bluuebunny/crossref_metadata_2025 huggingface dataset:
Emergent surgical interventions in noncritical traumatic long bone fractures and lactate monitoring: a retrospective cohort study
Authors: Hong Jeffrey , Malkoc Aldin , Salahpour Sofia , Wong David T. , Dong Fanglong , Neeki Michael
Published: April 2023

Background:

Serum lactate levels have been recommended as a standard in guiding resuscitation and management of post-traumatic orthopedic injuries. Studies have suggested an increased incidence of postoperative complications in trauma patients with injury severity scores (ISSs) greater than 18. However, in trauma patients without an elevated ISS, the role of lactate in guiding operative timing has not been explored. This study considers the role of lactate measurement with respect to surgical timing and predicting postoperative complications in trauma patients with long bone fractures and an ISS less than 16.

Materials and methods:

A total of 164 patients, ages 18 and above with long bone fractures and ISS less than 16 were sampled in the last 5 years. Demographic data was ascertained. Patients were placed into two cohorts with a serum preoperative lactate greater than or equal to 2.0 mmol/l and a serum preoperative lactate less than 2.0 mmol/l. Key endpoints included hospital mortality, length of hospitalization (LOH), discharge designation, and postoperative complications.

Results:

A total of 148 patients had a lactate level less than 2.0 mmol/l and 16 had a lactate greater than or equal to 2.0 mmol/l. There was no significant difference in demographics between these two preoperative lactate groups. There was no statistical difference when considering mortality, discharge designation, LOH, and postoperative complications.

Conclusion:

Lactate levels assist providers in guide resuscitative efforts in trauma patients. However, this study finds that preoperative lactate measurements and efforts made to normalize lactate level are not correlated with mortality, LOH, and postoperative complications in trauma patients with an ISS less than 16. This study does not support preoperative lactate normalization in guiding surgical timing.
High incidence of adult respiratory distress syndrome associated with amphetamine use in the burn population: a retrospective cohort study
Authors: Wong David T. , Malkoc Aldin
Published: April 2023

Background:

A high incidence of adult respiratory distress syndrome (ARDS) is observed in patients with a history of amphetamine use with limited studies addressing this exact topic. The authors sought to understand and compare the clinical features of patients experiencing amphetamine-associated lung injury with features of similar patients naïve to amphetamines, in a population of burn patients. Patients in this population tend to be young with few comorbidities offering a unique opportunity to study the relationship between amphetamine use and ARDS.

Materials and methods:

A total of 188 patients age 18 and older with total body surface area (TBSA) between 20 and 60% were sampled over 5 years. To capture the moderate to severe burn population, a lower limit of 20% was chosen while 60% was used as the upper limit to exclude patients likely to die from the burns alone. Patients eligible to be include in the study had to meet the TBSA criteria. Demographic data was ascertained. Patients were placed into two cohorts: the amphetamine positive group (AmPOS), the amphetamine negative group (AmNEG). Key endpoints included hospital mortality, length of ICU stay, development of ARDS, and cardiac output parameters. Nonparametric data was evaluated with the Mann–Whitney test and categorical variables were compared using χ
2.

Results:

Data from 49 patients with ARDS were collected retrospectively out of the 188 patients in this TBSA range. The incidence of amphetamine abuse in these burn patients is 14.9%. The average age of AmPOS and AmNEG patients was 36 and 34 and the average TBSA of burns in the AmPOS and AmNEG group was 51.8 and 45.2%. The mean onset of ARDS was 2.2 days for the AmPOS versus 3.3 days for the AmNEG (P=0.19). At admission, patients with amphetamine use exhibited less inhalational injury and a lower Acute Physiology and Chronic Health Evaluation II (APACHE II) score. In AmPOS, 64% developed ARDS compared to 19% in AmNEG (P<0.001). Mortality, time on a ventilator, ICU days, packed Red Blood Cell, Fresh Frozen Plasm, platelets transfused, and initial cardiac parameters all were not statistically significant. On the initial date of ARDS diagnosis, there was no statistically significant difference with PaO2/FiO2 and compliance (P=0.67), but positive end expiratory pressure requirements was higher in AmPOS (P=0.018).

Conclusions:

Amphetamine Use was associated with increased risk of developing ARDS in the burn population. This is despite having a better APACHE II and lower incidence of inhalational injury in the AmPOS group, supporting amphetamine as an independent risk factor for ARDS.
The role of magnetic resonance tumour regression grade in the prediction of regression and survival of rectal adenocarcinoma after long-course chemoradiotherapy: a cohort study
Authors: Chen Hui Lionel Raphael , Seow-En Isaac , Chok Aik Yong , Ngo Nye Thane , Cheng Tim-Ee Lionel , Tan Kwong-Wei Emile
Published: April 2023

Introduction:

Rectal cancer response to neoadjuvant long-course chemoradiotherapy (LCCRT) is assessed by magnetic resonance tumour regression grade (mrTRG) and this has an impact on surgical management. However, there is limited data on the correlation between mrTRG and pathological tumour regression grade (pTRG). This study aims to evaluate the correlation between mrTRG and pTRG and the prognostic value of mrTRG on survival.

