative transformer model based on the Llama 2 architecture, which was trained on a 12.5M superset of organic compounds drawn from diverse public sources. To allow for a maximum flexibility in usage and robustness in view of potentially incomplete data, we introduce Stochastic Context Learning (SCL) as a new training procedure. We demonstrate that the resulting model adeptly handles single- and multi-conditional organic molecule generation with up to four conditions, yet more are possible. The model generates valid molecular structures in SMILES notation while flexibly incorporating three numerical and/or one token sequence into the generative process, just as requested. The generated compounds are very satisfactory in all scenarios tested. In detail, we showcase the model’s capability to utilize token sequences for conditioning, either individually or in combination with numerical properties, making Llamol a potent tool for de novo molecule design, easily expandable with new properties.

Scientific contribution

We developed a novel generative transformer model, Llamol, based on the Llama 2 architecture that was trained on a diverse set of 12.5 M organic compounds. It introduces Stochastic Context Learning (SCL) as a new training procedure, allowing for flexible and robust generation of valid organic molecules with up to multiple conditions that can be combined in various ways, making it a potent tool for de novo molecular design.
Physicochemical modelling of the retention mechanism of temperature-responsive polymeric columns for HPLC through machine learning algorithms
Authors: Bandini Elena , Castellano Ontiveros Rodrigo , Kajtazi Ardiana , Eghbali Hamed , Lynen Frédéric
Published: June 2024

Temperature-responsive liquid chromatography (TRLC) offers a promising alternative to reversed-phase liquid chromatography (RPLC) for environmentally friendly analytical techniques by utilizing pure water as a mobile phase, eliminating the need for harmful organic solvents. TRLC columns, packed with temperature-responsive polymers coupled to silica particles, exhibit a unique retention mechanism influenced by temperature-induced polymer hydration. An investigation of the physicochemical parameters driving separation at high and low temperatures is crucial for better column manufacturing and selectivity control. Assessment of predictability using a dataset of 139 molecules analyzed at different temperatures elucidated the molecular descriptors (MDs) relevant to retention mechanisms. Linear regression, support vector regression (SVR), and tree-based ensemble models were evaluated, with no standout performer. The precision, accuracy, and robustness of models were validated through metrics, such as r and mean absolute error (MAE), and statistical analysis. At $$45\,^{\circ }\hbox {C}$$

45

∘

C

, logP predominantly influenced retention, akin to reversed-phase columns, while at $$5^{\circ }\hbox {C}$$

5
∘

C

, complex interactions with lipophilic and negative MDs, along with specific functional groups, dictated retention. These findings provide deeper insights into TRLC mechanisms, facilitating method development and maximizing column potential.
New insight in molecular detection of Mycobacterium tuberculosis
Authors: Mousavi-Sagharchi Seyyed Mohammad Amin , Afrazeh Elina , Seyyedian-Nikjeh Seyyedeh Fatemeh , Meskini Maryam , Doroud Delaram , Siadat Seyed Davar
Published: June 2024

Mycobacterium tuberculosis, the causative agent of tuberculosis, is a pathogenic bacterium that has claimed millions of lives since the Middle Ages. According to the World Health Organization’s report, tuberculosis ranks among the ten deadliest diseases worldwide. The presence of an extensive array of genes and diverse proteins within the cellular structure of this bacterium has provided us with a potent tool for diagnosis. While the culture method remains the gold standard for tuberculosis diagnosis, it is possible that molecular diagnostic methods, emphasis on the identification of mutation genes (e.g., rpoB and gyrA) and single nucleotide polymorphisms, could offer a safe and reliable alternative. Over the past few decades, as our understanding of molecular genetics has expanded, methods have been developed based on gene expansion and detection. These methods typically commence with DNA amplification through nucleic acid targeted techniques such as polymerase chain reaction. Various molecular compounds and diverse approaches have been employed in molecular assays. In this review, we endeavor to provide an overview of molecular assays for the diagnosis of tuberculosis with their properties (utilization, challenges, and functions). The ultimate goal is to explore the potential of replacing traditional bacterial methods with these advanced molecular diagnostic techniques.
From dysbiosis to defense: harnessing the gut microbiome in HIV/SIV therapy
Authors: Brenchley Jason M. , Serrano-Villar Sergio
Published: June 2024

Background

Although the microbiota has been extensively associated with HIV pathogenesis, the majority of studies, particularly those using omics techniques, are largely correlative and serve primarily as a basis for hypothesis generation. Furthermore, most have focused on characterizing the taxonomic composition of the bacterial component, often overlooking other levels of the microbiome. The intricate mechanisms by which the microbiota influences immune responses to HIV are still poorly understood. Interventional studies on gut microbiota provide a powerful tool to test the hypothesis of whether we can harness the microbiota to improve health outcomes in people with HIV.

