bluuebunny/crossref_metadata_2025 huggingface dataset:
The Augustinian tradition (2)
Authors: Cross Richard
Published: October 2024

Lombard’s use of the newly translated John of Damascus constrained all theologians to take on board the claim, mediated through John from Constantinope II, that Christ was ‘out of’ two natures and thus composite not merely of body and soul but also of divinity. This resulted in a complex attempt by Robert of Melun to incorporate this insight into a homo assumptus Christology. Robert makes a number of other innovations too: in particular, maintaining that the union of divine person and human being is effected by the possession of the Word’s personal property by the human nature. The chapter traces the attempts of John of Cornwall and Walter of St Victor to defend the homo assumptus theory, in a (failed) attempt to get this Christology canonized at Lateran III (1179). The chapter concludes with a series of arguments offered by Simon of Tournai and Alan of Lille against the homo assumptus Christology, principally on the grounds that the theory cannot secure the correct Christological reference for first-person singular pronouns uttered by Christ. The theory was largely abandoned by 1180.
The Boethian tradition
Authors: Cross Richard
Published: October 2024

Chalcedonian Christology was transmitted to the early Middle Ages principally by means of Boethius’s theological treatises. Gilbert of Poitiers and his followers (Peter of Vienna, Simon of Tournai, and Alan of Lille) were the main representatives of this Christology in the first half of the twelfth century. Bernard of Clairvaux accepted the homo assumptus Christology and mistakenly believed Gilbert’s view to be heterodox. His attempt to get Gilbert’s position condemned by Pope Eugene III at the Council of Rheims (1148) failed. Peter Lombard’s summary of Gilbert’s Boethian position incorporated materials from John of Damascus, who thus provided very significant authoritative counterweight to Augustine in the reception of Chalcedonian Christology as against the homo assumptus theology.
The non-aliquid Christology (1)
Authors: Cross Richard
Published: October 2024

Abelard’s students, concerned, like Abelard was, with safeguarding divine simplicity, developed an alternative Christology according to which Christ, identical with the second person of the Trinity, fails to be composed at all, on the grounds that body and soul are united to each other only by means of the union of each singly with the divine person. Hence, they do not compose anything (aliquid). The position originates in Roland of Bologna. Peter Lombard developed the view by drawing the further conclusion that the best way of construing the union of divine and human in Christ is in terms of the divine person having body and soul such that these are united to the person in a way akin to that in which clothing (habitus) is united to its wearer. The theory was developed by a number of Lombard’s students during the 1160s.
Macedonia
Authors: Archibald Zosia
Published: October 2024

Discussion of Macedonia before the time of Philip and Alexander has long been dominated by Nicholas Hammond’s view that Macedonians arrived on the Aegean coast as transhumant pastoralists taking part in a long-running, large-scale set of migrations. New archaeological evidence shows that there was, in fact, a high degree of continuity in settlement in the northern Aegean from the Late Bronze Age onward; Hammond’s migrations are a scholarly myth. That starting point leads to new perspectives on the establishment and expansion of the Temenid kingdom. Control over key resources such as timber and the gradual adoption of a Macedonian ethnic identity by neighboring, initially distinct groups were factors as important as military conquest in building the polity inherited by Philip.
Massalia
Authors: Domínguez Adolfo J.
Published: October 2024

The polis of Massalia, established at the end of the seventh century, rapidly developed into an important commercial center that controlled a network of coastal emporia in Iberia and elsewhere. Although Massalia maintained ties with the Greek mainland (e.g., by building a treasury at Delphi), its inhabitants’ concerns were more local than Panhellenic. Massalia took no part in the Persian Wars but did from an early period interact on friendly terms with Rome and frequently hostile terms with the Carthaginians. The study of Massalia gives us glimpses of what the Archaic Greek world looked like at and from its western fringes, in an environment where trade played as important a role as warfare in shaping the course of events.
Origin and evolution of the blue light receptor cryptochromes (CRY1/2) in aquatic angiosperms
Authors: Lu Bei , Li Wei , Zhang Yue , Chen Jinming
Published: October 2024

Cryptochromes (CRYs), which are responsible for sensing blue light in plants, play a critical role in regulating blue light signals and circadian rhythms. However, their functions extend beyond light detection, as they also aid plants in adapting to stress and potentially other regulatory mechanisms. Aquatic angiosperms, which independently evolved from various angiosperm lineages, have developed specific adaptations to unique light qualities and environmental stressors found in aquatic habitats compared to terrestrial ones. It was hypothesized that the sequences and regulatory networks of angiosperm CRY1/2 underwent adaptive evolution in different aquatic angiosperm lineages. To test this hypothesis, we compiled comprehensive datasets consisting of 55 green plant genomes (including 37 angiosperm genomes), 80 angiosperm transcriptomes, and 4 angiosperm expression networks. Through comparative analysis, we found that CRY1 originated from a common ancestor of seed plants, whereas CRY2 originated from a common ancestor of land plants. In angiosperms, the CRY1/2 sequences of aquatic lineages exhibited positive selection, and the conserved valine-proline motif of CRY2 showed a convergent loss in 2 aquatic species. Coexpressed genes associated with blue light receptors (CRY) showed adaptations to aquatic environments, specifically in relation to flooding and osmotic stress. These discoveries shed light on the adaptive evolution of CRY1/2, encompassing their origins, sequences, and regulatory networks. Furthermore, these results provide valuable insights for investigating the uncharacterized functions and regulatory pathways of CRY and offer potential targets for enhancing growth and adaptation in agricultural plants.
The Point of No Return: A Review Essay
Authors: Patterson Thomas E
Published: October 2024