Methods:

Between 2011 and 2016, patients with rectal cancer who underwent LCCRT and had post-LCCRT MRI were included in the study. Both mrTRG and pTRG were dichotomised into good responders (mrTRG 1–3 and pTRG 0–1) and poor responders (mrTRG 4–5 and pTRG 2–3). Correlation between mrTRG and pTRG was assessed with Cohen κ analysis. Survival analysis was performed with Kaplan–Meier test and Cox proportional hazard models.

Results:

There were 59 patients included in this study. There were significant reductions in anal sphincter and circumferential resection margin involvement in post-LCCRT MRI. Fair agreement was found between mrTRG and pTRG (κ=0.345). Sensitivity, specificity and accuracy of mrTRG 1–3 to predict good pathological response were 100%, 46.3% and 62.7%, respectively. On survival analysis, mrTRG 1–3 was not associated with improved overall survival and recurrence-free survival.

Conclusions:

While there is fair agreement in correlation between mrTRG and pTRG, MRI remains an objective, noninvasive assessment of tumour response. Further studies are required to improve the ability of mrTRG to predict good responders to LCCRT and evaluate its role as a prognostic marker for survival.
A prospective, international, bicentric study to evaluate PremiCron suture material for cardiac valve surgery – PREMIVALVE a cohort study
Authors: Rufa Magdalena , Ursulescu Adrian , Baumann Petra , Ferrer Manel T.
Published: April 2023

Introduction:

The most common age-related heart valve diseases include aortic valve stenosis and mitral valve insufficiency. The suture material is not the focus of most studies. The aim of the study was to assess the performance of PremiCron suture material for cardiac valve reconstruction and/or replacement under clinical routine. Performance was evaluated using the incidence of major adverse cardiac and cerebrovascular events (MACCE) combined with endocarditis.

Materials and methods:

The study was designed as an international, prospective, bicentric, observational, single-arm study to evaluate the PremiCron suture material in cardiac valve surgery and compare the outcome with literature data regarding postoperative complications. The primary endpoint was a composite of MACCE acquired in the hospital, combined with endocarditis occurring up to 6 months postoperatively. The secondary parameters were intraoperative handling of the suture, incidence of MACCE and other relevant complications and quality of life up to 6 months after surgery. Patients were examined at discharge, 30 days, and 6 months postoperatively.

Results:

A total of 198 patients were enrolled in two centers in Europe. The cumulative primary endpoint event rate was 5.0%, lower than the reference value of 8.2% from the literature. Comparison of the incidence of individual MACCE until discharge and endocarditis rate 6 months postoperatively also showed that our data were within the range of the published rates. Quality of life significantly increased from preoperatively to 6 months after surgery. Ease of handling of the suture material was rated as very good.

Conclusion:

The PremiCron suture material is safe and very eligible for cardiac valve replacement and/or cardiac valve reconstruction in a broad patient population with a cardiac valve disorder treated under daily clinical practice.
The role of community-based approaches in achieving universal health coverage: addressing the Nigerian narrative
Authors: Effiong Fortune B. , Ogbonna Chiemela P. , Agughalam Prosper I. , Okwukwu Miracle O. , Dike Innocent C. , Elebesunu Emmanuel E. , Uwishema Olivier
Published: April 2023

Universal health coverage (UHC) is aimed at ensuring that individuals and communities have affordable access to essential health care services without facing financial hardship. Achieving UHC and the third sustainable development goal of the United Nations requires that health systems transition from a vertical, top-down, curative approach toward one that puts people at the core of health care services, such as community-centered health interventions. Nigeria operates a decentralized health care system with the least focus on primary health care, making access to quality, and affordable health care for several citizens a challenge as the major percentage of the Nigerian population relies on primary health care services. The limited number of health care workers, the poor economic state, the inadequate health financing structures and high illiteracy rates have led to challenges such as low health service availability, hesitancy to utilize health interventions, high out-of-pocket expenditure rates, and health misinformation. These can be effectively tackled at the community level by revamping primary health care services, adequate and sustainable health financing, establishing Ward Development Committees, and the involvement of community stakeholders in health policy implementation. Employing such community-based approaches will ensure continuous progress of the Nigerian health care system toward UHC.
Xanthogranulomatous pyelonephritis mimicking renal cell carcinoma: a case report
Authors: Daoud Nagham , Ismaiel Nahar , Bashour George , Nammour Ali , Barri Ali , Alshehabi Zuheir
Published: April 2023

Introduction and importance:

Xanthogranulomatous pyelonephritis (XGPN) is a rare, serious, and chronic inflammatory disorder of the kidney characterized by a destructive process that invades the renal parenchyma, which is most commonly associated with urinary tract obstruction and infection. It affects women more often than men.

Case presentation:

Herein, the authors report a case of a 48-year-old male presented to their hospital with complaints of malaise, fever, chills, left flank pain, and a history of a staghorn calculus in the renal pelvis, which was removed by surgery 7 years ago. Ultrasonography and computed tomography scans showed an enlarged left kidney with cystic formation and pelvicalyceal system dilation with the presence of multiple large stones. The renogram showed a dysfunctioning left kidney. An open radical left nephrectomy was performed. Renal cell carcinoma (RCC) was suspected in both the gross and microscopic examinations. The immunohistochemistry was the decisive factor in confirming the diagnosis of XGPN.