Results

Here, we review the multifaceted role of the gut microbiome in HIV/SIV disease progression and its potential as a therapeutic target. We explore the complex interplay between gut microbial dysbiosis and systemic inflammation, highlighting the potential for microbiome-based therapeutics to open new avenues in HIV management. These include exploring the efficacy of probiotics, prebiotics, fecal microbiota transplantation, and targeted dietary modifications. We also address the challenges inherent in this research area, such as the difficulty in inducing long-lasting microbiome alterations and the complexities of study designs, including variations in probiotic strains, donor selection for FMT, antibiotic conditioning regimens, and the hurdles in translating findings into clinical practice. Finally, we speculate on future directions for this rapidly evolving field, emphasizing the need for a more granular understanding of microbiome-immune interactions, the development of personalized microbiome-based therapies, and the application of novel technologies to identify potential therapeutic agents.

Conclusions

Our review underscores the importance of the gut microbiome in HIV/SIV disease and its potential as a target for innovative therapeutic strategies.
Gut microbiota dysbiosis in hyperuricaemia promotes renal injury through the activation of NLRP3 inflammasome
Authors: Zhou Xinghong , Ji Shuai , Chen Liqian , Liu Xiaoyu , Deng Yijian , You Yanting , Wang Ming , He Qiuxing , Peng Baizhao , Yang Ying , Chen Xiaohu , Kwan Hiu Yee , Zhou Lin , Chen Jieyu , Zhao Xiaoshan
Published: June 2024

Background

The prevalence of hyperuricaemia (HUA), a metabolic disorder characterized by elevated levels of uric acid, is on the rise and is frequently associated with renal injury. Gut microbiota and gut-derived uremic toxins are critical mediators in the gut-kidney axis that can cause damage to kidney function. Gut dysbiosis has been implicated in various kidney diseases. However, the role and underlying mechanism of the gut microbiota in HUA-induced renal injury remain unknown.

Results

A HUA rat model was first established by knocking out the uricase (UOX). HUA rats exhibited apparent renal dysfunction, renal tubular injury, fibrosis, NLRP3 inflammasome activation, and impaired intestinal barrier functions. Analysis of 16S rRNA sequencing and functional prediction data revealed an abnormal gut microbiota profile and activation of pathways associated with uremic toxin production. A metabolomic analysis showed evident accumulation of gut-derived uremic toxins in the kidneys of HUA rats. Furthermore, faecal microbiota transplantation (FMT) was performed to confirm the effects of HUA-induced gut dysbiosis on renal injury. Mice recolonized with HUA microbiota exhibited severe renal injury and impaired intestinal barrier functions following renal ischemia/reperfusion (I/R) surgery. Notably, in NLRP3-knockout (NLRP3−/−) I/R mice, the deleterious effects of the HUA microbiota on renal injury and the intestinal barrier were eliminated.

Conclusion

Our results demonstrate that HUA-induced gut dysbiosis contributes to the development of renal injury, possibly by promoting the production of gut-derived uremic toxins and subsequently activating the NLRP3 inflammasome. Our data suggest a potential therapeutic strategy for the treatment of renal diseases by targeting the gut microbiota and the NLRP3 inflammasome.

Graphical Abstract
A multi-institutional series of a novel, recurrent TRIM24::MET fusion-driven infant-type hemispheric glioma reveals significant clinico-pathological heterogeneity
Authors: Gorodezki David , Chiang Jason , Viaene Angela N. , Sievers Philipp , Schmid Simone , Holzer Ursula , Paulsen Frank , Schuhmann Martin U. , Witt Olaf , Schittenhelm Jens , Ebinger Martin
Published: June 2024

Within the past decade, incremental integration of molecular characteristics into the classification of central nervous system neoplasms increasingly facilitated precise diagnosis and advanced stratification, beyond potentially providing the foundation for advanced targeted therapies. We report a series of three cases of infant-type hemispheric glioma (IHG) involving three infants diagnosed with neuroepithelial tumors of the cerebral hemispheres harboring a novel, recurrent TRIM24::MET fusion. Histopathology showed glial tumors with either low-grade or high-grade characteristics, while molecular characterization found an additional homozygous CDKN2A/B deletion in two cases. Two patients showed leptomeningeal dissemination, while multiple supra- and infratentorial tumor manifestations were found in one case. Following subtotal resection (two cases) and biopsy (one case), treatment intensity of adjuvant chemotherapy regimens did not reflect in the progression patterns within the reported cases. Two patients showed progression after first-line treatment, of which one patient died not responding to tyrosine kinase inhibitor cabozantinib. As the detection of a recurrent TRIM24::MET fusion expands the spectrum of renowned driving fusion genes in IHG, this comparative illustration may indicate a distinct clinico-pathological heterogeneity of tumors bearing this driver alteration. Upfront clinical trials of IHG promoting further characterization and the implementation of individualized therapies involving receptor tyrosine kinase inhibition are required.
snRNA-seq of human cutaneous neurofibromas before and after selumetinib treatment implicates role of altered Schwann cell states, inter-cellular signaling, and extracellular matrix in treatment response
Authors: Church Cameron , Fay Christian X. , Kriukov Emil , Liu Hui , Cannon Ashley , Baldwin Lauren Ashley , Crossman David K. , Korf Bruce , Wallace Margaret R. , Gross Andrea M. , Widemann Brigitte C. , Kesterson Robert A. , Baranov Petr , Wallis Deeann
Published: June 2024