Thomas Byrne Edsall is one of America's finest political journalists and a foremost amplifier of the work of political scientists and other scholars. Academic research bolsters his argument in virtually every chapter of The Point of No Return. The book is a collection of his New York Times columns, bookended by a new introduction and conclusion, spanning the period from Donald Trump's rise in the 2016 election to his attempt to overturn the presidential election four years later. A remarkable feature of Edsall's columns is how quickly he diagnosed emerging developments that would come to define our politics, including the Republican Establishment's rapid descent, Trump's unwavering and cult-like following, the pernicious effects of disinformation, the Democratic Party's inept response to social and cultural change, and the likelihood that Trump would not surrender power peacefully if he lost the 2020 election. A running theme throughout the book is the danger that Trump poses to the nation's democracy. The Point of No Return is the latest book in the four-decade career of a journalist who regularly has enlarged our understanding of American politics.
The Child Penalty Atlas
Authors: Kleven Henrik , Landais Camille , Leite-Mariante Gabriel
Published: October 2024

This paper builds a world atlas of child penalties in employment based on micro data from 134 countries. The estimation of child penalties is based on pseudo-event studies of first child birth using cross-sectional data. The pseudo-event studies are validated against true event studies using panel data for a subset of countries. Most countries display clear and sizable child penalties: men and women follow parallel trends before parenthood, but diverge sharply and persistently after parenthood. While this pattern is pervasive, there is enormous variation in the magnitude of the effects across different regions of the world. The fraction of gender inequality explained by child penalties varies systematically with economic development and proxies for structural transformation. At low levels of development, child penalties represent a minuscule fraction of gender inequality. But as economies develop — incomes rise and the labor market transitions from subsistence agriculture to salaried work in industry and services — child penalties take over as the dominant driver of gender inequality. The relationship between child penalties and development is validated using historical data from current high-income countries, back to the 1700s for some countries. Finally, because parenthood is often tied to marriage, we also investigate the existence of marriage penalties in female employment. In general, women experience both marriage and child penalties, but their relative importance depends on the level of development. The development process is associated with a substitution from marriage penalties to child penalties, with the former gradually converging to zero.
Training Equity Improves Health Equity
Authors: Kirton Carl A.
Published: October 2024

Addressing supply–demand issues to meet our health system's needs
A Deadly Mpox Strain Is Spreading in Africa
Authors: Roush Karen
Published: October 2024

Vaccination is the cornerstone of the global response.
Associations Between Physical, Cognitive, and Mental Health Domains of Post-Intensive Care Syndrome and Quality of Life: A Longitudinal Multicenter Cohort Study
Authors: Tilburgs Bram , Simons Koen S. , Corsten Stijn , Westerhof Brigitte , Rettig Thijs C. D. , Ewalds Esther , Zegers Marieke , van den Boogaard Mark
Published: October 2024

OBJECTIVES:

To explore associations between the physical, cognitive, and mental post-intensive care syndrome (PICS) health domains with changes in health-related quality of life (HRQoL) following ICU admission.

DESIGN:

A longitudinal prospective multicenter cohort study.

SETTING/PATIENTS:

Patients (n = 4092) from seven Dutch ICUs.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

At ICU admission, 3 and 12 months post-ICU, patients completed validated questionnaires regarding physical health problems, cognitive health problems, mental health problems, and HRQoL. Composite scores were created for the physical health domain (physical problems and fatigue) and mental health domain (anxiety, depression, and post-traumatic stress disorder). Adjusted multivariable linear regression analyses were performed, including covariables (e.g., patient characteristics, disease severity, pre-ICU HRQoL, etc.) to explore associations between the physical, cognitive, and mental health domains of PICS and changes in HRQoL at 3 and 12 months post-ICU. At 3 months (n = 3368), physical health problems (β = –0.04 [95% CI, –0.06 to 0.02]; p < 0.001), cognitive health problems (β = –0.05 [95% CI, –0.09 to –0.02]; p < 0.001), and mental health problems (β = –0.08 [95% CI, –0.10 to –0.05]; p < 0.001) were negatively associated with changes in HRQoL. Also, at 12 months (n = 2950), physical health problems (β = –0.06 [95% CI, –0.08 to –0.03]; p < 0.001), cognitive health problems (β = –0.04 [95% CI, –0.08 to –0.01]; p < 0.015), and mental health problems (β = –0.06 [95% CI, –0.08 to –0.03]; p < 0.001) were negatively associated with changes in HRQoL.