Clinical discussion:

Preoperative and postoperative diagnosis of XGPN can sometimes be difficult due to diverse differential diagnoses. The misinterpretation of ‘foam cells’ as ‘clear cells’ consistent with RCC is the most important diagnostic challenge for pathologists.

Conclusion:

The unusual findings of this case report suggest a careful evaluation of patients with a renal cystic mass, that can be misdiagnosed as a RCC. A combined computed tomography scan evaluation together with histopathology and immunohistochemistry are essential for a correct diagnosis of this rare renal entity.
De novo mutation of the TSC2 gene in patient with Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders (TAND) Phenotype: a case report
Authors: Triono Agung , Herini Elisabeth S. , Iskandar Kristy , Hadiyanto Marissa L. , Diantika Kania , Wijayanti Veronica W. , Gunadi
Published: April 2023

Introduction:

Tuberous sclerosis complex (TSC) is a neurocutaneous disease caused by a mutation in the TSC1 or TSC2 gene. There are several neuropsychiatric manifestations associated with TSC known as TSC-associated neuropsychiatric disorder (TAND). This article concerns neuropsychiatric manifestations in children with the TSC2 gene mutation, with genetic analysis findings using whole-exome sequencing.

Case:

A 17-year-old girl presented with TSC, absence and focal epilepsy, borderline intellectual functioning, organic psychosis, and renal angiomyolipoma. She was emotionally unstable and preoccupied with irrelevant fears. In the physical examination, we found multiple hypomelanotic maculae, angiofibroma, and a shagreen patch. The intellectual assessment result with the Wechsler Adult Intelligence Scale at 17 was borderline intellectual functioning. Brain MRI showed cortical and subcortical tubers in the parietal and occipital lobes. Whole-exome sequencing was conducted, and the result was a missense mutation in exon 39 of the TSC2 gene [NM_000548.5:c.5024C>T (NP_000539.2:p.Pro1675Leu)]. The Sanger sequencing of the patient’s parents revealed no mutations in the TSC2 gene, confirming the patient’s de novo mutation. The patient was given several antiepileptic and antipsychotic drugs.

Clinical discussion:

Neuropsychiatric manifestation is a common phenotype in the TSC variant, and psychosis is one of the rare TAND symptoms in children.

Conclusions:

The neuropsychiatric phenotype and genotype in TSC patients are rarely reported and evaluated. We reported a female child with epilepsy, borderline intellectual functioning, and organic psychosis associated with a de novo mutation of the TSC2 gene. Organic psychosis is a rare symptom of TAND which also manifested in our patient.
Acute cerebral ischemic stroke as a presentation of polycythemia vera: a case report and a review of literature
Authors: Siyad Mohamed Osman , Osman Mohamed Farah , Adan Abdisamad Mohamed , Hassan Mohamed Sheikh , Jeele Mohamed Osman Omar
Published: April 2023

Introduction:

Polycythemia vera (PV) is a disease of stem cells characterized by pan hyperplastic, malignant, and neoplastic bone marrow conditions. It is characterized by an increased absolute red blood cell count due to uncontrolled red blood cell synthesis, as well as excessive white blood cell and platelet production. Although the relationship between PV and stroke, especially ischemic stroke, is widely known around the world, no previous cases have been reported from Somalia.

Case presentation:

In the presenting study, we report a 60-year-old male patient who presented with a right-side weakness for 3 days. After laboratory and brain imaging, he was diagnosed with an acute cerebral infarct affecting the left basal ganglion secondary to PV.

Conclusions:

PV as the cause of ischemic stroke is a rare condition but can be encountered in clinical practice, and clinicians should be familiar with this combination.
Subpectoral Implant Placement is not Protective Against Postmastectomy Radiotherapy-Related Complications Compared to Prepectoral Placement
Authors: Hassan Abbas M. , Asaad Malke , Morris Natalie , Kumar Saloni , Liu Jun , Mitchell Melissa P. , Shuck John W. , Clemens Mark W. , Butler Charles E. , Selber Jesse C.
Published: April 2023

Background:

Postmastectomy radiotherapy (PMRT) is associated with altered cosmetic outcomes and higher complication rates in implant-based breast reconstruction (IBR). Conventional wisdom suggests that muscle coverage is somewhat protective against PMRT-related complications. In this study, we compared surgical outcomes in patients who underwent two-stage prepectoral versus subpectoral IBR in the setting of PMRT.

Methods:

We performed a retrospective cohort study of patients who underwent mastectomy and PMRT with two-stage IBR from 2016 to 2019. The primary outcome was breast-related complications, including device infection; the secondary outcome was device explantation.

Results:

We identified 179 reconstructions (101 prepectoral, 78 subpectoral) in 172 patients with a mean follow-up time of 39.7±14.4 months. There were no differences between the prepectoral and subpectoral reconstructions in rates of breast-related complications (26.7% and 21.8%, respectively; P = .274), device infection (18.8% and 15.4%, respectively; P = .307), skin flap necrosis (5.0% and 1.3%, respectively; P = .232), or device explantation (20.8% and 14.1%, respectively; P = .117). In adjusted models, compared with prepectoral device placement, subpectoral device placement was not associated with a lower risk of breast-related complications (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.41-1.36), device infection (HR, 0.73; 95% CI, 0.35-1.49), or device explantation (HR, 0.58; 95% CI, 0.28-1.19).

