bluuebunny/crossref_metadata_2025 huggingface dataset:
Cefiderocol use for the treatment of infections by carbapenem-resistant Gram-negative bacteria: an Italian multicentre real-life experience
Authors: Piccica Matteo , Spinicci Michele , Botta Annarita , Bianco Vincenzo , Lagi Filippo , Graziani Lucia , Faragona Alessandro , Parrella Roberto , Giani Tommaso , Bartolini Andrea , Morroni Gianluca , Bernardo Mariano , Rossolini Gian Maria , Tavio Marcello , Giacometti Andrea , Bartoloni Alessandro
Published: October 2023

Background

Cefiderocol is a novel siderophore cephalosporin with promising activity against most carbapenem-resistant Gram-negative bacteria (CRGNB). However, extensive postmarketing experiences are lacking. This study aimed to analyse the early experience on cefiderocol postmarketing use at three tertiary care hospitals in Italy.

Methods

We retrospectively included patients with infections caused by CRGNB treated with cefiderocol at three Italian tertiary care hospitals from 1 March 2021 to 30 June 2022. A multivariate Cox model was used to identify predictors of 30 day mortality. A propensity score (PS) analysis with inverse probability weighting (IPW) was also performed to compare the treatment effect of cefiderocol monotherapy (CM) versus combination regimens (CCRs).

Results

The cohort included 142 patients (72% male, median age 67 years, with 89 cases of Acinetobacter baumannii infection, 22 cases of Klebsiella pneumoniae, 27 cases of Pseudomonas aeruginosa and 4 of other pathogens). The 30 day all-cause mortality was 37% (52/142). We found no association between bacterial species and mortality. In multivariate analysis, a Charlson Comorbidity Index >3 was an independent predictor of mortality (HR 5.02, 95% CI 2.37–10.66, P < 0.001). In contrast, polymicrobial infection (HR 0.41, 95% CI 0.21–0.82, P < 0.05) was associated with lower mortality. There was no significant difference in mortality between patients receiving CM (n = 70) and those receiving a CCR (n = 72) (33% versus 40%, respectively), even when adjusted for IPW-PS (HR 1.11, 95% CI 0.63–1.96, P = 0.71).

Conclusions

Real-life data confirm that cefiderocol is a promising option against carbapenem-resistant Gram-negative infections, even as monotherapy.
The role of health system penetration rate in estimating the prevalence of type 1 diabetes in children and adolescents using electronic health records
Authors: Li Piaopiao , Lyu Tianchen , Alkhuzam Khalid , Spector Eliot , Donahoo William T , Bost Sarah , Wu Yonghui , Hogan William R , Prosperi Mattia , Schatz Desmond A , Atkinson Mark A , Haller Michael J , Shenkman Elizabeth A , Guo Yi , Bian Jiang , Shao Hui
Published: October 2023

Objective

Having sufficient population coverage from the electronic health records (EHRs)-connected health system is essential for building a comprehensive EHR-based diabetes surveillance system. This study aimed to establish an EHR-based type 1 diabetes (T1D) surveillance system for children and adolescents across racial and ethnic groups by identifying the minimum population coverage from EHR-connected health systems to accurately estimate T1D prevalence.

Materials and methods

We conducted a retrospective, cross-sectional analysis involving children and adolescents <20 years old identified from the OneFlorida+ Clinical Research Network (2018-2020). T1D cases were identified using a previously validated computable phenotyping algorithm. The T1D prevalence for each ZIP Code Tabulation Area (ZCTA, 5 digits), defined as the number of T1D cases divided by the total number of residents in the corresponding ZCTA, was calculated. Population coverage for each ZCTA was measured using observed health system penetration rates (HSPR), which was calculated as the ratio of residents in the corresponding ZTCA and captured by OneFlorida+ to the overall population in the same ZCTA reported by the Census. We used a recursive partitioning algorithm to identify the minimum required observed HSPR to estimate T1D prevalence and compare our estimate with the reported T1D prevalence from the SEARCH study.

Results

Observed HSPRs of 55%, 55%, and 60% were identified as the minimum thresholds for the non-Hispanic White, non-Hispanic Black, and Hispanic populations. The estimated T1D prevalence for non-Hispanic White and non-Hispanic Black were 2.87 and 2.29 per 1000 youth, which are comparable to the reference study’s estimation. The estimated prevalence of T1D for Hispanics (2.76 per 1000 youth) was higher than the reference study’s estimation (1.48-1.64 per 1000 youth). The standardized T1D prevalence in the overall Florida population was 2.81 per 1000 youth in 2019.

Conclusion

Our study provides a method to estimate T1D prevalence in children and adolescents using EHRs and reports the estimated HSPRs and prevalence of T1D for different race and ethnicity groups to facilitate EHR-based diabetes surveillance.
Determination of Lactose in Lactose-Free and Low-Lactose Milk, Milk Products, and Products Containing Dairy Ingredients by the LactoSens®R Amperometry Method: Final Action 2020.01
Authors: Halbmayr-Jech Elisabeth , Kittl Roman , Weinmann Patrick , Schulz Christopher , Kowalik Anna , König Matthias , Korp Jasmin , Sygmund Christoph , Brunelle Sharon L
Published: October 2023

Background

The LactoSens®R method was previously shown to have acceptable accuracy and repeatability precision as required by AOAC Standard Method Performance Requirements (SMPR®) 2018.009 for determination of lactose in low-lactose or lactose-free milk, milk products, and products containing dairy ingredients and was awarded Official Method of AnalysisSM (OMA) First Action status in 2020.

