bluuebunny/crossref_metadata_2025 huggingface dataset:
High lipoprotein(a) is a risk factor for peripheral artery disease, abdominal aortic aneurysms, and major adverse limb events
Authors: Thomas Peter E. , Vedel-Krogh Signe , Kamstrup Pia R.
Published: October 2024

Purpose of review

To summarize evidence from recent studies of high lipoprotein(a) as a risk factor for peripheral artery disease (PAD), abdominal aortic aneurysms (AAA), and major adverse limb events (MALE). Additionally, provide clinicians with 10-year absolute risk charts enabling risk prediction of PAD and AAA by lipoprotein(a) levels and conventional risk factors.

Recent findings

Numerous studies support high lipoprotein(a) as an independent risk factor for PAD, AAA, and MALE. The strongest evidence is from the Copenhagen General Population Study (CGPS) and the UK Biobank, two large general population-based cohorts. In the CGPS, a 50 mg/dl higher genetically determined lipoprotein(a) associated with hazard ratios of 1.39 (1.24–1.56) for PAD and 1.21 (1.01–1.44) for AAA. Corresponding hazard ratio in the UK Biobank were 1.38 (1.30–1.46) and 1.42 (1.28–1.59). In CGPS participants with levels at least 99th (≥143 mg/dl) vs, less than 50th percentile (≤9 mg/dl), hazard ratios were 2.99 (2.09–4.30) for PAD and 2.22 (1.21–4.07) for AAA, with a corresponding incidence rate ratio for MALE of 3.04 (1.55–5.98) in participants with PAD.

Evidence from both observational and genetic studies support high lipoprotein(a) as a causal risk factor for PAD, AAA, and MALE, and highlight the potential of future lipoprotein(a)-lowering therapy to reduce the substantial morbidity and mortality associated with these diseases.
Corneal Epithelial Remodeling After Hyperopic SMILE: A 4-Year Study
Authors: Fu Dan , Zhang Luoli , Shang Jianmin , Lin Feng , Han Tian , Zhou Xingtao
Published: October 2024

Purpose:

The purpose of this study was to investigate dynamic changes in corneal epithelial thickness (ET) after hyperopic small incision lenticule extraction (SMILE).

Methods:

This observational study included 18 eyes of 16 patients who were scheduled for hyperopic SMILE. High-resolution spectral-domain optical coherence tomography and a custom image segmentation algorithm were applied to measure corneal dynamic ET over a central 6 mm area. ET was analyzed among different corneal sectors (central, pericentral, and peripheral) at baseline and multiple postoperative time points (1 day, 1 month, 6 months, 2 years, and 4 years). Correlation analysis was performed between ET changes and preoperative and intraoperative parameters.

Results:

The mean spherical equivalent of hyperopia correction was +2.64 ± 1.00 D, and the average age of enrolled 16 patients was 32.4 ± 10.8 years. At the last follow-up, 72% of eyes kept or improved corrected distance visual acuity, with 2 eyes that lost 2 lines. 72% of eyes were within ±1.0 D of target refraction, and 56% were within ±0.5 D. Average ET decreased by 11.0% (5.9 ± 2.3 μm) from 53.2 ± 3.5 μm to 47.4 ± 4.2 μm 4 years postoperatively (P<0.001). The ET at center 2 mm decreased most significantly by 14.5% (7.9 ± 2.9 μm), followed by the pericentral area by 10.5% (5.6 ± 2.3 μm). ET and front corneal curvature stabilized 1 month after surgery. No correlation was found between refraction regression and ET changes.

Conclusions:

Hyperopic SMILE induced significant central ET thinning. ET remodeling in the 6 mm area stabilized after 1 month and did not underlie refractive changes.
Determination of Mandibular Morphology in a Turkish Population With Bipolar I Disorder Using Panoramic Radiography
Authors: Bahadir Hakan , Yetimoğlu Nihal , Oflezer Özlem , Erkiran Murat
Published: September 2024