Conclusion:

Device placement plane was not predictive of complication rates in IBR in the setting of PMRT. Two-stage prepectoral IBR provides safe long-term outcomes with acceptable postoperative complication rates comparable to those with subpectoral IBR, even in the setting of PMRT.
Tsuneonella litorea sp. nov., a novel carotenoid-producing bacterium isolated from coastal sediment
Authors: He Yizhou , Liu Yang , Pei Tao , Duan Jiao , Du Juan , Deng Xiaoqin , Zhu Honghui
Published: April 2023

A Gram-stain-negative, aerobic, non-motile and pleomorphic bacterium designated as YG55T was isolated from a coastal sediment sample. Growth was found to occur at 10–37 °C (optimum, 28 °C), at pH 6–9 (optimum, pH 8) and in 0–6 % NaCl (optimum, 1 %). The results of 16S rRNA gene-based analysis showed that strain YG55T was related to the members of the genus

Tsuneonella

and shared the highest identity of 99.4 % with

Tsuneonella dongtanensis

GDMCC 1.2307T, followed by

Tsuneonella troitsensis

JCM 17037T (98.4 %). The phylogenomic results indicated that strain YG55T formed an independent branch distinct from the reference type strains. The 22.7 and 21.8 % digital DNA–DNA hybridization (dDDH) values and 83.0 and 81.8 % average nucleotide identity (ANI) values between strain YG55T and the two relatives were below the species definition thresholds of 70 % (dDDH) and 95–96 % (ANI), indicating that the strain represents a novel genospecies. The results of chemotaxonomic characterization indicated that the major cellular fatty acids of strain YG55T were summed feature 8 (C18 : 1
 ω6c and/or C18 : 1
 ω7c), C14 : 0 2OH and C16 : 0; the main polar lipids comprised diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine and sphingoglycolipid; the respiratory quinone was ubiquinone-10. The genomic size and DNA G+C contents were 3.03 Mbp and 66.98 %. The strain contained carotenoid biosynthesis genes and could produce carotenoids. Based on its genotypic and phenotypic characteristics, strain YG55T is concluded to represent a novel species of the genus

Tsuneonella

, for which the name Tsuneonella litorea sp. nov. is proposed. The type strain is YG55T (=GDMCC 1.2590 T=KCTC 82812T).
Utility of a new lower limb and trunk functional evaluation for pitchers with focus on the physical characteristics of players with a throwing disorder
Authors: Matsui Tomoyuki , Azuma Yoshikazu , Hiramoto Machiko , Seo Kazuya , Miyazaki Tetsuya , Matsuzawa Kanta , Kida Noriyuki , Morihara Toru
Published: April 2023

Objectives

A pitching motion involves three-dimensional whole body movement. Proper pelvic and trunk rotation movement are important for the prevention of throwing injuries. Given that throwing is not a simple rotation movement, the evaluation of proper motion should reflect muscle strength as well as coordination and pitching motion characteristics. We have devised a throwing rotational assessment (TRA) as a new evaluation of the total rotation angle required for throwing. The purpose of this study was to examine the characteristics of players with throwing disorders compared to a pain-free group using TRA.

Materials and methods

The subjects consisted of 164 high school baseball pitchers who participated in a medical check. Pain-induced tests included an elbow hyperextension test and an intra-articular shoulder impingement test. Pitchers who felt pain in either test were classified into a disorder group (n=61). With the subjects in a position similar to the foot contact phase of throwing, the rotation angles of the pelvis and trunk were measured. All tests were performed in the throwing and opposite directions.

Results

The disorder group had significantly lower average rotation angles of the pelvis and trunk in the throwing direction and the rotation angle of the trunk in the opposite direction compared to the healthy group.

Conclusion

TRA reflects the complex whole body rotation movement. Reductions in rotational angles as assessed in TRA may be associated with throwing disorders. TRA is a simple method that may be useful in the early detection of a throwing disorder and could be used in the systematic evaluation during a medical check, as well as during self-check in the sports field.
Multiomic approach and Mendelian randomization analysis identify causal associations between blood biomarkers and subcortical brain structure volumes
Authors: Jain Pritesh , Yates Madison , de Celis Carlos Rubin , Drineas Petros , Jahanshad Neda , Thompson Paul , Paschou Peristera
Published: April 2023