Objective

The method was subjected to a multilaboratory validation (MLV) study to evaluate the reproducibility precision of the method.

Methods

Fourteen validation materials were provided to 15 laboratories in seven countries as blind duplicates. The materials ranged from 0 to 173 mg/100 g lactose. Each laboratory analyzed the blind duplicates according to OMA 2020.01. The data were analyzed for repeatability and reproducibility precision.

Results

RSDr values varied from 2.81 to 8.76%, and RSDR values varied from 4.25 to 12.5%. When sorted by category and concentration range, these results met the repeatability and reproducibility criteria required by SMPR 2018.009.

Conclusions

The data generated in the MLV support the adoption of OMA 2020.01 as Final Action status.

Highlights

The LactoSensR method, as described by OMA 2020.01, provides an accurate and precise determination of lactose in a variety of low-lactose and lactose-free milk, milk products, and products containing dairy ingredients in minutes.
Effects of dietary epidermal growth factor supplementation on liver antioxidant capacity of piglets with intrauterine growth retardation
Authors: Tang Xiaopeng , Xiong Kangning , Li Meijun
Published: October 2023

The present experiment was conducted to study the effects of dietary epidermal growth factor (EGF) supplementation on the liver antioxidant capacity of piglets with intrauterine growth retardation (IUGR). The present study consists of two experiments. In experiment 1, six normal-birth-weight (NBW) and six IUGR newborn piglets were slaughtered within 2 to 4 h after birth to compare the effects of IUGR on the liver antioxidant capacity of newborn piglets. The results showed that compared with NBW piglets, IUGR piglets had a lower birth weight and liver relative weight; IUGR piglets had a higher serum malondialdehyde (MDA) level, liver MDA level and hydrogen peroxide (H2O2) level, and had a lower liver total antioxidant capacity (T-AOC) level and glutathione peroxidase (GSH-Px) activity; IUGR trended to increase serum alanine aminotransferase activity, aspartate aminotransferase activity, and H2O2 level, and trended to decrease liver total superoxide dismutase activity. In experiment 2, six NBW piglets, and 12 IUGR piglets weaned at 21 d of age were randomly divided into the NC group (NBW piglets fed with basal diet); IC group (IUGR piglets fed with basal diet), and IE group (IUGR piglets fed with basal diet plus 2 mg/kg EGF), and feeding for 14 d. Organ index, serum parameters, liver antioxidant capacity, and liver antioxidant-related genes expression were measured. The results showed that compared to the IC group, dietary EGF supplementation (IE group) significantly reduced serum malondialdehyde level and H2O2 level, and liver protein carbonyl (PC) level and 8-hydroxydeoxyguanosine level of piglets with IUGR; dietary EGF supplementation (IE group) significantly increased serum T-AOC level, liver T-AOC level and GSH-Px activity; dietary supplemented with EGF (IE group) enhanced liver Nrf2, NQO1, HO1, and GPX1 mRNA expression compared to IC group. Pearson’s correlation analysis further showed that EGF can alleviate liver oxidative injury caused by IUGR and improve the performance of IUGR piglets. In conclusion, EGF exhibited potent protective effects on IUGR-induced liver oxidative injury, by activating the Nrf2 signaling pathway to mediate the expression of downstream antioxidant enzymes and phase II detoxification enzymes (NQO1 and HO1), thereby alleviating liver oxidative damage and promoting the growth performance of IUGR piglets.
Dynamics of mitochondrial adaptation and energy metabolism in rainbow trout (Oncorhynchus mykiss) in response to sustainable diet and temperature
Authors: Idenyi John N , Eya Jonathan C , Abanikannda Mosope F , Huber David H , Gannam Ann L , Sealey Wendy M
Published: October 2023