CONCLUSIONS:

PICS symptoms in the physical, cognitive, and mental domains are all negatively associated with changes in HRQoL at 3 and 12 months post-ICU. At 3 months, PICS symptoms in the mental domain seem to have the largest negative associations. At 12 months, the associations of PICS in the mental and physical domains are the same. This implies that daily ICU care and follow-up care should focus on preventing and mitigating health problems across all three PICS domains to prevent a decrease in HRQoL.
A Narrative Review of Chromatographic Bioanalytical Methods for Quantifying Everolimus in Therapeutic Drug Monitoring Applications
Authors: Nascimento Julia O. , Costa Edlaine R. , Estrela Rita , Moreira Fernanda L.
Published: October 2024

Background:

Methods for measuring drug levels in the body are crucial for improving therapeutic drug monitoring (TDM) and personalized medicine. In solid-organ transplants, TDM is essential for the management of immunosuppressive drugs to avoid toxicity and organ rejection. Everolimus is a commonly used immunosuppressant with a small range of safe doses; therefore, it is important to adjust the dose according to each patient's needs. Therefore, reliable methods are required to accurately measure everolimus levels. This study aims to conduct a comprehensive and updated narrative review of chromatographic bioanalytical methods for everolimus quantification.

Methods:

The authors searched for original research articles published between 2013 and 2023 in Scopus and PubMed and found 295 articles after removing duplicates. Based on their titles and summaries, 30 articles were selected for a detailed review and 25 articles were included in the final analysis.

Results:

Among the 25 studies, 16 used protein precipitation, mainly with methanol, to prepare the samples, 12 used high-performance liquid chromatography, 11 used ultra-performance liquid chromatography, and 2 used both. Almost all the studies (24 of 25) used tandem mass spectrometry for detection, whereas only 1 used ultraviolet.

Conclusions:

This comprehensive review of bioanalytical methods for measuring everolimus using chromatography is a useful resource for researchers developing bioanalytical methods for TDM applications. Future trends in everolimus measurement include achieving lower detection limits, owing to the trend of reducing drug doses in therapy by improving sample extraction techniques and using more sensitive methods.
Managing Complicated Nontuberculous Mycobacteria Infections in Plastic Surgery
Authors: García-Ruza Miriam , Blanco Juan , Campusano Katherine , Silva Douglas , Claro Franklin , de Waard Jacobus H.
Published: October 2024

Nontuberculous mycobacteria (NTM) infections after cosmetic surgery have become an increasing concern. These infections are often initially misdiagnosed and treated with standard antibiotic regimens, which fail to resolve the underlying infection, leading to prolonged patient suffering. In this case study, we describe a chronic wound infection caused by Mycobacterium abscessus subsp. bolletii after a muscle-repair abdominoplasty. This case illustrates the diagnostic and therapeutic challenges plastic surgeons face in successfully treating such infections. Initial obstacles included the isolation of co-contaminating bacteria that masked the NTM infection, the use of antibiotics ineffective against the specific NTM species, and the failure to identify the infection source. In this instance, contaminated skin marker ink used to mark the rectus muscle, combined with a nonabsorbable (permanent) suture for muscle repair, led to the development of a biofilm that acted as a persistent reservoir for the infection, resistant to antibiotic treatments. Complete resolution was achieved only after evaluation by a plastic surgeon experienced in treating NTM infections and the subsequent removal of the permanent suture. The delayed suture removal contributed to a 15-month recovery period. This case underscores the importance of early recognition of NTM infections after cosmetic procedures. By sharing this case, we aim to raise awareness of NTM infections and help prevent future cases of misdiagnosis and prolonged antibiotic treatments. Key points regarding the diagnosis, sources of infection, and treatment options for NTM infections are highlighted in this article using "text boxes" to emphasize the most important information and provide concise summaries of critical insights.
Quick action required: revealing pheochromocytoma as the hidden trigger behind postoperative hypertensive crisis
Authors: Calçada Alexandre , Costa Vasco , Lêdo Lia , Freire Pedro
Published: October 2024

Managing patients who present with elevated blood pressure (BP) requires careful but expeditious assessment and triage to differentiate between those at immediate risk of complications and those for whom BP elevation does not pose an immediate threat to health. We present a case of a 54-year-old healthy male patient who experienced refractory hypertension during the immediate postoperative period following nasal surgery. Additional gastrointestinal symptoms and imaging findings made it possible to consider a catecholamine-producing tumour as the primary cause. Despite efforts, managing hypertension continued to be a challenge, and major neurologic complications arose within the following hours.

This case illustrates the potential for rapid changes in the clinical scene during hypertensive emergency management. If not addressed promptly, a routine postoperative complication (at first glance) can turn into serious complications, particularly when there are uncommon underlying causes involved.
Is pancreaticoduodenectomy justified for metastatic melanoma to the ampulla of Vater?
Authors: Hsi Chieh-Ning , Wang Shin-E , Shyr Bor-Shiuan , Chen Shih-Chin , Shyr Yi-Ming , Shyr Bor-Uei
Published: October 2024

Background:

Metastatic melanoma of the ampulla of Vater is rare. The purpose of this study was to summarize the characteristics and outcomes of metastatic melanoma in the ampulla of Vater and highlight the impact of surgery on the prognosis of patients with metastatic melanoma.

Methods:

Pooled data from a case encountered at our institution and from all sporadic cases published on PubMed and MEDLINE between 1996 and 2023 were analyzed.

Results:

Fourteen patients with metastatic melanoma in the ampulla of Vater were enrolled. Seventy-three percent of primary melanomas were cutaneous and 27% were mucosal. Jaundice was the most common symptom (86%). The size of metastatic melanoma to the ampulla ranged from 1.5 cm to 8 cm, with a median of 2.75 cm. Concomitant metastasis to other organs occurred in 82% of the patients at the time of diagnosis, most commonly in the brain, lungs, and liver (36% each). Among the reported cases, pancreaticoduodenectomy was performed in five patients. The overall 1-year survival rate was 27.3%, with a median survival of four months. Wide excision of the primary lesion and chemotherapy significantly improved survival rates (p= 0.048). There is a trend toward improved survival in patients undergoing pancreaticoduodenectomy followed by chemotherapy.