Alterations in subcortical brain structure volumes have been found to be associated with several neurodegenerative and psychiatric disorders. At the same time, genome-wide association studies (GWAS) have identified numerous common variants associated with brain structure. In this study, we integrate these findings, aiming to identify proteins, metabolites, or microbes that have a putative causal association with subcortical brain structure volumes via a two-sample Mendelian randomization approach. This method uses genetic variants as instrument variables to identify potentially causal associations between an exposure and an outcome. The exposure data that we analyzed comprised genetic associations for 2,994 plasma proteins, 237 metabolites, and 103 microbial genera. The outcome data included GWAS data for seven subcortical brain structure volumes including accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. Eleven proteins and six metabolites were found to have a significant association with subcortical structure volumes. We found causal associations between amygdala volume and granzyme A as well as association between accumbens volume and plasma protease c1 inhibitor. Among metabolites, urate had the strongest association with thalamic volume. No significant associations were detected between the microbial genera and subcortical brain structure volumes. We also observed significant enrichment for biological processes such as proteolysis, regulation of the endoplasmic reticulum apoptotic signaling pathway, and negative regulation of DNA binding. Our findings provide insights to the mechanisms through which brain volumes may be affected in the pathogenesis of neurodevelopmental and psychiatric disorders and point to potential treatment targets for disorders that are associated with subcortical brain structure volumes.
Homeobox Transcription Factor HbxA Influences Expression of over One Thousand Genes in the Model FungusAspergillus nidulans
Authors: Pandit S.S. , Zheng J. , Yi Y. , Lorber S. , Puel O. , Dhingra S. , Espeso E.A. , Calvo A.M
Published: April 2023

In fungi, conserved homeobox-domain (HD) proteins are transcriptional regulators governing development. InAspergillusspecies, several HD transcription factor genes have been identified, among them,hbxA/hbx1. For instance, in the opportunistic human pathogenAspergillus fumigatus,hbxAis involved in conidial production and germination, as well as virulence and secondary metabolism (SM), including production of fumigaclavines, fumiquinazolines, and chaetominine. In the agriculturally important fungusAspergillus flavus,disruption ofhbx1results in fluffy aconidial colonies unable to produce sclerotia.hbx1also regulates production of aflatoxins, cyclopiazonic acid and aflatrem. Furthermore, transcriptome studies revealed thathbx1has a broad effect on theA. flavusgenome, including numerous genes involved in SM. These studies underline the importance of the HbxA/Hbx1 regulator, not only in developmental processes but also in the biosynthesis of a broad number of fungal natural products, including potential medical drugs and mycotoxins. To gain further insight into the regulatory scope of HbxA inAspergilli, we studied its role in the model fungusAspergillus nidulans. Our present study of theA. nidulans hbxA-dependent transcriptome revealed that more than one thousand genes are differentially expressed when this regulator was not transcribed at wild-type levels, among them numerous transcription factors, including those involved in development as well as in SM regulation. Furthermore, our metabolomics analyses revealed that production of several secondary metabolites, some of them associated withA. nidulans hbxA-dependent gene clusters, was also altered in deletion and overexpressionhbxAstrains compared to the wild type, including synthesis of nidulanins A, B and D, versicolorin A, sterigmatocystin, austinol, dehydroaustinol, and three unknown novel compounds.
XMAP: Cross-population fine-mapping by leveraging genetic diversity and accounting for confounding bias
Authors: Cai Mingxuan , Wang Zhiwei , Xiao Jiashun , Hu Xianghong , Chen Gang , Yang Can
Published: April 2023

Fine-mapping prioritizes risk variants identified by genome-wide association studies (GWASs), serving as a critical step to uncover biological mechanisms underlying complex traits. However, several major challenges still remain for existing fine-mapping methods. First, the strong linkage disequilibrium among variants can limit the statistical power and resolution of fine-mapping. Second, it is computationally expensive to simultaneously search for multiple causal variants. Third, the confounding bias hidden in GWAS summary statistics can produce spurious signals. To address these challenges, we develop a statistical method for cross-population fine-mapping (XMAP) by leveraging genetic diversity and accounting for confounding bias. By using cross-population GWAS summary statistics from global biobanks and genomic consortia, we show that XMAP can achieve greater statistical power, better control of false positive rate, and substantially higher computational efficiency for identifying multiple causal signals, compared to existing methods. Importantly, we show that the output of XMAP can be integrated with single-cell datasets, which greatly improves the interpretation of putative causal variants in their cellular context at single-cell resolution.
Activity-Guided Proteomic Profiling of Proteasomes Uncovers a Variety of Active (And Inactive) Proteasome Species
Authors: Sahoo Manisha Priyadarsini , Lavy Tali , Sahu Indrajit , Kleifeld Oded
Published: April 2023

Proteasomes are multi-subunit, multi-catalytic protein complexes present in eukaryotic cells that degrade misfolded, damaged, or unstructured proteins. In this study, we used an activity-guided proteomic methodology based on a fluorogenic peptide substrate to characterize the composition of proteasome complexes in WT yeast, and the changes these complexes undergo upon the deletion of Pre9 (Δα3) or of Sem1 (ΔSem1).

A comparison of whole-cell proteomic analysis to activity-guided proteasome profiling indicates that the amounts of proteasomal proteins and proteasome interacting proteins in the assembled active proteasomes differ significantly from their total amounts in the cell as a whole. Using this activity-guided approach, we characterized the changes in the abundance of subunits of various active proteasome species in different strains, quantified the relative abundance of active proteasomes across these strains, and charted the overall distribution of different proteasome species within each strain. The distributions obtained by our mass spectrometry-based quantification were markedly higher for some proteasome species than those obtained by activity-based quantification alone, suggesting that the activity of some of these species is impaired. The impaired activity appeared mostly among 20SBlm10proteasome species which account for 20% of the active proteasomes in WT.