Neurofibromatosis Type 1 (NF1) is caused by loss of function variants in the NF1 gene. Most patients with NF1 develop skin lesions called cutaneous neurofibromas (cNFs). Currently the only approved therapeutic for NF1 is selumetinib, a mitogen -activated protein kinase (MEK) inhibitor. The purpose of this study was to analyze the transcriptome of cNF tumors before and on selumetinib treatment to understand both tumor composition and response. We obtained biopsy sets of tumors both pre- and on- selumetinib treatment from the same individuals and were able to collect sets from four separate individuals. We sequenced mRNA from 5844 nuclei and identified 30,442 genes in the untreated group and sequenced 5701 nuclei and identified 30,127 genes in the selumetinib treated group. We identified and quantified distinct populations of cells (Schwann cells, fibroblasts, pericytes, myeloid cells, melanocytes, keratinocytes, and two populations of endothelial cells). While we anticipated that cell proportions might change with treatment, we did not identify any one cell population that changed significantly, likely due to an inherent level of variability between tumors. We also evaluated differential gene expression based on drug treatment in each cell type. Ingenuity pathway analysis (IPA) was also used to identify pathways that differ on treatment. As anticipated, we identified a significant decrease in ERK/MAPK signaling in cells including Schwann cells but most specifically in myeloid cells. Interestingly, there is a significant decrease in opioid signaling in myeloid and endothelial cells; this downward trend is also observed in Schwann cells and fibroblasts. Cell communication was assessed by RNA velocity, Scriabin, and CellChat analyses which indicated that Schwann cells and fibroblasts have dramatically altered cell states defined by specific gene expression signatures following treatment (RNA velocity). There are dramatic changes in receptor-ligand pairs following treatment (Scriabin), and robust intercellular signaling between virtually all cell types associated with extracellular matrix (ECM) pathways (Collagen, Laminin, Fibronectin, and Nectin) is downregulated after treatment. These response specific gene signatures and interaction pathways could provide clues for understanding treatment outcomes or inform future therapies.
Online peer editing: the influence of comments, tracked changes and perception of participation on students’ writing performance
Authors: Shulgina Galina , Costley Jamie , Shcheglova Irina , Zhang Han , Sedova Natalya
Published: June 2024

While peer-editing is considered an important part of developing students’ academic writing, questions remain about how different types of peer-editing affect subsequent student performance. The present study looked at a group of university students (N = 149) engaged in peer editing of one another’s essays in an online security studies course. The analysis was conducted from two perspectives: feedback givers and feedback receivers. More specifically, the relationships between the giving of comments and tracking changes in peer’s work and writing score on essays were explored. The results showed that there was a positive correlation between the total number of received comments and the student's writing score, whereas there was no correlation for the number of tracked changes (neither words deleted, nor words added). Surprisingly, students who assume that peers provide high quality tracked changes demonstrate worse writing performance. This research shows the importance of nuance in understanding peer editing types and their influence on students’ performance, as well as highlighting potential complexities of the interplay between students’ collaborative activities, their performance, and their attitudes.
Sedimentary evolution pattern influenced by sequence stratigraphy: a case study of the Nanpu Sag, Bohai Bay Basin, China
Authors: Sun Zhongqiang , Lin Shuangyue , Wang Guangqun , Liu Longlong , Wang Mengqi
Published: June 2024

Identifying and characterizing sedimentary evolution patterns are crucial for assessing the distributions of source and reservoir rocks, which are fundamental to hydrocarbon exploration. This study analyzed the stratigraphic sequence, lithological characteristics, sedimentary lithofacies, individual well sedimentary sequences, and seismic reflection properties. The analysis revealed six fourth-order sequences, including progradational and regressive sequences, indicative of water level changes. The sediment sources for the second and third sub-members of the Eocene Shahejie Formation's third member (Es32+3) in the Nanpu Sag were identified as the Baigezhuang and Xinanzhuang Uplifts. Predominantly, the sandstones are lithic arkose and feldspathic litharenite, both of which exhibit low compositional and structural maturity. Notably, 22 lithofacies and 8 lithofacies associations suggest fan delta processes. This study identified three fundamental seismic reflection package reflection types. These lithofacies associations, sedimentary sequences, and seismic reflections serve as critical indicators for determining sedimentary environments. The results from the sedimentary facies analysis indicate that the Es32+3 Formation developed fan delta deposits, controlled by the sequence of the sedimentary evolution pattern. The potential of these fan delta sediments to form oil and gas reservoirs is significant. Therefore, precise characterization of the sedimentary evolution pattern is essential for a comprehensive understanding of basin dynamics and hydrocarbon potential.
Solar activity dependence for the relationship between nighttime medium-scale traveling ionospheric disturbance and sporadic E (Es) layer activities in summer during 1998–2019 over Japan
Authors: Maheswaran Veera Kumar , Otsuka Yuichi , Baskaradas James A. , Devanaboyina Venkata Ratnam , Subramanian Sriram , Shinbori Atsuki , Sori Takuya , Nishioka Michi , Perwitasari Septi
Published: June 2024