Conclusion:

Given the availability of effective systemic therapies, metastatic melanoma of the ampulla of Vater does not necessarily preclude major surgeries.
Examining the Effect of Peppermint Oil on Postoperative Nausea After Cervical Surgery
Authors: Cetin Nurdan , Kose Gulsah , Gokbel Aykut
Published: October 2024

PURPOSE: The aim of this study was to investigate the effect of peppermint oil aromatherapy on postoperative nausea and vomiting (PONV) and hemodynamic parameters in patients undergoing single-level cervical surgery. METHODS: This prospective randomized controlled study consisted of 76 single-level cervical surgery patients admitted to the neurosurgery department between March 2021 and November 2022. The patients were randomized into 2 groups: the intervention group received peppermint oil aromatherapy through inhalation, whereas the control group received routine clinical treatment. Both groups were observed for the presence and severity of PONV, the use of antiemetics, and hemodynamic parameters at minute 5, 35, 65, and 95, and at hour 2, 6, 12, and 24 after surgery. RESULTS: In the control group, 18 (47.8%) patients experienced nausea, 11 (28.9%) experienced vomiting, and 7 (18.4%) used antiemetics. In contrast, the intervention group included only 2 (5.3%) patients who experienced nausea, and none of those patients experienced vomiting or used antiemetics. It was determined that peppermint oil had a 40% effect on reducing PONV, 34% effect on reducing postoperative antiemetic use, and 75% effect on reducing severity of nausea. Hemodynamic parameters did not differ significantly between the 2 groups. The systolic blood pressure of the control group was significantly greater than that of the intervention group only at minute 95 and at hour 24 after surgery. CONCLUSIONS: The results suggest that the use of peppermint oil aromatherapy can have a positive effect on reducing the presence and severity of PONV and the need for antiemetic medication in patients undergoing single-level cervical surgery.
Efficacy of physical activity in polycystic ovary syndrome treatment
Authors: Parmar Sehej-Leen Kaur , Whooten Rachel
Published: October 2024

Purpose of review

Physical activity (PA) is acknowledged as an important component of lifestyle therapy in the management of polycystic ovary syndrome (PCOS). The purpose of this current systematic review is to analyze recent literature assessing the role of PA and exercise interventions as potential treatment for PCOS.

Recent findings

The recent literature published since 2022 has focused on understanding the specific benefits of different PA modalities on PCOS pathophysiology, suggesting that high intensity exercise may relay greater metabolic improvements, although results are still inconclusive; expanding our understanding of the impact PA has on a wider range of outcomes, including sleep, quality of life, inflammation, and DNA methylation; and recognizing barriers and limitations of implementing efficacious PA interventions for individuals with PCOS.

Current literature supports a role for PA in improving PCOS-related cardiometabolic and reproductive outcomes; however, there is still a significant evidence gap of high-quality studies assessing optimal exercise regimens as well as strategies for implementing PA interventions in real-world settings for individuals with PCOS.
The analgesic effect of acupuncture in neuropathic pain: regulatory mechanisms of DNA methylation in the brain
Authors: Jang Jae-Hwan , Lee Yoon Jae , Ha In-Hyuk , Park Hi-Joon
Published: October 2024

Recent research has demonstrated that chronic pain, resulting from peripheral nerve injury, leads to various symptoms, including not only allodynia and hyperalgesia but also anxiety, depression, and cognitive impairment. These symptoms are believed to arise due to alterations in gene expression and neural function, mediated by epigenetic changes in chromatin structure. Emerging evidence suggests that acupuncture can modulate DNA methylation within the central nervous system, contributing to pain relief and the mitigation of comorbidities. Specifically, acupuncture has been shown to adjust the DNA methylation of genes related to mitochondrial dysfunction, oxidative phosphorylation, and inflammation pathways within cortical regions, such as the prefrontal cortex, anterior cingulate cortex, and primary somatosensory cortex. In addition, it influences the DNA methylation of genes associated with neurogenesis in hippocampal neurons. This evidence indicates that acupuncture, a treatment with fewer side effects compared with conventional medications, could offer an effective strategy for pain management.
Impact of Photon-counting Detector Computed Tomography on a Quantitative Interstitial Lung Disease Machine Learning Model
Authors: Koo Chi Wan , Huls Sean J. , Baffour Francis , McCollough Cynthia H. , Yu Lifeng , Bartholmai Brian J. , Zhou Zhongxing
Published: October 2024

Purpose:

Compare the impact of photon-counting detector computed tomography (PCD-CT) to conventional CT on an interstitial lung disease (ILD) quantitative machine learning (QML) model.

Materials and Methods:

A QML model analyzed 52 CT exams from patients who underwent same-day conventional and PCD-CT for suspected ILD. Lin’s concordance correlation coefficient (CCC) assessed agreement between conventional and PCD-CT QML results. A CCC >0.90 was regarded as excellent, 0.9 to 0.8 as good, and <0.80 as a poor concordance. Spearman rank correlation evaluated the association between pulmonary function test results (PFT) and QML features (reticulation [R], honeycombing [HC], ground glass [GG], interstitial lung disease [ILD], and vessel-related structures [VRS]). Correlations were statistically significant if the 95% CI did not include 0.00 and P value <0.05.