The presence of specific craniofacial deviations may be evidence of abnormal early brain development in bipolar disorder (BD). This study aimed to compare mandibular morphology in patients with BD versus nonpsychiatric controls using panoramic radiography. A total of 215 recorded images, 70 patients with BD and 145 controls, were evaluated. Seven mandibular parameters of the ramus height (RH), condylar height (CH), gonial angle (GA), antegonial angle (AGA), antegonial notch depth (AND), ramal notch depth (RND), and bigonial width (BGW) were measured in a blinded manner. Group analysis was conducted separately for males and females. The univariate comparisons showed increased values in RH, CH, AND, RND, and BGW and decreased values in GA in males with BD compared with male controls. In addition, females with BD had higher RH, CH, RND, and BGW values in comparison to female controls. The differences were statistically significant. Data from multivariate analyses revealed that increases in RH and BGW values in both sexes were significant predictive variables that distinguished patients with BD from controls. Moreover, deeper AND was the most prominent predictor that distinguished male patients with BD from male controls. The identification of subtle changes in mandibular measurements is consistent with the notion of impaired neurodevelopment in BD.
Psychological Assessment of Health Care Workers in the Aftermath of the February 2023 Earthquakes in Turkey
Authors: Sehlikoğlu Şeyma , Yastibaş Kaçar Cennet , Yilmaz-Karaman Imran Gokcen
Published: October 2024

Objective:

The goal of this study was to examine the psychological and physical effects experienced by health care workers (HCWs) participating in the response to the February 2023 earthquakes in Turkey and to identify any associated factors.

Methods:

An online survey was used to collect data from HCWs on duty in earthquake-stricken areas. The following assessment tools were utilized: Posttraumatic Stress Disorder (PTSD) Checklist for DSM-5, Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, Maslach Burnout Inventory, Posttraumatic Growth Inventory, and Short Form-12.

Results:

A total of 175 HCWs with a mean age of 37.27 years participated in the study. Of these, 39.4% suffered from PTSD, 30.3% experienced depression, and 31.4% experienced anxiety. Female gender, loss of significant others, and previous psychiatric treatment were found to be associated with worse mental health. Nurses tended to have higher levels of PTSD than the medical doctors; the medical doctors had significantly lower scores on the Posttraumatic Growth Inventory compared with the nurses and the other HCWs and lower mental component summary scores on the Short Form-12 compared with the other HCWs. Meeting basic needs and subjective evaluation of teamwork were also linked to mental health. The study also found that marital status, age, and length of time spent in earthquake-stricken areas were associated with scores on the Maslach Burnout Inventory.

Conclusions:

After the earthquake in Turkey, HCWs experienced a significant amount of various adverse mental health outcomes related to certain demographic variables such as gender, profession, previous psychiatric treatment, loss of relatives, and evaluation of living conditions and teamwork. Since HCWs play an essential role in reducing the harmful effects of disasters, recognizing groups at risk and planning tailored interventions may help prevent mental health issues.
Mobile Delivery Program to Prevent Relapse and Improve Functioning in Patients With Psychiatric Diseases
Authors: Sanzone Erin M. , Kam Olivia , Sanzone Kaitlin E. , Bai Michael , Rodecker Nicole , Shad Mujeeb U. , Varghese Sajoy P. , Barlati Stefano , Kirschner Matthias , Kooner Pavan , Velligan Dawn I. , Aiyer Rohit , Waszkiewicz Napoleon , Castle David J. , Cowan Ronald L. , Koola Maju Mathew
Published: October 2024

The term “revolving door patients” refers to those who are frequently rehospitalized for relapse. This phenomenon can be explained by a multitude of factors, including a lack of medical and/or social support. On the basis of a review of various modalities of psychiatric treatment, such as long-acting injectables, assisted outpatient treatment, and telehealth, it is clear that a major underlying issue among people with psychiatric diseases who lack insight into their mental and physical health is medication nonadherence. Therefore, we propose a mobile delivery program (MDP) in which health care professionals deliver medications and care to psychiatric patients in their own homes. The target patient population for MDP is patients with medication nonadherence, frequent emergency department visits, and missed appointments. Patients with mental illnesses, especially schizophrenia, are disproportionately represented among the homeless and incarcerated populations. By implementing MDP, we can help break the cycle of incarceration for patients with mental illnesses and homelessness. In addition, the cost of transportation and salaries for the mobile delivery team would be considerably lower than the billions of dollars spent each year due to relapses, emergency department visits, inpatient admissions, and crime leading to long-term stays in correctional facilities. This model has the potential to reduce relapse, improve functioning, and reduce excess morbidity and mortality. Substantial cost savings for health services can, in turn, be expected.
Patient-Reported Quality of Life for Osteoradionecrosis Reconstruction in the Head and Neck: A Longitudinal Framework and Risk Factors
Authors: Wu Robin T. , Lin Jennifer An‐Jou , Su Charlie Chun-Lin , Wei Fu-Chan
Published: October 2024

Background:

Osteoradionecrosis (ORN) is an aggressive sequela of head and neck cancer, treatment of which focuses on functional restoration and quality-of-life (QoL). This study aims to identify risks for poor QoL in ORN reconstruction and build a chronologic, longitudinal framework for QoL.