To investigate solar activity dependence of the coupling between medium-scale traveling ionosphere disturbance (MSTID) and sporadic E (Es) layer, we analyzed the total electron content (TEC) obtained from a Japanese global positioning system (GPS) receivers and ionosonde at Kokubunji (35.7° N, 139.5° E) in Japan during the summer period of May–August from 1998 to 2019. To obtain perturbation TEC caused by MSTIDs, the detrended TEC is calculated by subtracting 1-h moving averages from the measured TEC for each pair of GPS satellite and receiver. The detrended TEC data are mapped on to the geographical coordinates to make detrended 2-D maps with spatial resolution of 0.15° × 0.15° in longitude and latitude. The MSTID activity is defined as a ratio of the standard deviation to the background TEC over Kokubunji in Japan. Day-to-day variations of the MSTID activity during summer nights was compared to Es layer parameters [critical frequency ($${f}_{o}Es$$

f
o

E
s

) and $${\Delta f}_{o-b}\equiv {f}_{o}Es-{f}_{b}E$$

Δ
f

o
-
b

≡

f
o

E
s
-

f
b

E

, where $${f}_{{\text{b}}}Es$$

f
b

E
s

is blanketing frequency] derived from ionosonde station at Kokubunji. We have found that the correlation coefficient between the MSTID activity and $${f}_{o}Es$$

f
o

E
s

($${\Delta f}_{o-b}$$

Δ
f

o
-
b

) between 1998 and 2019 is 0.5 3 (0.46) on average, suggesting that there is an electrodynamical coupling between the Es layer and F region could generate nighttime MSTIDs. We also have found that the correlation coefficient positively correlates with solar activity. This finding indicates that in the high solar activity conditions, when the growth rate of Perkins instability is relatively low, generation of the polarization electric fields in the $$Es$$

Es

layer could play a more important role to grow MSTIDs than in the low solar activity conditions.

Graphical Abstract
Evaluation of starch granules based on hydroxypropylcellulose as a substitute for excipient lactose
Authors: Yoshikawa Tomohiro , Okamoto Hiroyo , Takeuchi Kenta , Hirata Atsushi , Otake Hiroko , Nagai Noriaki
Published: June 2024

Background

The improvement in flowability and adhesion of starch powder (SP) is essential for using starch as an excipient for lactose intolerant patients. In this study, we attempted to evaluate the usefulness of hydroxypropylcellulose with molecular weight 80,000 (HPC-80) in the preparation of the starch granules (SG) as a substitute for excipient lactose.

Methods

Hydroxypropylcellulose with molecular weight 30,000 (HPC-30) and HPC-80 were used as binders to prepare the SG, and defined as HPC-30-SG and HPC-80-SG, respectively. Mean particle size (D50) was measured according to the Method, Optical Microscopy of Particle Size Determination in Japanese Pharmacopoeia, Eighteenth Edition, and storage stability were evaluated by measuring of the physical properties after vortexing the granules for 180 s (physical impact). The product loss rate was calculated from the weight change of the various excipients before and after the one dose packaging (ODP).

Results

The D50 of SP (30 µm) was smaller than that of the lactose powder (115 µm). The granulation with 0.75–3% HPC-30 and HPC-80 increased the particle size of SP, and the D50 in 1.5% HPC-30-SG (255 µm) and HPC-80-SG (220 µm) were higher than that of lactose. The excipient was removed from the heat seal of the ODP, and upon visual inspection, a large amount of starchy material was observed to be adhering to the paper in the SP. On the other hand, the low recovery rate in SP was attenuated by the granulation with HPC-30 and HPC-80. In the both HPC-30 and HPC-80, the improvement in recovery rate reached a plateau at 1.5%, and the levels of recovery rate was similar to that of lactose. The recovery rate in the 0.75–3% HPC-30-SG and 0.75% HPC-80-SG were decreased by the physical impact, however, the recovery rate and amount of 1.5% and 3% HPC-80-SG were not affected by the physical impact, and these levels were similar to that of lactose.