Impacts of plant-based ingredients and temperatures on energy metabolism in rainbow trout was investigated. A total of 288 fish (mean body weight: 45.6 g) were fed four isocaloric, isolipidic, and isonitrogenous diets containing 40% protein and 20% lipid and formulated as 100% animal-based protein (AP) and a blend of 50% fish oil (FO) and 50% camelina oil (CO); 100% AP and100% CO; 100% plant-based protein (PP) and a blend of 50% FO and 50% CO or 100% PP and 100% CO at 14 or 18 °C for 150 d. Diet did not significantly affect weight gain (WG) (P = 0.1902), condition factor (CF) (P = 0.0833) or specific growth rate (SGR) (P = 0.1511), but diet significantly impacted both feed efficiency (FE) (P = 0.0076) and feed intake (FI) (P = 0.0076). Temperature did not significantly affect WG (P = 0.1231), FE (P = 0.0634), FI (P = 0.0879), CF (P = 0.8277), or SGR (P = 0.1232). The diet × temperature interaction did not significantly affect WG (P = 0.7203), FE (P = 0.4799), FI (P = 0.2783), CF (P = 0.5071), or SGR (P = 0.7429). Furthermore, temperature did not influence protein efficiency ratio (P = 0.0633), lipid efficiency ratio (P = 0.0630), protein productive value (P = 0.0756), energy productive value (P = 0.1048), and lipid productive value (P = 0.1386); however, diet had significant main effects on PER (P = 0.0076), LPV (P = 0.0075), and PPV (P = 0.0138). Temperature regimens induced increased activities of mitochondrial complexes I (P = 0.0120), II (P = 0.0008), III (P = 0.0010), IV (P < 0.0001), V (P < 0.0001), and citrate synthase (CS) (P < 0.0001) in the intestine; complexes I (P < 0.0001), II (P < 0.0001), and CS (P = 0.0122) in the muscle; and complexes I (P < 0.0001), II (P < 0.0001), and III (P < 0.0001) in the liver. Similarly, dietary composition significantly affected complexes I (P < 0.0001), II (P < 0.0001), IV (P < 0.0001), V (P < 0.0001), and CS (P < 0.0001) in the intestine; complexes I (P < 0.0001), II (P < 0.0001), III (P = 0.0002), IV (P < 0.0001), V (P = 0.0060), and CS (P < 0.0001) in the muscle; and complexes I (P < 0.0001), II (P < 0.0001), IV (P < 0.0001), V (P < 0.0001), and CS (P < 0.0001) in the liver activities except complex III activities in intestine (P = 0.0817) and liver (P = 0.4662). The diet × temperature interaction impacted CS activity in the intestine (P = 0.0010), complex II in the muscle (P = 0.0079), and complexes I (P = 0.0009) and II (P = 0.0348) in the liver. Overall, comparing partial to full dietary substitution of FO with CO, partial dietary replacement showed similar effects on complex activities.
Baseline characteristics may impact treatment duration of cabazitaxel in patients with mCRPC: a subanalysis of data from a post-marketing surveillance
Authors: Matsubara Nobuaki , Matsuyama Hideyasu , Kazama Hirotaka , Seto Takeshi , Sunaga Yoshinori , Suzuki Kazuhiro
Published: October 2023

Objective

Cabazitaxel has demonstrated improvements in overall survival among patients with metastatic castration-resistant prostate cancer (mCRPC) in the pivotal comparison clinical trials TROPIC, PROSELICA and CARD. However, these trials include mCRPC patients with similar characteristics, and there are limited data on how baseline characteristics affect treatment discontinuation in the patient population.

Methods

To assess individual factors that may impact the discontinuation rate of cabazitaxel treatment, we conducted a post hoc analysis of data from a nationwide all-case, post-marketing surveillance of cabazitaxel in Japan. Patients were grouped according to the number of cabazitaxel treatment cycles received (1–2 and ≥3 cycles). Predictive factors were identified through multivariate logistic regression analysis.

Results

Across 660 patients with metastatic castration-resistant prostate cancer, 70.2% received ≥3 cycles of cabazitaxel treatment. Those receiving 1–2 cycles of cabazitaxel had a greater proportion of patients with poorer Eastern Cooperative Oncology Group Performance Status, presence of lung and liver metastases, higher prostate-specific antigen level and prior radiation therapy at baseline. Regardless of the number of cabazitaxel cycles received, the primary reason for discontinuation was progression of disease rather than adverse events. Compared with those receiving 1–2 cycles, a lower proportion of patients receiving 3–10 and ≥11 cycles of cabazitaxel treatment experienced adverse events. Multivariate analysis showed a significant association between early discontinuation and presence of liver lesions, poorer Eastern Cooperative Oncology Group Performance Status and higher prostate-specific antigen level at baseline.

Conclusions

Post-marketing surveillance data suggest physicians should individualize cabazitaxel treatment based on certain patient characteristics at baseline.
Transforming Lost Time into Migration Capital: Hazara Refugee Social and Cultural Capital Development in Indonesia
Authors: Fiske Lucy
Published: October 2023

Refugees spend an average of 17 years living in limbo. This time is usually seen by refugees and scholars as ‘lost’ or ‘wasted’ time. Pierre Bourdieu theorized time as critical in accumulating social and cultural capital; foundations of socio-economic status. Families with greater economic capital can provide their offspring with more ‘time free from economic necessity’, enabling activities that will enhance their status. Time and economic capital are often de-linked by refugee journeys, stripping refugees of economic capital, but leaving an over-abundance of time. This paper uses Bourdieu’s work on time and capital to examine how refugees in one community use time during multi-year transit. Based on fieldwork with a single community, this paper argues that, rather than ‘wasting’ time, members of this community are using refugee time to accumulate social and cultural capital, which some then convert to migration capital and hasten their refugee journeys.
An interaction between eIF4A3 and eIF3g drives the internal initiation of translation
Authors: Chang Jeeyoon , Shin Min-Kyung , Park Joori , Hwang Hyun Jung , Locker Nicolas , Ahn Junhak , Kim Doyeon , Baek Daehyun , Park Yeonkyoung , Lee Yujin , Boo Sung Ho , Kim Hyeong-In , Kim Yoon Ki
Published: October 2023