Results:

Conventional and PCD-CT QML results had good to excellent concordance (CCC ≥0.8) except for total HC (CCC <0.8), likely related to better PCD-CT honeycombing delineation. Overall, compared with conventional CT, PCD-CT had consistently more statistically significant correlation with PFT for HC (9 PCD vs. 2 conventional of 28 total and regional associations), similar correlation for R (20 PCD vs. 18 conventional of 28 associations) and VRS (19 PCD vs. 23 conventional of 28 associations), and less correlation for GG extent (12 PCD vs. 20 conventional associations).

Conclusions:

There is strong agreement between conventional and PCD-CT QML ILD features except for HC. PCD-CT improved HC but decreased GG extent correlation with PFT. Therefore, even though most quantitative features were not impacted by the newer PCD-CT technology, model adjustment is necessary.
Risk Factors for Postoperative Complications Following Mandibular Fracture Repair
Authors: Resnick Eric , Hassan Bashar A. , Er Seray , Pope Pharibe , Lamaris Gregory A. , Grant Michael P. , Pan Judy
Published: October 2024

Complications following mandibular fracture repair (MFR) may carry significant morbidity to patients. The purpose of our study is to determine the risk factors for postoperative complications following MFR. The authors conducted a retrospective cohort study of trauma patients who underwent MFR in 2018 and 2019. Excluded were patients below 18 years old and those with postoperative follow-up <2 weeks. The primary outcome was the incidence of major and minor postoperative complications following MFR. Of n=275 patients included, mean (SD) age was 35 (14) years and median (IQR) follow up was 49 (26–117) days. Most patients [n=208 (76%)] underwent both maxillomandibular/intermaxillary fixation (MMF/IMF) and open reduction and internal fixation (ORIF). The incidence of major postoperative complications was 19% (n=51) including malunion [n=8 (2.9%)], malocclusion [n=21 (7.6%)], and unplanned reoperation [n=26 (9.5%)]. The incidence of minor postoperative complications was 61% (n=167). Alcohol use at the time of surgery and greater MISS score were associated with greater odds of major complications [adjusted odds ratio (aOR) 95% CI: 3.4 (1.2–9.0), 1.09 (1.02–1.160), respectively]. Smoking at the time of surgery and moderately (>2 mm) and severely displaced fractures (>4 mm) were associated with greater odds of minor complications [aOR (95% CI): 2.1 (1.04–4.2), 2.7 (1.2–6.4), 2.7 (1.1–6.6), respectively]. Alcohol use, smoking, greater MISS score, and displaced fractures >2 mm were significant risk factors for postoperative complications following MFR. Our findings can help guide informed decision making and surgical planning in patients with mandibular fractures.
No benefit from the addition of low-dose ketamine infusion to standard evidence-based care of patients with multiple rib fractures
Authors: Macheel Chad , Farhat Joseph , Gipson Jonathan , Lindbloom Peter , West Michaela A.
Published: October 2024

BACKGROUND

Multiple rib fractures from blunt thoracic trauma cause significant morbidity. Optimal current management includes multimodal analgesia, pulmonary hygiene, and early mobilization. Low-dose ketamine infusion (LDKI) has been proposed as an adjunctive analgesic in this setting. A prior study reported decreased pain scores with LDKI in patients with multiple rib fractures. We hypothesized that LDKI would decrease morphine milligram equivalents (MMEs) in patients with multiple rib fractures.

METHODS

A prospective randomized placebo-controlled trial was performed in adult (18 years or older) patients with three or more rib fractures. A prestudy power analysis calculated an 80% chance of identifying a 15% decrease in MMEs with 50 subjects. The study was approved by the institutional review board and informed consent obtained in all subjects. Demographic (age, sex) and injury specific information (Injury Severity Score, number of rib fractures) were obtained. Subjects were randomized 1:1 to receive continuous LDKI (0.1 mg/kg/h) or placebo infusion (0.9% NaCl) for ≤48 hours. All patients received a standard evidence-based multidisciplinary protocol for rib fractures management. Primary outcome measure was MME use or pulmonary complications. Statistical comparison of LDKI versus placebo was performed using the Mann-Whitney U test.

RESULTS

All 50 enrolled subjects (placebo, 25; LDKI, 25) received study drug infusion. The two groups were well matched for age, Injury Severity Score, and number of rib fractures. We observed no differences in the Day 1 (p = 0.961), Day 2 (p = 0.373), or total MMEs (p = 0.946) between groups. Similar total MME use was observed when subjects who received ≥40 hours of study drug and were compared (p = 0.924). Use of LDKI did not alter subsequent need for opiate analgesics postinfusion, hospital length of stay, pulmonary complications, or need for readmission.

CONCLUSION

The addition of LDKI to an established multimodal, evidence-based protocol for management of multiple rib fractures did not decrease opiate usage or impact pulmonary complications.