Conclusions

The use of HPC-80 as a binder of SG was found to produce a higher quality granule product than conventional HPC-based SG. This finding is useful in streamlining the preparation of starch-based powdered medicine in clinical applications.
A case of successful management for spontaneous rupture of paraganglioma treated with preoperative transcatheter arterial embolization
Authors: Nakagawa Masataka , Tanimine Naoki , Sakai Hiroshi , Nakano Ryosuke , Kuroda Shintaro , Ohira Masahiro , Tahara Hiroyuki , Ide Kentaro , Kobayashi Tsuyoshi , Arihiro Kouji , Ohdan Hideki
Published: June 2024

Background

Tumors arising from catecholamine-producing chromophil cells in paraganglia are termed paragangliomas (PGLs), which biologically resemble pheochromocytomas (PCCs) that arise from the adrenal glands. Spontaneous rupture of a PGL is rare and can be fatal. Although elective surgery for ruptured PCCs after transcatheter arterial embolization (TAE) has been shown to provide good outcomes, the efficacy of TAE pretreatment for ruptured PGL remains unknown.

Case presentation

A 65-year-old female with hypertension and tachycardia was diagnosed with a 3-cm PGL located behind the inferior vena cava. The patient was scheduled to undergo an elective surgery with antihypertensive therapy. However, she presented with a chief complaint of abdominal pain and was diagnosed with intratumoral hemorrhage. Urgent TAE was performed that successfully achieved hemorrhage control. After TAE, serum levels of both epinephrine and norepinephrine were within the normal range. Abdominal computed tomography revealed resolving retroperitoneal hematoma. Elective open surgery was performed without significant intraoperative bleeding or fluctuations in blood pressure.

Conclusion

We report a case of successful preoperative TAE for functional PGL to control intraoperative blood pressure fluctuations and bleeding. Preoperative TAE could be a useful procedure for the surgical preparation of functional PGL, including unruptured cases.
A case of endoscopic submucosal dissection of esophageal acantholytic Paget’s disease with discontinuously spreading and unclear neoplastic extension
Authors: Satomi Hidetoshi , Ishiguro Shingo , Murayama Sei , Kanesaka Takashi , Michida Tomoki , Ishihara Ryu , Honma Keiichiro
Published: June 2024

Background

Paget's disease (PD) is a carcinoma, in which irregular atypical cells with abundant cytoplasm proliferate mainly within the epithelium and is classified into PD occurring in the breast and extramammary Paget's disease (EMPD) occurring outside the breast. Essentially, extramammary PD is reported as a tumor for which it is difficult for surgeons to properly determine the line of resection.

Case presentation

An 83-year-old male was admitted to our hospital because of roughness of the esophageal epithelium during the follow-up examination for a gastric ulcer. A preoperative biopsy revealed squamous cell carcinoma; therefore, endoscopic submucosal dissection (ESD) was performed.

Conclusions

The characteristic feature in this patient was the distribution of tumor cells and, accordingly, the difficulty in identifying the neoplastic distribution. In this patient, the odd distribution and growth pattern of the tumor cells made it difficult for the operator to identify the distribution of the lesion preoperatively.
Intestinal obstruction secondary to perforation of Meckel’s diverticulum caused by dentures: a case report and review of literature
Authors: Tian Gaoyuan , Yuan Zefeng , Luo Ming , Zhang Yujin , Kong Bin
Published: June 2024

Background

Meckel’s diverticulum (MD) is the most common congenital abnormality of the gastrointestinal tract. However, MD is rare in clinical practice, and perforation of a MD by a foreign body is even rarer. Preoperative diagnosis is difficult because there is often insufficient information; therefore it is usually diagnosed intraoperatively. Although rare, it should be considered as a differential diagnosis in patients who have ingested foreign bodies.

Case presentation

The following is the case of a 52-year-old female patient who was admitted because of generalized abdominal pain for 5 days, related to nausea and vomiting. She also stopped passing gas. Inflammatory indicators were elevated, and computed tomography (CT) revealed gas–liquid levels in the small intestine and high-density objects in the ileum. Based on the patient’s condition, laparotomy was performed instead because the laparoscopic procedure was difficult to perform. Intraoperatively, a foreign body perforated the diverticulum of the terminal ileum, resulting in the development of an abdominal abscess. Finally, we performed resection of the ileal diverticula and partial resection of the ileum. After the surgery, it was confirmed that the foreign bodies were two dentures accidentally eaten by the patient.

Conclusion

A thorough understanding of the clinical presentation, imaging features, and treatment of MD and its complications will assist clinicians in making prompt and accurate diagnoses and providing symptomatic treatment.
Epidemiology of Non-Contact Muscle Injuries in the Italian Male Elite Under-19 Football (Soccer) Championship
Authors: Magistrali Massimo , Stefanini Luca , Abate Michele , Biancalana Giulio , Stegagno Andrea , Cugia Paolo , Candoli Piero , Anania Giuseppe , Lucchese Pier Luigi , Gaddi Diego , Volpi Piero , Mariani Francesco , Boldrini Lorenzo , Filippi Nicola , Cerrone Annunziata , Sirtori Cristiano , Battaglino Paolo , Bravin Guido , Del Fabro Emilio , Berti Mattia , Vecchini Eugenio , Minetto Marco A.
Published: June 2024

Background

While extensive research exists on muscle injuries among adult football players, a notable gap persists in studies concerning younger footballers. The aim of the current study is to provide epidemiological data on the characteristics of time-loss muscle injuries in young football players participating in the Italian Under-19 male elite Championship (“Primavera 1”).