An RNA structure or modified RNA sequences can provide a platform for ribosome loading and internal translation initiation. The functional significance of internal translation has recently been highlighted by the discovery that a subset of circular RNAs (circRNAs) is internally translated. However, the molecular mechanisms underlying the internal initiation of translation in circRNAs remain unclear. Here, we identify eIF3g (a subunit of eIF3 complex) as a binding partner of eIF4A3, a core component of the exon-junction complex (EJC) that is deposited onto spliced mRNAs and plays multiple roles in the regulation of gene expression. The direct interaction between eIF4A3-eIF3g serves as a molecular linker between the eIF4A3 and eIF3 complex, thereby facilitating internal ribosomal entry. Protein synthesis from in vitro-synthesized circRNA demonstrates eIF4A3-driven internal translation, which relies on the eIF4A3-eIF3g interaction. Furthermore, our transcriptome-wide analysis shows that efficient polysomal association of endogenous circRNAs requires eIF4A3. Notably, a subset of endogenous circRNAs can express a full-length intact protein, such as β-catenin, in an eIF4A3-dependent manner. Collectively, our results expand the understanding of the protein-coding potential of the human transcriptome, including circRNAs.
m7GHub V2.0: an updated database for decoding the N7-methylguanosine (m7G) epitranscriptome
Authors: Wang Xuan , Zhang Yuxin , Chen Kunqi , Liang Zhanmin , Ma Jiongming , Xia Rong , de Magalhães João Pedro , Rigden Daniel J , Meng Jia , Song Bowen
Published: October 2023

With recent progress in mapping N7-methylguanosine (m7G) RNA methylation sites, tens of thousands of experimentally validated m7G sites have been discovered in various species, shedding light on the significant role of m7G modification in regulating numerous biological processes including disease pathogenesis. An integrated resource that enables the sharing, annotation and customized analysis of m7G data will greatly facilitate m7G studies under various physiological contexts. We previously developed the m7GHub database to host mRNA m7G sites identified in the human transcriptome. Here, we present m7GHub v.2.0, an updated resource for a comprehensive collection of m7G modifications in various types of RNA across multiple species: an m7GDB database containing 430 898 putative m7G sites identified in 23 species, collected from both widely applied next-generation sequencing (NGS) and the emerging Oxford Nanopore direct RNA sequencing (ONT) techniques; an m7GDiseaseDB hosting 156 206 m7G-associated variants (involving addition or removal of an m7G site), including 3238 disease-relevant m7G-SNPs that may function through epitranscriptome disturbance; and two enhanced analysis modules to perform interactive analyses on the collections of m7G sites (m7GFinder) and functional variants (m7GSNPer). We expect that m7Ghub v.2.0 should serve as a valuable centralized resource for studying m7G modification. It is freely accessible at: www.rnamd.org/m7GHub2.
Inhibition of CDK12 elevates cancer cell dependence on P-TEFb by stimulation of RNA polymerase II pause release
Authors: Wang Zhijia , Himanen Samu V , Haikala Heidi M , Friedel Caroline C , Vihervaara Anniina , Barborič Matjaž
Published: October 2023

P-TEFb and CDK12 facilitate transcriptional elongation by RNA polymerase II. Given the prominence of both kinases in cancer, gaining a better understanding of their interplay could inform the design of novel anti-cancer strategies. While down-regulation of DNA repair genes in CDK12-targeted cancer cells is being explored therapeutically, little is known about mechanisms and significance of transcriptional induction upon inhibition of CDK12. We show that selective targeting of CDK12 in colon cancer-derived cells activates P-TEFb via its release from the inhibitory 7SK snRNP. In turn, P-TEFb stimulates Pol II pause release at thousands of genes, most of which become newly dependent on P-TEFb. Amongst the induced genes are those stimulated by hallmark pathways in cancer, including p53 and NF-κB. Consequently, CDK12-inhibited cancer cells exhibit hypersensitivity to inhibitors of P-TEFb. While blocking P-TEFb triggers their apoptosis in a p53-dependent manner, it impedes cell proliferation irrespective of p53 by preventing induction of genes downstream of the DNA damage-induced NF-κB signaling. In summary, stimulation of Pol II pause release at the signal-responsive genes underlies the functional dependence of CDK12-inhibited cancer cells on P-TEFb. Our study establishes the mechanistic underpinning for combinatorial targeting of CDK12 with either P-TEFb or the induced oncogenic pathways in cancer.
Lineage specific 3D genome structure in the adult human brain and neurodevelopmental changes in the chromatin interactome
Authors: Rahman Samir , Dong Pengfei , Apontes Pasha , Fernando Michael B , Kosoy Roman , Townsley Kayla G , Girdhar Kiran , Bendl Jaroslav , Shao Zhiping , Misir Ruth , Tsankova Nadia , Kleopoulos Steven P , Brennand Kristen J , Fullard John F , Roussos Panos
Published: October 2023

The human brain is a complex organ comprised of distinct cell types, and the contribution of the 3D genome to lineage specific gene expression remains poorly understood. To decipher cell type specific genome architecture, and characterize fine scale changes in the chromatin interactome across neural development, we compared the 3D genome of the human fetal cortical plate to that of neurons and glia isolated from the adult prefrontal cortex. We found that neurons have weaker genome compartmentalization compared to glia, but stronger TADs, which emerge during fetal development. Furthermore, relative to glia, the neuronal genome shifts more strongly towards repressive compartments. Neurons have differential TAD boundaries that are proximal to active promoters involved in neurodevelopmental processes. CRISPRi on CNTNAP2 in hIPSC-derived neurons reveals that transcriptional inactivation correlates with loss of insulation at the differential boundary. Finally, re-wiring of chromatin loops during neural development is associated with transcriptional and functional changes. Importantly, differential loops in the fetal cortex are associated with autism GWAS loci, suggesting a neuropsychiatric disease mechanism affecting the chromatin interactome. Furthermore, neural development involves gaining enhancer-promoter loops that upregulate genes that control synaptic activity. Altogether, our study provides multi-scale insights on the 3D genome in the human brain.
STAMarker: determining spatial domain-specific variable genes with saliency maps in deep learning
Authors: Zhang Chihao , Dong Kangning , Aihara Kazuyuki , Chen Luonan , Zhang Shihua
Published: October 2023