LEVEL OF EVIDENCE

Therapeutic/Care Managaement; Level I.
Nuclear effects play an important role in determining codon usage-dependent human gene expression
Authors: Garg Renu , Xie Pancheng , Duan Jiabin , Liu Huan , Liu Yi
Published: October 2024

Codon usage biases play a significant role in determining gene expression levels. Codon usage was thought to primarily influence translation-dependent processes. Here we show that codon usage optimality correlates genome-wide with nuclear mRNA and transcription levels in human cells, suggesting a nuclear role for codon usage. A genome-wide non-biased CRISPR-Cas9 screen was performed to identify factors involved in codon usage effects on gene expression. The identified factors include the CCR4-NOT complex subunit CNOT4 and many nuclear factors, including nuclear RNA exosome, PAXT complex components, and transcription factors. The CCR4-NOT complex has been shown to affect codon usage-dependent co-translational mRNA decay in yeast. Surprisingly, human CNOT4 was found to be highly enriched in nucleus and its influence on codon usage-dependent gene expression is largely caused by its impact on nuclear RNA levels due to transcriptional effect. On the other hand, nuclear exosome and PAXT complex, regulates nuclear mRNA stability through the RNA quality control pathway, leading to preferential cytoplasmic accumulation of mRNAs with optimal codon usage. Overall, our findings suggest that codon usage biases are due to selection on both translation-dependent and independent processes; different nuclear mechanisms play a key role in determining nucleotide composition-dependent gene expression levels in human cells.
Histopathology of extracutaneous tissues in a uremic calciphylaxis patient treated with human amnion-derived mesenchymal stem cells: a comparison with ESKD patients
Authors: Li Cui , Lu Shijiu , Yang Guang , Cao Yue , Zeng Ming , Liu Kang , Yuan Yanggang , Ding Yan , Su Zhonglan , Xu Fangyan , Ren Wenkai , Liu Wei , Xu Yi , Zhang Jing , Ye Xiaoxue , Jiang Chunyan , Cui Yugui , Ma Xiang , Ning Song , Xiao Yujie , Luan Changxing , Ji Qiang , Zhang Zhiwei , Gu Mufeng , Xing Changying , Wang Xiuqin , Liang Ningxia , Chen Feng , Liu Jiayin , Qin Lianju , Yu Youjia , Wang Ningning
Published: October 2024

Background

Calciphylaxis, which mostly affects individuals with end-stage kidney disease (ESKD), is also known as calcific uremic arteriolopathy (CUA). It is a rare and fatal disease that manifests with calcification and thrombosis of microvessels, ischemia, and necrosis in skin tissues(ORPHA:280062). Histopathological features of extracutaneous tissues of CUA patients undergoing human amnion–derived mesenchymal stem cell (hAMSC) treatment remain unknown.

Methods

A female CUA patient, treated with hAMSCs for 20 months, passed away due to stroke. Histopathological features of her extracutaneous tissues were compared with those of ESKD patients (n = 7). Raman spectroscopy was applied to identify the composition of calcifications. The distribution of hAMSCs, derived from the amnion of a male fetus, in tissues of the CUA patient was determined by detecting the Y chromosome using reverse-transcription–polymerase chain reaction.

Results

Microvessel lesions were more prevalent in the extracutaneous tissues of the CUA patient than in those of ESKD patients, although the regenerated skin showed normal histological characteristics. The CUA patient exhibited calcifications of microvessel media, including the microvessels in the lungs, kidneys, spleen, pancreas, and uterus. Her mitral valve and kidney displayed severe calcification, identified as calcium phosphate with some calcium carbonate. hAMSCs were not detected in the tissues of the CUA patient.

Conclusion

Under the treatment strategy with hAMSCs, based on the effects of skin regeneration, microvascular lesions in the extracutaneous tissues of the CUA patient were more severe than those in ESKD patients. CUA should be considered a systemic disease when identifying treatment targets.
Clinical and Genetic Spectrum of Fanconi Anaemia in Australia and New Zealand
Authors: Fluhler Hannah , Granger Elissah , Sharp Michael , Harris Caitlin , Mckinley Mark , Riyat Sarbjit , Krieg Christine , Deans Andrew , Fraser Chris , Cross Siobhan , Carter Tina , Worgan Lisa , Nelson Adam , Fox Lucy C. , Nicholl Jillian , Attwood Alison , McLeman Lorna , Hughes David , Conyers Rachel , Kujan Omar , Velleuer-Carlberg Eunike , Nandini Adayapalam , Crismani Wayne
Published: October 2024

Fanconi anaemia (FA) is a rare genetic condition which predisposes to progressive bone marrow failure, a specific spectrum of malignancies including head and neck squamous cell carcinoma (HNSCC), and an array of other clinical manifestations. The clinical and genetic spectrum of FA in Australia and New Zealand remains relatively undescribed in the literature and is limited to case reports. In this study, we conducted the first comprehensive investigation of FA within this region combining cohort data and case reports, aiming to elucidate its diagnostic patterns, clinical manifestations, and genetic characteristics. Our findings reveal a positive correlation between national testing rates and case detection, across states and territories of Australia, suggesting that targeted testing strategies may enhance the identification of FA cases. Further, our analysis demonstrates that the physical and genetic profiles of FA patients in Australia and New Zealand resemble those observed in other international cohort studies. This study emphasises the continued significance of cytogenetic testing for FA while stressing the need for heightened awareness among medical professionals. FA, once perceived primarily as a paediatric condition, now demands vigilance across all age groups due to advances in medical care and complementary detection methods such as high-throughput sequencing. This study also underscores the heightened susceptibility of individuals with FA in Australia and New Zealand to HNSCC, consistent with observations in other regions worldwide.
Disentangling heritability and plasticity effects onPopulus fremontiileaf reflectance across a temperature gradient
Authors: Seeley M. M. , Thomson E. , Allan G. J , Wiebe B. C. , Whitham T. G. , Hultine K. R. , Cooper H. F. , Asner G. P. , Doughty C.E.
Published: October 2024