Results

Conducted as a multicentre, prospective, observational cohort study, this research gathered injury data from the 2022-23 season across 14 of the 18 Clubs in the first Italian Under-19 championship. The cohort comprised 391 players with a mean age (± standard deviation) of 18.0 ± 0.4 years. A total of 479 injuries were reported, resulting in 14,231 days of activity lost. Of these, muscle injuries were 209 (44%), accounting for 4,519 (32%) days lost. Overall muscle injuries incidence was 1.82/1000 hours, with a mean injury burden of 39.4 days lost/1000 hours. Almost all muscle injuries (206 out of 209: 98.5%) occurred in hamstrings, quadriceps, adductors, calf and iliopsoas. Hamstrings injuries were the most burdensome (18.8 days lost/1000 hours) accounting for nearly half of all days lost due to muscle injuries. Incidence and burden of adductors injuries (0.25 injuries and 4.1 days lost/1000 hours, respectively) were found to be comparable to calf injuries (0.24 injuries and 4.7 days lost/1000 hours, respectively). Iliopsoas injuries accounted for a noteworthy portion of the total, with an injury incidence of 0.16/1000 hours and a burden of 3.3 days lost/1000 hours. Injuries with myo-tendinous or myo-aponeurotic involvement demonstrated delayed return-to-football compared to those without such involvement (35.6 vs. 18.5 days, p < 0.0001).

Conclusions

The study highlighted a peculiar distribution of non-contact muscle injuries among elite young football players. While hamstring injuries were confirmed as the most burdensome, incidence and burden of adductors and calf injuries were found to be similar. A significant incidence and burden of iliopsoas injuries were observed. These findings suggest potential implementations for targeted injury prevention strategies in the Italian male elite Under-19 football Championship.
Dietary factors in relation to hypertension: a mendelian randomization study
Authors: Cai Jiasheng , Sun Xiaochen , Li Mingxuan , Luo Rong , Wang Wei , Wang Zilong , Akkaif Mohammed Ahmed , Liu Haibo
Published: June 2024

Background

Observational studies have elucidated the associations between dietary factors and hypertension. Nevertheless, the exploration of these relationships using Mendelian randomization remains scarce currently.

Methods

The Mendelian randomization approach investigated the potential causal relationships between 16 dietary factors and hypertension. To achieve this, we identified genetic variants associated with these dietary factors by utilizing data from European-descent genome-wide association studies with a stringent significance threshold (P < 5 × 10 − 8). Subsequently, we obtained genetic associations with hypertension from the extensive FinnGen Study, encompassing 92,462 cases and 265,626 controls. Our primary analytical method was the inverse variance weighted method, and we also conducted assessments for heterogeneity and pleiotropy to ensure the robustness and reliability of our findings.

Results

The study revealed significant associations with hypertension risk for various dietary factors. Specifically, higher weekly alcohol consumption (OR: 1.53, 95% CI: 1.19–1.96) and more frequent alcohol intake (OR: 1.20, 95% CI: 1.08–1.33) were positively correlated with an increased risk of hypertension. Likewise, increased poultry intake (OR: 3.25, 95% CI: 1.83–5.78) and beef intake (OR: 1.80, 95% CI: 1.09–2.97) were also linked to a higher risk of hypertension. Conversely, there were protective factors associated with a decreased risk of hypertension. These included consuming salad and raw vegetables, dried fruits, cheese, and cereals. It is important to note that no evidence of pleiotropy was detected, underscoring the robustness of these findings.

Conclusions

This study uncovered causal relationships between various dietary factors and hypertension risk. Specifically, alcohol consumption in terms of drinks per week and intake frequency, as well as poultry and beef intake, were causally associated with an elevated risk of hypertension. In contrast, consuming salad/raw vegetables, dried fruits, cheese, and cereals demonstrated an inverse causal association with hypertension, suggesting a potential protective effect.
Deep learning reconstruction for lumbar spine MRI acceleration: a prospective study
Authors: Tang Hui , Hong Ming , Yu Lu , Song Yang , Cao Mengqiu , Xiang Lei , Zhou Yan , Suo Shiteng
Published: June 2024

Background

We compared magnetic resonance imaging (MRI) turbo spin-echo images reconstructed using a deep learning technique (TSE-DL) with standard turbo spin-echo (TSE-SD) images of the lumbar spine regarding image quality and detection performance of common degenerative pathologies.

Methods

This prospective, single-center study included 31 patients (15 males and 16 females; aged 51 ± 16 years (mean ± standard deviation)) who underwent lumbar spine exams with both TSE-SD and TSE-DL acquisitions for degenerative spine diseases. Images were analyzed by two radiologists and assessed for qualitative image quality using a 4-point Likert scale, quantitative signal-to-noise ratio (SNR) of anatomic landmarks, and detection of common pathologies. Paired-sample t, Wilcoxon, and McNemar tests, unweighted/linearly weighted Cohen κ statistics, and intraclass correlation coefficients were used.