Spatial transcriptomics characterizes gene expression profiles while retaining the information of the spatial context, providing an unprecedented opportunity to understand cellular systems. One of the essential tasks in such data analysis is to determine spatially variable genes (SVGs), which demonstrate spatial expression patterns. Existing methods only consider genes individually and fail to model the inter-dependence of genes. To this end, we present an analytic tool STAMarker for robustly determining spatial domain-specific SVGs with saliency maps in deep learning. STAMarker is a three-stage ensemble framework consisting of graph-attention autoencoders, multilayer perceptron (MLP) classifiers, and saliency map computation by the backpropagated gradient. We illustrate the effectiveness of STAMarker and compare it with serveral commonly used competing methods on various spatial transcriptomic data generated by different platforms. STAMarker considers all genes at once and is more robust when the dataset is very sparse. STAMarker could identify spatial domain-specific SVGs for characterizing spatial domains and enable in-depth analysis of the region of interest in the tissue section.
Resolving altered base-pairing of RNA modifications with DNA nanoswitches
Authors: Todkari Iranna Annappa , Chandrasekaran Arun Richard , Punnoose Jibin Abraham , Mao Song , Haruehanroengra Phensinee , Beckles Camryn , Sheng Jia , Halvorsen Ken
Published: October 2023

There are >170 naturally occurring RNA chemical modifications, with both known and unknown biological functions. Analytical methods for detecting chemical modifications and for analyzing their effects are relatively limited and have had difficulty keeping pace with the demand for RNA chemical biology and biochemistry research. Some modifications can affect the ability of RNA to hybridize with its complementary sequence or change the selectivity of base pairing. Here, we investigate the use of affinity-based DNA nanoswitches to resolve energetic differences in hybridization. We found that a single m3C modification can sufficiently destabilize hybridization to abolish a detection signal, while an s4U modification can selectively hybridize with G over A. These results establish proof of concept for using DNA nanoswitches to detect certain RNA modifications and analyzing their effects in base pairing stability and specificity.
Detection of queuosine and queuosine precursors in tRNAs by direct RNA sequencing
Authors: Sun Yu , Piechotta Michael , Naarmann-de Vries Isabel , Dieterich Christoph , Ehrenhofer-Murray Ann E
Published: October 2023

Queuosine (Q) is a complex tRNA modification found in bacteria and eukaryotes at position 34 of four tRNAs with a GUN anticodon, and it regulates the translational efficiency and fidelity of the respective codons that differ at the Wobble position. In bacteria, the biosynthesis of Q involves two precursors, preQ0 and preQ1, whereas eukaryotes directly obtain Q from bacterial sources. The study of queuosine has been challenging due to the limited availability of high-throughput methods for its detection and analysis. Here, we have employed direct RNA sequencing using nanopore technology to detect the modification of tRNAs with Q and Q precursors. These modifications were detected with high accuracy on synthetic tRNAs as well as on tRNAs extracted from Schizosaccharomyces pombe and Escherichia coli by comparing unmodified to modified tRNAs using the tool JACUSA2. Furthermore, we present an improved protocol for the alignment of raw sequence reads that gives high specificity and recall for tRNAs ex cellulo that, by nature, carry multiple modifications. Altogether, our results show that 7-deazaguanine-derivatives such as queuosine are readily detectable using direct RNA sequencing. This advancement opens up new possibilities for investigating these modifications in native tRNAs, furthering our understanding of their biological function.
ClinicalOmicsDB: exploring molecular associations of oncology drug responses in clinical trials
Authors: Moon Chang In , Elizarraras John Michael , Lei Jonathan Thomas , Jia Byron , Zhang Bing
Published: October 2023

Matching patients to optimal treatment is challenging, in part due to the limited availability of real-world clinical datasets for predictive biomarker identification. The growing integration of omics profiling into clinical trials presents a new opportunity to tackle this challenge. Here, we introduce ClinicalOmicsDB, a web application for exploring molecular associations of oncology drug responses in clinical trials. This database includes transcriptomic data from 40 clinical trial studies, with 5913 patients spanning 11 cancer types. These studies include 67 treatment arms with a variety of chemotherapy, targeted therapy and immunotherapy drugs, and their combinations, which we organize based on an established ontology for easier navigation. The web application provides users with three options to explore molecular associations of oncology drug responses, focusing on studies, treatments or genes, respectively. Gene set analysis further connects treatment response to pathway activity and tumor microenvironment attributes. The user-friendly web interface of ClinicalOmicsDB streamlines interactive analysis. A Rust-based backend speeds up response time, and application programming interfaces and an R package enable programmatic access. We use three case studies to demonstrate the utility of this resource in human cancer studies. ClinicalOmicsDB is freely available at http://trials.linkedomics.org/.
The cytokinin receptor OHK4/OsHK4 regulates inflorescence architecture in rice via an IDEAL PLANT ARCHITECTURE1/WEALTHY FARMER’S PANICLE-mediated positive feedback circuit
Authors: Chun Yan , Fang Jingjing , Savelieva Ekaterina M , Lomin Sergey N , Shang Jiangyuan , Sun Yinglu , Zhao Jinfeng , Kumar Ashmit , Yuan Shoujiang , Yao Xuefeng , Liu Chun-Ming , Arkhipov Dmitry V , Romanov Georgy A , Li Xueyong
Published: October 2023