Globally, vegetation biodiversity is expected to decline as the rate of plant adaptation struggles to keep pace with rising temperatures. To support conservation efforts through remote sensing, we disentangled the nested effects of genetic and environmental influences on reflectance spectra, leveraging spectroscopy to assess plant adaptations to temperature. Specifically, we quantified the relative effect of plasticity and heritability onPopulus fremontii(Fremont cottonwood) leaf reflectance using clonal replicates propagated from 16 populations and grown across three common gardens spanning a mean annual temperature gradient representing the thermal range ofP. fremontii. We used variance partitioning to decompose phenotypic variation expressed in the leaf spectra into genotypic and environmental components to estimate broad-sense heritability. Heritability was strongly expressed in the spectral red edge (∼680-750nm) and shortwave infrared (∼1400-3000nm), though the heritability peak in the red edge was sensitive to extreme temperatures. By comparing distances of group centroids in principal component space, we determined thatP. fremontiiintraspecific spectral variation was shaped by the interaction between common garden site conditions and source population. Support vector machine models indicated pronounced environmental influence on spectral variation, asP. fremontiisource population and garden location were classified at 71.8% and 92.6% accuracy, respectively. These findings emphasize the utility of reflectance data in separating genetic and environmental influences on plant phenotypes, offering a pathway to scale these insights across broader landscapes and aid in the conservation and management of vulnerable ecosystems in a warming climate.
Low-Rank Full Matrix Factorization for dropout imputation in single cell RNA-seq and benchmarking with imputation algorithms for downstream applications
Authors: Huang Jinghan , Chow Anson C.M. , Tang Nelson L.S. , Yam Sheung Chi Phillip
Published: October 2024

Background

While single cell RNA sequencing becomes a powerful technology, the presence of the large number of zero counts represents a challenge for both wet-lab processing and data analysis. Imputation of these dropouts can now be performed by three categories of algorithms: Model or smoothing, Matrix theory or Deep learning. However, two fundamental questions remain unsettled: (1) whether imputation should be performed; (2) which imputation algorithm to use with various downstream applications. Notably, imputation is not commonly used in real scRNA-seq applications because of their uncertain benefits, concerns about false inferences in downstream applications, and the lack of in-depth benchmark.

Methods

Here, we performed two tasks. First, we developed an algorithm using adaptive low-rank full matrix factorization (afMF) based on a previous limited implementation confined to using low rank matrix decomposition (ALRA). Second, to evaluate the impact of various imputation algorithms on downstream analyses, a new benchmark framework incorporating commonly used downstream applications was developed. This benchmark framework put emphasis on real datasets which had ground truth or matched bulk data such that algorithm performance was compared to more convinced data rather than less realistic simulated parameters.

Results

Our results indicated that afMF and ALRA (matrix based) provided good imputation and outperformed raw log-normalization in various downstream applications. afMF outperformed ALRA in several evaluations (cell-level differential expression analysis, GSEA, classification, biomarker prediction, clustering, SC-bulk profiling similarity). Besides, afMF ranked among the top levels in automatic cell type annotation, trajectory inference by DPT, and AUCell & SCENIC. Both showed acceptable scalability, while afMF had longer running time. MAGIC (smoothing based) and AutoClass (deep learning based) also performed well but may produce false positives. In contrast, more complicated methods (other deep learning or model based) were prone to overfitting and data distortion. We also found that certain downstream algorithms are not compatible with imputation, including trajectory inference with Slingshot and cell-cell communication. Prior imputation either showed no improvement or generated false positive findings with these downstream applications.

Conclusions

We hope this in-depth evaluation and the algorithm developed in this study can enhance the selection of appropriate imputation algorithm for specific scRNA-seq downstream analyses.

The algorithm and the benchmark framework are available at GitHub:https://github.com/GO3295/SCImputation
Mobility of Four Structural Regions Drives Isoform-Specific Properties of Plant LPOR
Authors: Gabruk Michał , Łuszczyński Mateusz , Szafran Katarzyna , Ogrodzińska Wiktoria , Rubenstein Brenda M. , da Silva Gabriel Monteiro
Published: October 2024

Light-dependent protochlorophyllide oxidoreductase (LPOR) is a photocatalytic enzyme in the chlorophyll (Chl) biosynthetic pathway that underwent duplications in angiosperms, resulting in the emergence of multiple isoforms across various plant species. The physiological roles of these LPOR homologs remained unclear, so we selected six plant species with different number of isoforms of the enzyme and characterized their properties in vitro.

Our findings revealed that these isoforms vary in their affinity for the reaction product, chlorophyllide (Chlide), as well as for NADPH under lipid-free conditions and in reaction mixtures supplemented with plant lipids. Additionally, we observed differences in their oligomerization behavior.