Results

Scan time for TSE-DL and TSE-SD protocols was 2:55 and 5:17 min:s, respectively. The overall image quality was either significantly higher for TSE-DL or not significantly different between TSE-SD and TSE-DL. TSE-DL demonstrated higher SNR and subject noise scores than TSE-SD. For pathology detection, the interreader agreement was substantial to almost perfect for TSE-DL, with κ values ranging from 0.61 to 1.00; the interprotocol agreement was almost perfect for both readers, with κ values ranging from 0.84 to 1.00. There was no significant difference in the diagnostic confidence or detection rate of common pathologies between the two sequences (p ≥ 0.081).

Conclusions

TSE-DL allowed for a 45% reduction in scan time over TSE-SD in lumbar spine MRI without compromising the overall image quality and showed comparable detection performance of common pathologies in the evaluation of degenerative lumbar spine changes.

Relevance statement

Deep learning-reconstructed lumbar spine MRI protocol enabled a 45% reduction in scan time compared with conventional reconstruction, with comparable image quality and detection performance of common degenerative pathologies.

Key points

• Lumbar spine MRI with deep learning reconstruction has broad application prospects.

• Deep learning reconstruction of lumbar spine MRI saved 45% scan time without compromising overall image quality.

• When compared with standard sequences, deep learning reconstruction showed similar detection performance of common degenerative lumbar spine pathologies.

Graphical Abstract
Quantum chemical modelling, molecular docking, synthesis and experimental anti-microbial activity of 1,4-diazepan linked piperidine derivative
Authors: Agrawal Khushbu , Patel Tarun M. , Thakur Shavi , Patel Kruti , Mittal Sumit
Published: June 2024

Background

In this work, we represent synthesis, in silico analysis and biological activity of 1,4 diazepine linked piperidine derivatives (6a–6o). All the derivatives were screened for their anti-microbial activity against gram-positive (Staphylococcus aureus, Bacillus Subtills, Bacillus megaterium) and gram-negative (Escherichia coli, Pseudonymous, Shigella sp.) bacteria. Compounds were synthesized from reaction of tert-butyl 1,4-diazepane-1-carboxylic, butyryl chloride and varied aromatic aldehyde, further characterized by 1H NMR and LCMS spectral techniques.

Result

Using ampicillin as a positive control, the synthetic compounds 6a–6o were tested for their in-silico study and experimental anti-microbial activity against gram-positive (Staphylococcus aureus, Bacillus Subtills, Bacillus megaterium) and gram-negative (Escherichia coli, Pseudonymous, Shigella sp.) bacteria. According to in vitro assay compound 6a, compound 6c, compound 6d, compound 6m and compound 6I showed higher activity against all the tested strains. Molecule 6i, compound 6j, compound 6k, compound 6f has good to moderate antibacterial activity. DFT computations were used to optimize the molecular geometry at the B3LYP/6-31G (d, p) theoretical level. The corresponding energy values of molecular orbitals were visualized using optimized geometries. Moreover, Auto Dock Vina 1.2.0 is used to assess molecular docking against two target proteins, Bacillus subtilis (PDB ID: 6UF6) and Protease Vulgaris (PDB ID: 5HXW). The target molecule 6b displayed the best binding energies for both. Additionally, we calculated the ADME for each molecule (6a–6o).

Conclusion

All fifteen synthesized compounds were screened for their in vitro and in silico analysis. In vitro analysis for anti-microbial activity was carried out against gram-positive (Staphylococcus aureus, Bacillus Subtills, Bacillus megaterium) and gram-negative (Escherichia coli, Pseudonymous, Shigella sp.) bacteria and compound 6a, compound 6c, compound 6d, compound 6m and compound 6I exhibits more potent activity towards all tested strains. Molecular docking is performed against target proteins, L-amino acid deaminase from Proteus Vulgaris and LcpA ligase from Bacillus subtilis, representing the Gram-negative bacterium and Gram-positive bacterium, respectively. Compound 6b showed the highest no. of interaction with protein according to molecular docking. With the advent of innovative techniques like ADME, we select their hit compounds early on and anticipate future pharmacokinetic and pharmacodynamic benefits and drawbacks of these promising therapeutic candidates.