Inflorescence architecture is important for rice (Oryza sativa) grain yield. The phytohormone cytokinin (CK) has been shown to regulate rice inflorescence development; however, the underlying mechanism mediated by CK perception is still unclear. Employing a forward genetic approach, we isolated an inactive variant of the CK receptor OHK4/OsHK4 gene named panicle length1, which shows decreased panicle size due to reduced inflorescence meristem (IM) activity. A 2-amino acid deletion in the long α-helix stalk of the sensory module of OHK4 impairs the homodimerization and ligand-binding capacity of the receptor, even though the residues do not touch the ligand-binding domain or the dimerization interface. This deletion impairs CK signaling that occurs through the type-B response regulator OsRR21, which acts downstream of OHK4 in controlling inflorescence size. Meanwhile, we found that IDEAL PLANT ARCHITECTURE1(IPA1)/WEALTHY FARMER'S PANICLE (WFP), encoding a positive regulator of IM development, acts downstream of CK signaling and is directly activated by OsRR21. Additionally, we revealed that IPA1/WFP directly binds to the OHK4 promoter and upregulates its expression through interactions with 2 TCP transcription factors, forming a positive feedback circuit. Altogether, we identified the OHK4-OsRR21-IPA1 regulatory module, providing important insights into the role of CK signaling in regulating rice inflorescence architecture.
Caduceus vs. Rod of Asclepius: A Serpentine Dilemma in Medical Iconography
Authors: Shah Muhammad Hamza , Usman Salim , Roy Sakshi , Ahluwalia Arjun , Harky Amer
Published: October 2023

This scholarly inquiry delves into the historical significance of two enduring medical symbols: the Rod of Asclepius and the Caduceus. Tracing their origins back to ancient Greek mythology, we uncover their distinct identities and profound meanings as symbols of healing, unity among medical practitioners, and ethical responsibilities. Beyond aesthetics, these emblems serve as powerful educational tools, fostering universal understanding and connecting modern medicine to its historical heritage. Consequently, embracing their true essence can inspire genuine dedication to the noble mission of caring for others.
Finding the world’s oldest mammals: sieving, dialectical materialism, and squabbles
Authors: Benton Michael J , Gill Pamela G , Whiteside David I
Published: October 2023

Mammals (or properly, mammaliaforms) originated in the Late Triassic and the first 50 Myr of their evolution through Late Triassic and Early Jurassic are best documented by rich faunas from numerous localities around Bristol in south-west England and in South Wales. The mode of preservation of the fossils, in sediment washed into karst features such as caves, is unusual but has led to a demand for specialized processing methods to extract the exquisitely preserved tiny teeth and bones from huge volumes of sediment. This rich documentation of the oldest mammals has made them especially important for mammalian palaeobiology on a global scale. The first specimens were found in the 1860s, and collection and study has been sporadic, with especially fruitful times in the 1860s, and then from 1938–1979. Throughout, the field collecting, processing, and interpretation of the fossils has been fraught, with heated debates between leading protagonists during the second half of the past century. Here, we track the substantial contributions made by Charles Moore, Walter Kühne, Rex Parrington, Kenneth Kermack, Pamela Robinson, and others, using published sources, unpublished letters and notebooks, and interviews, to establish some of the facts about the most heated public disputes.
An Efficient Method for Screening Rice Breeding Lines Against Races of Magnaporthe oryzae
Authors: Oliveira-Garcia Ely , Budot Bernard Orense , Manangkil Jennifer , Lana Felipe Dala , Angira Brijesh , Famoso Adam , Jia Yulin
Published: October 2023

Rice blast, caused by Magnaporthe oryzae, is the most destructive rice disease worldwide. The disease symptoms are usually expressed on the leaf and panicle. The leaf disease intensity in controlled environmental conditions is frequently quantified using a 0 to 5 scale, where 0 represents the absence of symptoms, and 5 represents large eyespot lesions. However, this scale restricts the qualitative classification of the varieties into intermediate resistant and susceptible categories. Here, we develop a 0 to 6 scale for blast disease that allows proper assignment of rice breeding lines and varieties into six resistance levels (highly resistant, resistant, moderately resistant, moderately susceptible, susceptible, and highly susceptible). We evaluated 40 common rice varieties against four major blast races (IB1, IB17, IB49, and IE1-K). Varieties carrying the Pi-ta gene were either highly resistant, resistant, or moderately resistant to IB17. The IE1-K race was able to break Pi-ta-mediated resistance of the rice varieties. The Pi-z gene conferred resistance to the IB17 and IE1-K races. The varieties M201, Cheniere, and Frontier were highly susceptible (score 6; 100% disease) to the race IE1-K. Moreover, varieties that were resistant or susceptible to all four blast races also showed similar levels of resistance/susceptibility to blast disease in the field. Taken together, our data proved that the 0 to 6 blast scale can efficiently determine the resistance levels of rice varieties against major blast races. This robust method will assist rice breeding programs to incorporate durable resistance against major and emerging blast races.

[Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Variations Among Crop Seasons and Inoculum Availability Have a Higher Impact on Grapevine Rust Epidemics than Training Systems or Plastic Cover
Authors: Dutra Pamela S. S. , de Camargo Meyriele P. , Navas-Cortés Juan A. , Amorim Lilian
Published: October 2023

Canopy management practices can be effective as part of the integrated management of grapevine diseases. This study aimed to determine whether training systems and plastic covers can contribute to prevent Asian grapevine leaf rust (AGLR) development. Additionally, the influence of crop season and inoculum availability on AGLR development was investigated. Six-season experiments were carried out to characterize 16 epidemics that developed from natural inoculum (NI) or artificial inoculum (AI) sources (NI + AI), conducted in different training systems and with or without the plastic cover. The Richards model was fitted to each AGLR disease progress curve to estimate and compare the onsets and intensities of epidemics using eight curve elements. Principal components analysis (PCA) identified the incidence progress rate, the area under the severity progress curve, final disease severity, time to disease onset, and time to reach the inflection point as the main descriptors for AGLR epidemics. The results showed that AGLR epidemic development was related mainly to differences in inoculum availability and climatic conditions throughout the seasons and to a lower extent to the training system and plastic cover. The earliest disease onset was observed in epidemics when the NI was supplemented with an AI source. Differences in AGRL intensity were correlated to accumulated precipitation, being less severe in autumn-winter than in the spring-summer season. The present findings provided a better understanding of the structure and the seasonal variation of AGLR in cultivar ‘Niagara Rosada’. The strategies for reducing and/or delaying inoculum buildup among seasons are discussed.
Assessment of Endophytic Fungal Community in Palm Leaves and Their Biocontrol Potential
Authors: Dhillon Braham , Graham Franchesca , Laughinghouse H. Dail , Chakrabarti Seemanti
Published: October 2023

Microbial endophytes live asymptomatically within a host plant and contribute positively to its fitness. Endophytes associate ubiquitously with all plants examined so far and form an integral part of the host for processes such as nutrient uptake and stress response and traits like disease resistance. Well-characterized host–endophyte interaction models exist, but little is known about the microbiome of the monocot plant host, palm. In this study, we identified the endophytic fungal community associated with mule palm leaves with an objective to test their antagonist effects on lethal pathogens of palms. The leaflets of mule palms were sampled across five sites in Central and South Florida, and fungal endophytes were identified using culture-dependent (CD) and amplicon sequence-based culture-independent (CI) methods. Operational taxonomic units (OTUs) corresponding to phylum Ascomycota were identified by both approaches, whereas Basidiomycota were only detected using the CI method. Among the ascomycetes, a small (22%) overlap in the OTUs at the genus level was observed between the two methods, whereas the majority (64%) of OTUs were detected using the CI approach. In vitro cocultivation of endophytes with palm pathogens was observed to produce three distinct interaction phenotypes: inhibition zone, niche establishment, and overlapping growth. Eight endophytes capable of inhibiting fungal pathogen growth in vitro were also identified, suggesting a biocontrol potential for endophyte-derived secondary metabolites. A better understanding of the composition, assembly, and ecology of palm-associated microbial communities would eventually lead to healthy and resilient palms.

[Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Preliminary fracture reduction in children with type III supracondylar humerus fractures during the COVID-19 pandemic
Authors: Zou Chengda , Liu Wendong , Zhen Yunfang , Zhang Fuyong , Liu Yao , Guo Zhixiong , Wang Xiaodong , Liu Ya
Published: October 2023

During the COVID-19 pandemic, the time elapsed from injury to definitive surgery necessitated delay in type III pediatric supracondylar humerus fractures. Preliminary fracture reduction was recommended in these fractures while waiting for operative treatment. The purpose of this study was to evaluate whether preliminary reduction afforded a better treatment experience and improved outcomes. A retrospective cohort analysis of 161 type III supracondylar humerus fractures compared treatment with preliminary closed fracture reduction and delayed percutaneous pin placement (110 children) to delayed combined closed reduction and pin placement (51 children) in a children’s medical center. Of the preliminary reduction group, 22 (20%) required analgesic pain relief, compared to 18 (35%) in the non-preliminary reduction group (P = 0.037), and the preliminary reduction group had statistically less pain (assessed using the Faces Pain Scale-Revised rating) the first night after injury and the first-night post-CRPP (P = 0.019, P = 0.008). Cast splitting was more frequent in the non-preliminary reduction group, 11 patients (22%) than in the preliminary reduction group, 10 patients (9%; P = 0.029). The operative times in the preliminary reduction group were shorter (P < 0.001). If delay is necessary for complete repair of type III supracondylar humerus fractures, a preliminary fracture reduction with a temporary cast can be recommended, as these children will experience a more comfortable interval, with less swelling and pain, and potentially a shorter operation. Level of Evidence: Level III—therapeutic study.
Subject matter predicts where top pediatric spine articles are shared: citations vs. social media
Authors: Farivar Daniel , Illingworth Kenneth D , Lin Adrian J , Nigh Evan D , Finkel Ryan , Skaggs David L
Published: October 2023