To identify the factors behind this impaired activity, we mapped and quantified known proteasome-interacting proteins. Our results suggested that some of the reduced activity might be due to the association of the proteasome inhibitor Fub1. Additionally, we provide novel evidence for the presence of non-mature and therefore inactive proteasome protease subunits β2 and β5 in the fully assembled proteasomes.

Significance Statement

Proteasomes, essential protein complexes in eukaryotic cells, degrade misfolded, damaged, or unstructured proteins. Here we present an activity-guided proteomic method to characterize the composition and abundance of proteasomes. When applied to yeast proteasomes, this method revealed discrepancies between proteasome distributions determined by mass spectrometry and peptidase activity. This implies that a substantial portion of the proteasomes may exhibit reduced activity. Our findings indicate that these changes in proteasome activity could be linked to proteasome inhibition by Fub1. Furthermore, we identified signature peptides that indicate incomplete maturation of some of the β2 and β5 proteolytic subunits in fully assembled proteasomes, suggesting that proteasome core particle assembly can proceed even without the complete maturation of all β subunits.
Race Corrections in Clinical Algorithms Can Help Correct for Racial Disparities in Data Quality
Authors: Zink Anna , Obermeyer Ziad , Pierson Emma
Published: April 2023

Despite ethical and historical arguments for removing race corrections from clinical algorithms, the consequences of removal remain unclear. An important and underdiscussed consideration in this debate is the fact that medical data quality frequently varies across race groups. For example, family history of cancer is an essential predictor in cancer risk prediction algorithms but is less reliably documented for Black patients and may therefore be less predictive of cancer outcomes. We assessed whether race corrections could allow risk prediction models to capture varying data quality by race, focusing on colorectal cancer risk prediction. Using data from the Southern Community Cohort Study, we analyzed 77,836 adults with no history of colorectal cancer at baseline. We assessed whether the predictive relationship between self-reported family history of colorectal cancer and 10-year colorectal cancer risk differed by race. We then compared two cancer risk prediction algorithms -- a race-blind algorithm which included standard colorectal cancer risk factors but not race, and a race-corrected algorithm which additionally included race. Family history predicted 10-year colorectal cancer risk among White patients (OR: 1.74, 95% CI 1.25-2.38), but not Black patients (OR: 0.98, 95% CI 0.72-1.29). Relative to the race-blind algorithm, the race-corrected algorithm improved predictive performance, as measured by goodness of fit in a likelihood ratio test (p-value <0.001) and AUROC among Black patients (0.611 versus 0.608, p-value 0.006). Because the race-blind algorithm underpredicted risk for Black participants, the race-corrected algorithm increased the fraction of Black participants among the predicted high-risk group, potentially increasing access to screening. Race corrections can allow risk prediction algorithms to model varying data quality by race group, which frequently occurs in clinical settings.
Infusing behavior science into large language models for activity coaching
Authors: Vardhan Madhurima , Hegde Narayan , Nathani Deepak , Rosenzweig Emily , Karthikesalingam Alan , Seneviratne Martin
Published: April 2023

Large language models (LLMs) have shown promise for task-oriented dialogue across a range of domains. The use of LLMs in health and fitness coaching is under-explored. Behavior science frameworks such as COM-B, which conceptualizes behavior change in terms of capability (C), Opportunity (O) and Motivation (M), can be used to architect coaching interventions in a way that promotes sustained change. Here we aim to incorporate behavior science principles into an LLM using two knowledge infusion techniques: coach message priming (where exemplar coach responses are provided as context to the LLM), and dialogue re-ranking (where the COM-B category of the LLM output is matched to the inferred user need). Simulated conversations were conducted between the primed or unprimed LLM and a member of the research team, and then evaluated by 8 human raters. Ratings for the primed conversations were significantly higher in terms of empathy and actionability. The same raters also compared a single response generated by the unprimed, primed and re-ranked models, finding a significant uplift in actionability from the re-ranking technique. This is a proof of concept of how behavior science frameworks can be infused into automated conversational agents for a more principled coaching experience.

Institutional Review Board (IRB)

The study does not involve human subjects beyond the volunteer annotators. IRB approval was not sought for this research.
Lower delayed but comparable working memory performance in patients with Parkinson disease
Authors: Lee Eun-Young
Published: April 2023

Intruduction

The present study examined nature of memory deficits and its associations with MRI structural metrics in patients with Parkinson disease (PD).

Methods

Nineteen PD and 23 matched controls underwent two memory experiments. In experiment 1 (delayed memory task), subjects were asked to remember an array of colored rectangles with varying memory set sizes [Low-Load (2 items), Low-Load with distractors, & High-Load (5 items)]. After a 7s delay period, they reported whether the orientation of any relevant figures had changed (test period). In experiment 2 (working memory task), memory arrays were presented in varying set sizes (2 to 6 items) but with no distractors and they were followed by a 2s delay period and subsequent test period. Brain MRI data were acquired to assess morphological differences (volumes and cortical thickness) in brain areas related to attentional filtering (middle frontal gyrus and basal ganglia) and memory storage and consolidation (intraparietal sulcus and medial temporal corticies).