Graphical abstract
Identifying the role of industrial heritage in the European Capital of Culture programme
Authors: Jones Zachary M. , Zhang Xinwen
Published: June 2024

There has been an increasing level of recognition of the interaction between cultural mega-events and built heritage in recent years. While research has broadly identified the need to align strategies and visions, as well as involve heritage actors and local communities, there has not been a systematic investigation of the position of industrial heritage within this tableau. This paper examines in depth the European Capital of Culture (ECoC) programme, as it is one of the longest standing Capital of Culture programmes in the world and has a significant record of investment and urban transformation. In this paper, we survey and categorise the inclusion of industrial heritage within the ECoC programme in 36 host cities and regions spread across Europe. This research provides the most comprehensive understanding to date of the specific forms of interaction between industrial heritage and ECoCs to better understand the kinds of relationships that have taken place. We then explore in detail the projects and decisions made in the cases of the 2023 Elefsina, 2017 Pafos and 2008 Liverpool ECoCs.
Modeling Klebsiella pneumonia infections and antibiotic resistance dynamics with fractional differential equations: insights from real data in North Cyprus
Authors: Amilo David , Bagkur Cemile , Kaymakamzade Bilgen
Published: June 2024

This study presents an enhanced fractional-order mathematical model for analyzing the dynamics of Klebsiella pneumonia infections and antibiotic resistance over time. The model incorporates fractional Caputo derivative operators and kernel, to provide a more comprehensive understanding of the complex temporal dynamics. The model consists of three groups: Susceptible (S), Infected (I), and Resistant (R) individuals, each controlled by a fractional differential equation. The model represents the interaction between infection, recovery from infection, and the possible development of antibiotic resistance in susceptible individuals. The existence, uniqueness, stability, and alignment of the model’s prediction to the observed data were analyzed and buttressed with numerical simulations. The results show that imipenem has the highest efficacy compared with ertapenem and meropenem category drugs. The estimated reproduction number and reproduction coefficient illustrate the potential impact of this model in improving treatment strategies, while the memory effects highlight the advantages of fractional differentiation. The model predicts an increased possibility of antibiotic resistance despite effective treatment, suggesting a new treatment approach.
Cisplatin and capecitabine as definitive chemoradiation for squamous cell carcinoma of the anal canal (SCCAC): A prospective cohort.
Authors: Dornellas Abraão , Bonadio Renata Colombo , Moraes Priscila Muniz , Galhera Denis , Victor Carolina Ribeiro , Chen Andre Tsin Chih , Muratori Carolina Teixeira , Ortega Cinthia , Alves Henrique Souza , Ibrahim Karim , Nahas Caio , Marques Carlos Frederico , Alban Luciana Bastos Valente , Braghiroli Maria Ignez , Hoff Paulo Marcelo , Venchiarutti Moniz Camila M
Published: June 2024

e15503

Background: SCCAC is a rare disease. The standard of care treatment with curative intent is chemoradiation (CRT) with mitomycin (MMC) or cisplatin (CDDP) plus infusional 5-Fluoracil (5-FU). Capecitabine may replace 5-FU in MMC doublet. However, MMC and infusional pumps are frequently unavailable in underdeveloped countries. CCDP and capecitabine are widely available, but there is no prospective data about the feasibility and efficacy of this combination in a definitive SCCAC CRT setting. Methods: A Prospective cohort study aimed to evaluate the safety and efficacy of treatment with chemoradiation with CDDP 60mg/m2 D1 and D29 plus Capecitabine 825mg/m2 BID in a population without MMC and infusional pump access. Eligible patients (pts) had T2-4, N0-3, and M0 disease candidates for a full curative CRT regimen. The study data were prospectively collected using REDCap. The primary endpoint was the response by RECIST v.1.1 at 24 weeks(w). The secondary endpoints included toxicity by CTCAE v.5.0, adherence, PFS, and OS. Results: We enrolled 40 consecutive pts between Aug/2019-Dec/2022 in a tertiary cancer center in Brazil. The median age was 61y, the majority were stage III (n = 31, 77.5%) and ECOG 1 (n = 20, 50%). HIV+ serology was observed in 11 pts (27,5%). All patients received CRT, with a median dose of 54Gy in the primary tumor and 45Gy in the elective nodes. At 8w, 35% (n = 14) had a complete response (CR), 50% (n = 20) partial response (PR), and 2.5% (n = 1) progressive disease (PD). At 6 months, CR was observed in 55% (n = 22), PR in 22.5% (n = 9), and PD in 10% (n = 4). 11 pts had disease recurrence, and six died. 1y OS was 94.7% (IC95%: 80.7- 98.6%), and 1y PFS was 75.3% (IC95%:57.8 - 86.3%). Colostomy-free survival at one year was 89.6% (IC95%: 74.7 - 95.9%). Median PFS and OS were not reached with a 2-year median follow-up. Regarding toxicities, radiodermatitis was observed in 94% (n = 36), nausea in 90% (n = 36), and diarrhea in 65% (n = 26). Any grade 3/4 toxicity was present in 27.5% (n = 11), being the majority of radiodermatitis. Four older pts (average age 73y) had definitive suspension of treatment due to toxicity, 06 pts were hospitalized because of a skin infection, and one died due to treatment toxicity. Conclusions: Definitive chemoradiotherapy with cisplatin and capecitabine is feasible; however, older populations require extra attention to early toxicities management.