Study design: Systematic review. The purpose of this study was to compare the top 25 articles on pediatric spine surgery by number of citations and Altmetric score. All published articles pertaining to pediatric spine surgery from 2010 to 2021 were assessed for: Altmetric scores, Altmetric score breakdown (e.g. Twitter, News), citation counts, and article topics. The top 25 Altmetric articles and top 25 cited articles were identified. Out of the 50 total articles, only 3 (6.0%) overlapped between the two groups. The top Altmetric articles had averages (mean ± SD) of 167 ± 130 Altmetric score and 66 ± 135 citations, while the top citation articles had averages of 22 ± 45 Altmetric score and 196 ± 114 citations. When evaluating article topics, articles on ‘back pain’ (36% vs. 4%; P = 0.003) and ‘backpacks’ (16% vs. 0%; P = 0.030) were published significantly more in the top Altmetric group, while articles on ‘scoliosis’ (93% vs. 36%; P < 0.001) and ‘growth friendly surgery’ (24% vs. 4%; P = 0.041) were published significantly more in the top citation group. The total number of citations and online mentions for both groups are presented in Table 2. The biggest differences were the top Altmetric score articles receiving greater percentages of Twitter mentions relative to overall mentions (87% vs. 57%). The most socially popular articles focused on back pain and backpacks, and the most cited articles focused on scoliosis and growth-friendly surgery. Twitter had the most mentions of all social media for both the top cited articles and the top Altmetric articles.
Bado III Monteggia in children – treatment options and outcome: an ultrasound control study
Authors: Nuiding Isabelle , Knorr Christian , Schneidmüller Dorien , Adrian Miriam , Schmittenbecher Peter , Kertai Michael A.
Published: October 2023

The Bado III Monteggia lesion is an uncommon fracture in children. Radial head dislocation can occur due to intra- or extra-articular fractures of the olecranon. In extra-articular ulnar fractures, heterogeneous operative methods are proposed in different case reports. The objective of this study is to determine if closed reduction of the ulnar fracture, either without osteosynthesis or by using TEN, is a safe treatment option. In a multicenter study, we retrospectively analyzed 26 children who were treated for an extra-articular proximal metaphyseal ulnar fracture with dislocation of the radial head. These patients underwent a follow-up examination after an average of four years. The investigation included a physical examination, visualization of the elbow anatomy, and specifically, the radial head retention in the joint by ultrasound. Of the 26 patients, 18 were treated by closed reduction and intramedullary osteosynthesis (TEN), 7 were treated by closed reduction and cast immobilization without osteosynthesis, and 1 child was treated by open reduction of the ulna and plate osteosynthesis. In the follow-up examination, 25 children showed an excellent outcome, as well as inapparent sonography. Although this is a retrospective study with different types of treatment, closed reduction of the ulna with or without osteosynthesis appears to be effective. We believe that the correct primary reduction is the key to an excellent long-term outcome. Regarding the invasiveness of the treatment, reduction without or with TEN osteosynthesis should be the preferred approach in extra-articular pediatric Bado III fractures.
Bone alterations of pamidronate therapy in children with cerebral palsy complicating orthopedic management
Authors: Almeida Da Silva Luiz Carlos , Kaymaz Burak , Hori Yusuke , Montufar Wright Parma E. , Rogers Kenneth J. , Trionfo Arianna , Howard Jason J. , Bowen J. Richard , Shrader M. Wade , Miller Freeman
Published: October 2023

Cerebral palsy (CP) is a heterogeneous group of disorders with different clinical types and underlying genetic variants. Children with CP are at risk for fragility fractures secondary to low bone mineral density, and although bisphosphonates are prescribed for the treatment of children with bone fragility, there is limited information on long-term bone impact and safety. Children with CP usually present overtubulated bones, and the thickening of cortical bone by pamidronate treatment can potentially further narrow the medullary canal. Our purpose was to report bone alterations attributable to pamidronate therapy that impact orthopedic care in children with CP. The study consisted of 41 children with CP treated with pamidronate for low bone mineral density from 2006 to 2020. Six children presented unique bone deformities and unusual radiologic features attributed to pamidronate treatment, which affected their orthopedic care. The cases included narrowing of the medullary canal and sclerotic bone, atypical femoral fracture, and heterotopic ossification. Treatment with bisphosphonate reduced the number of fractures from 101 in the pretreatment period to seven in the post-treatment period (P < 0.001). In conclusion, children with CP treated with bisphosphonate have a reduction in low-energy fractures; however, some fractures still happen, and pamidronate treatment can lead to bone alterations including medullary canal narrowing with sclerotic bone and atypical femoral fractures. In very young children, failure to remodel may lead to thin, large femoral shafts with cystic medullary canals. More widespread use of bisphosphonates in children with CP may make these bone alterations more frequent. Level of evidence: Level IV: Case series with post-test outcomes.
Atypical Cleft Hand: Surgical Technique for Grasping Improvement
Authors: de Novaes França Bisneto Edgard , Filippini Lorimier Fernandes Laura , Leomil de Paula Emygdio José , Mattar Júnior Rames
Published: October 2023

Introduction:

We present 6 cases of children with atypical cleft hand and discuss a surgical technique. Clinically, participants presented with a lack of pulp-to-pulp pinch due to metacarpophalangeal ligament insufficiency and difficulty grasping large objects because of the narrowed first web.

Materials and Methods:

Second metacarpal resection and Z-plasty, creating a wide first web. The second extensor digitorum communis tendon was transferred to improve the thumb metacarpophalangeal joint stability.

Conclusions:

The surgical technique presented in this paper did improve function in oligodactyly or type-IIA atypical cleft hand.