Results

Compared to controls, PD patients had lower memory capacity scores in all memory conditions for the experiment 1 (p <0.021) whereas there were no memory score group differences in any memory set sizes for the experiment 2 (p>0.06). In addition, there were no group differences in structural metrics for any ROI and no asccociations of strucrutal metrics with delayed memory scores (p>0.056).

Discussion

The present findings suggest that both lower attentional filtering and memory storage may contribute to lower delayed memory scores in PD. Memory storage capacity for visuospatial working memory in PD, however, appeared to be comparable to that of controls at least in the absence of apparent distractors. In addition, lower delayed memory in PD may partly be associated with early brain structural or functional changes that may occur before morphological changes.
Mycobacterial Metabolic Model Development for Drug Target Identification
Authors: Bannerman Bridget P. , Oarga Alex , Júlvez Jorge
Published: April 2023

Antibiotic resistance is increasing at an alarming rate, and three related mycobacteria are the source of widespread infections in humans. According to the World Health Organization,Mycobacterium leprae, which causes leprosy, is still endemic in tropical countries; Mycobacterium tuberculosis is the second largest infectious disease killer worldwide after COVID-19;Mycobacteroides abscessus, a group of non-tuberculous mycobacteria, causes lung infections and other health-care-associated infections in humans. Due to the rise in resistance to common antibacterial drugs, it is critical to develop alternatives to traditional treatment procedures. Furthermore, an understanding of the biochemical mechanisms underlying pathogenic evolution is important for the treatment and management of these diseased conditions.

In this study, metabolic models have been developed for two bacterial pathogens,M. leprae, andM. abscessus, and a new computational tool has been used to identify potential drug targets, which are referred to as bottleneck reactions. The genes, reactions, and pathways in each of these organisms have been highlighted; the potential drug targets can be further explored as broad-spectrum antibacterials and the unique drug targets to each pathogen are significant for precision medicine initiatives.

The models and associating datasets are available in GigaScience and the following repositories:

M. abscessus

Biomodels:https://www.ebi.ac.uk/biomodels/MODEL2203300002

https://www.patmedb.org/Bacteria/Mabscessus

M. leprae

Biomodels:https://www.ebi.ac.uk/biomodels/MODEL2203300001

https://www.patmedb.org/Bacteria/Mleprae
Radial askew endodermal cell divisions reveal IRK functions in division orientation
Authors: Rony R. M. Imtiaz Karim , Campos Roya , Perez-Henriquez Patricio , Van Norman Jaimie M.
Published: April 2023

Oriented cell divisions establish plant tissue and organ patterning and produce different cell types; this is particularly true of the highly organized Arabidopsis root meristem. Mutant alleles ofINFLORESCENCE AND ROOT APICES RECEPTOR KINASE(IRK) exhibit excess cell divisions in the root endodermis. IRK is a transmembrane receptor kinase that localizes to the outer polar domain of these cells, which suggests directional signal perception is necessary to repress endodermal cell division. Here, a detailed examination revealed many of the excess endodermal divisions inirkhave division planes that specifically skew towards the outer lateral side, therefore we termed them ‘radial askew’ divisions. Expression of an IRK truncation, lacking the kinase domain, retains polar localization and rescues these radial askew divisions, but the roots exhibit excess periclinal endodermal divisions. Using markers of cell identity, we show that the daughters of radial askew divisions transition from endodermal to cortex identity similar to those of periclinal divisions. These results extend the requirement for IRK beyond repression of cell division activity to include cell division plane positioning. Based on its polarity, we propose that IRK at the outer lateral endodermal cell face participates in division plane positioning to ensure normal root ground tissue patterning.
Engineering living immunotherapeutic agents for improved cancer treatment
Authors: Gwisai Tinotenda , Günther Sina , Vizovisek Matej , Jacobs Mira , Schuerle Simone
Published: April 2023

Bacteria-based biohybrid agents are emerging as a promising strategy for cancer therapy due to their ability to actively target tumors, trigger localized inflammation and induce tumor regression. There has been growing interest in using bacteria that are responsive to external cues, such as magnetic fields, to facilitate the formation of robust colonies in tumor the achieve the threshold for clinical efficacy. Several studied have demonstrated the potential of innately magnetically responsive bacteria, known as magnetotactic bacteria (MTB), as steerable agents, however, their immunostimulatory properties and therapeutic effects are yet to be explored. Here, we characterize key properties of human immune cell responses and the behavior of the MTB strainMagnetospirillum magneticumAMB-1 in physiological environments. This work investigates the ability of MTB to maintain magnetic properties, viability in whole blood, cytokine production by macrophages, and the ability to increase uptake of cancer cell material by dendritic cells. This study also explores the use of MTB-liposome complexes for effective delivery of therapeutic payloads. Overall, this study establishes the potential of MTB as a versatile, combined drug delivery platform for immune-mediated cancer therapy.
Event-related potential (ERP) evidence of early visual processing differences in cystinosis
Authors: Horsthuis Douwe J. , Molholm Sophie , Foxe John J. , Francisco Ana A.
Published: April 2023

Cystinosis, a rare lysosomal storage disease, is characterized by cystine crystallization and accumulation within tissues and organs, including the kidneys and brain. Its impact on neural function appears mild relative to its effects on other organs, but therapeutic advances have led to substantially increased life expectancy, necessitating deeper understanding of its impact on neurocognitive function.