Our experimental approach generated a dataset comprising several hundred pairs of spectra, recorded before and after reaction-triggering illumination. This data was used to analyze the correlation between fluorescence emission maxima before and after photoconversion. The analysis showed that some isoforms rapidly release Chlide after the reaction, while others retain the pigment in the binding pocket, especially at high NADPH concentrations. These results suggest that LPOR isoforms differ in their rates of Chlide release and complex disassembly, potentially influencing the overall rate of the Chl biosynthetic pathway, even in mature leaves.

We further analyzed the flexibility of these isoforms using AlphaFold2 predictions, identifying four regions of the enzyme that are particularly mobile. Two of these regions are involved in pigment binding, while the other two play a role in oligomerization. Based on these findings, we propose a model of conformational changes that drive the formation of LPOR oligomers.
Deciphering molecular determinants of GPCR-G protein receptor interactions by complementary integrative structural biology methods
Authors: Castel Jérôme , Botzanowski Thomas , Brooks Ieva , Frechard Alexandre , Bey Gilbert , Schroeter Marine , Del Nero Elise , Debaene François , Ciesielski Fabrice , Zeyer Denis , Cianferani Sarah , Morales Renaud
Published: October 2024

Many physiological processes are dependent on G protein-coupled receptors (GPCRs), the biggest family of human membrane proteins and a significant class of therapeutic targets. Once activated by external stimuli, GPCRs use G proteins and arrestins as transducers to generate second messengers and trigger downstream signaling, leading to diverse signaling profiles. The G protein-coupled bile acid receptor 1 (GPBAR1, also known as Takeda G protein-coupled receptor 5, TGR5) is a class A bile acid membrane receptor that regulates energy homeostasis and glucose and lipid metabolism. GPBAR1/G protein interactions are implicated in the prevention of diabetes and the reduction of inflammatory responses, making GPBAR1 a potential therapeutic target for metabolic disorders. Here, we present an integrated structural biology approach combining hydrogen/deuterium exchange mass spectrometry (HDX-MS) and cryo-electron microscopy (cryo-EM) to identify the molecular determinants of GPBAR1 conformational dynamics upon G protein binding. Thanks to extensive optimization of both HDX-MS and cryo-EM workflows, we achieved over 99% sequence coverage along with a 2.5-Å resolution structure, both of which are state-of-the-art and solely obtained for complete GPCR complexes. Altogether, our results provide information on the under-investigated GPBAR1 binding mode to its cognate G protein, pinpointing the synergic and powerful combination of higher (cryo-EM) and lower (HDX-MS) resolution structural biology techniques to dissect GPCR/G protein binding characteristics.

Short statement

This work highlights the utility of integrating cryo-EM and HDX-MS for studying large multiprotein complexes such as GPCR/G protein complexes. Cryo-EM offers high-resolution structural details, while HDX-MS reveals the dynamic conformational changes during assembly, providing a comprehensive structural view of difficult-to-study membrane protein systems.
ConvNTC: Convolutional neural tensor completion for predicting the disease-related miRNA pairs and cell-related drug pairs
Authors: Liu Pei , Liang Xiao , Li Yue , Luo Jiawei
Published: October 2024

Systematic investigation of high-order molecular interactions can deepen our understanding of the mechanisms underlying biological systems. However, effectively capturing both multilinear and nonlinear relationships to accurately identify the complex triplet relationships remains a challenge. In this paper, we present a novelConvolutinalNeuralTensorCompletion (ConvNTC) to model triplet network connections. ConvNTC consists of a multilinear module and nonlinear module. The former is a tensor decomposition approach that integrates multiple constraints to learn the tensor factor embeddings. The latter contains three components: an embedding generator to produce position-specific index embeddings for each tensor entry in addition to the factor embeddings, a convolutional encoder to perform nonlinear feature mapping while preserving the tensor’s rank-one property, and a Kolmogorov-Arnold Network (KAN) based predictor to effectively capture high-dimensional relationships aligned with the intrinsic structure of real-world data. We demonstrate ConvNTC on two triplet prediction tasks of the disease-related miRNA pairs and cell-related drug pairs, respectively. Comprehensive experiments against ten state-of-the-art methods demonstrate the superiority of ConvNTC in terms of triplet imputation. ConvNTC reveals promising prognostic values of the miRNA-miRNA interactions on breast cancer and detects synergistic drug combinations in cancer cell lines. The source code is available athttps://github.com/Liangyushi/ConvNTC.
Birds migrate longitudinally in response to the resultant Asian monsoons of the Qinghai-Tibet Plateau uplift
Authors: Zhang Wenyuan , Gu Zhongru , Chen Yangkang , Zhang Ran , Zhan Xiangjiang
Published: October 2024

The uplift of the Qinghai-Tibet Plateau is one of the greatest geological events on Earth, pivotally shaping biogeographic patterns across continents, especially for migratory species that need to overcome topographical barriers to fulfil their annual circle. However, how the uplift influences animal migration strategies remains largely unclear. We compare the current flyways of 50 avian species migrating across the plateau with those reconstructed before the uplift as a counterfactual. We find that the major effect of the plateau uplift is changing avian migratory directions from the latitudinal to the longitudinal. The monsoon system generated by the uplift rather than the high elevationper seshapes those changes. These findings unveil how an important global geological event has influenced biogeographic patterns of migratory birds, yielding testable hypotheses for how observed avian distributions emerge.