Behavioral difficulties have been reported in cystinosis in the visual and visual-processing domain. Very little is known, however, about how the brains of people living with cystinosis process visual information, although cysteamine accumulation in the retina is a prominent feature of cystinosis. Here, electrophysiology was recorded during a Go/No-Go task to investigate early visual processing in cystinosis, compared to an age-matched control group. Analyses focused on early stages of cortical visual processing.

The groups differed in their initial cortical response, with individuals with cystinosis exhibiting a significantly larger visual evoked potential (VEP) in the 130 to 150 ms time window. The timing and topography of this response suggested an enhanced P1 in cystinosis that could be the result of cortical hyperexcitability and/or differences in attentional engagement and explain, at least partially, the visual and visual-spatial difficulties described in this population. The groups also differed in the associations between neural responses and verbal abilities: While controls with higher IQ scores presented larger neural responses, that relationship was not observed in cystinosis.
Parasitism does not reduce thermal limits in the intermediate host of a bopyrid isopod
Authors: Sasaki Matthew , Woods Charles , Dam Hans G.
Published: April 2023

Parasitism has strong effects on community dynamics. Given the detrimental effects parasites have on host health, infection or infestation might be expected to reduce upper thermal limits, increasing the vulnerability of host species to future climate change. Copepods are integral components of aquatic food webs and biogeochemical cycles. They also serve as intermediate hosts in the life cycle of parasitic isopods in the family Bopyridae. Given the important effects both copepods and isopod parasites play in aquatic communities, it is important to understand how the interaction between parasite and host affects thermal limits in order to better predict how community dynamics may change in a warming climate. Here we examined the effect of infestation by larvae of a bopyrid isopod on cosmopolitan copepodAcartia tonsato test the hypothesis that infestation reduces thermal limits. To aid with this work, we developed an affordable, highly portable system for measuring critical thermal maxima of small ectotherms. We also used meta-analysis to summarize the effects of parasitism on critical thermal maxima in a wider range of taxa to help contextualize our findings. Contrary to both our hypothesis and the results of previous studies, we observed no reduction of thermal limits by parasitism inA. tonsa. These results suggest that life history of the host and parasite may interact to determine how parasite infestation affects environmental sensitivity.
A collection ofTrichodermaisolates from natural environments in Sardinia, a biodiversity hotspot, reveals a complex virome that includes negative-stranded mycoviruses with unprecedented genome organizations
Authors: Pagnoni Saul , Oufensou Safa , Balmas Virgilio , Bulgari Daniela , Gobbi Emanuela , Forgia Marco , Migheli Quirico , Turina Massimo
Published: April 2023

TheTrichodermagenus includes soil-inhabiting fungi that provide important ecological services in their interaction with plants and other fungi. They are exploited for biocontrol. A collection ofTrichodermaisolates from the Sardinia island (a biodiversity hotspot) had been previously characterized. Here we started a characterization of the viral components associated to 113 selectedTrichodermaisolates, representatives of the collection. We carried out NGS sequencing of ribosome depleted total RNA following a bioinformatic pipeline that detects virus RNA-dependent RNA polymerases (RdRP) and other conserved virus protein sequences. This pipeline detected 17 viral RdRPs. Two of them correspond to viruses already detected in other regions of the world. The remaining 15 represent isolates of new virus species: surprisingly, eight of them are from new negative stranded RNA viruses, which for the first time are reported in the genusTrichoderma. Among them is a cogu-like virus, very closely related to plant-infecting viruses. Regarding the positive strand viruses, it is noticeable the presence of an ormycovirus belonging to a recently characterized group of bi-segmented ssRNA genome viruses with still uncertain phylogenetic assignment. Finally, for the first time we report a bipartite mononegavirales-infecting fungi: the proteins encoded by the second genomic RNA were used to re-evaluate a number of viruses in thePenicillimonavirusandPlasmopamonavirusgenera, here shown to be bipartite and to encode a conserved polypeptide having structural conservation with the nucleocapsid (NC) domain of members of the Rabhdoviridae.

IMPORTANCE

Trichodermais a genus of fungi of great biotechnological impact in multiple industrial fields. The possibility to investigate a diverse collection ofTrichodermaisolates allowed us to characterize both double-stranded and single-stranded virus genomes belonging to three of the major phyla that constitute the RNA viral kingdom, thus further increasing the taxa of viruses infecting this genus. To our knowledge here we report for the first time negative-stranded RNA viruses infectingTrichodermaspp. and throughin silicostructural analysis a new conserved domain of nucleocapsids common among some mymonavirids. Obtaining such a library of mycoviruses could be the basis for further development of targeted virus-induced gene silencing or gene editing (VIGS/VIGE) tools; in addition, the many biotechnological applications of this fungus, will require to assess the qualitative (commercial) stability of strains, linked to positive or negative effects caused by mycovirus infections.