Methods:

A prospective database of reconstructions performed by the senior author was reviewed from 2015-2023. QoL metrics (University of Washington [UWQoL]v4) were prospectively administered prior to surgery, one year post-operatively, and each yearly follow-up.

Results:

56 ORN patients were included (average 58.2years, mean 6,412Gy radiation). Reconstruction commonly was achieved with the fibula(55.4%) and anterolateral-thigh flaps(37.5%). The total complication rate was 23.2%, median 10.7mo post-operatively.

Both “health-related QoL in comparison with prior to cancer diagnosis” (62.5 vs 43.5;p=0.030) and “Overall QoL during the past 7-days” (50.5 vs 41.7;p=0.029) were higher post-ORN reconstruction than before. Physical-QoL was higher pre-cancer reconstruction (79.0) than prior to ORN reconstruction (50.6;p<0.001) and following reconstruction (52.5;p=0.001). Social-emotional function was higher following ORN reconstruction compared to pre-reconstruction (68.7 vs 59.6;p=0.010).

On multi-variate analysis, both post-operative social-emotional and physical function were impacted by betelnut use (p=0.038;p=0.025). Poor improvement in QoL from pre to post-ORN reconstruction were affected by maxilla involvement (p=0.048), fistula (p=0.004), and hardware issues (p=0.001).

Conclusions:

Our longitudinal experience trended decline in QoL at ORN diagnosis with gradual improvement following reconstruction, with eventual social-emotional, pain, anxiety, chewing, and global-QoL significantly improved following surgery. Betelnut was a risk factor for poor post-operative QoL. Maxillary involvement, post-op fistula and hardware issues were risks for non-improvement in QoL.
Diagnosis and Screening of Velocardiofacial Syndrome by Evaluating Facial Photographs Using a Deep Learning-Based Algorithm
Authors: Baek Rong-Min , Cho Anna , Chung Yoon Gi , Jeon Yonghoon , Kim Hunmin , Hwang Hee , Kang Jiwon , Myung Yujin
Published: October 2024

Background:

Early detection of rare genetic diseases, including velocardiofacial syndrome (VCFS), is essential for patient well-being. However, their rarity and limited clinical experience of physicians make diagnosis challenging. Deep learning algorithms have emerged as promising tools for efficient and accurate diagnosis. This study investigates the use of a deep learning algorithm to develop a face recognition model for diagnosing VCFS.

Methods:

The study employed publicly available labeled face datasets to train the multitask cascaded convolutional neural networks (MTCNN) model. Subsequently, we examined the binary classification performance for diagnosing VCFS using the most efficient face recognition model. A total of 98 VCFS patients (920 facial photographs) and 91 non-VCFS controls (463 facial photographs) were randomly divided into training and test sets. Additionally, we analyzed whether the classification results matched the known facial phenotype of VCFS.

Results:

The face recognition model demonstrated high accuracy, ranging from 94% to 99%, depending on the training dataset. The accuracy of the binary classification diagnostic model varied from 81% to 88% when evaluating with photographs taken at various angles, but reached 95% evaluating with frontal photographs only. Gradient-weighted class activation mapping heatmap revealed the high importance level of perinasal and periorbital areas, exhibiting consistency with the conventional facial phenotypes of VCFS.

Conclusion:

This study shows the feasibility and effectiveness of MTCNN-based model for detecting VCFS solely from facial photographs. The high accuracy underscores the potential of deep learning in aiding early diagnosis of rare genetic diseases, facilitating timely interventions for patient care.
Aesthetic Specialization: A Comparative Study Across Medical and Surgical Specialties
Authors: Katz Abigail , Oleru Olachi , Wang Anya , Seyidova Nargiz , Mandelbaum Max , Melamed Eitan , Taub Peter J.
Published: October 2024

Background:

Post-residency fellowship training has become increasingly popular as a career option. Specifically, the subspecialty of aesthetic surgery has grown tremendously over the past two decades within several fields, including plastic and reconstructive surgery (PRS), otolaryngology, dermatology, and ophthalmology. However, the popularity of aesthetic specialization through fellowship remains unknown. The present study aims to analyze trends in aesthetic specialization across these specialties and compare its popularity to other fellowships.

Methods:

A retrospective review of data from the San Francisco Match, National Resident Matching Program, American Society for Dermatologic Surgery, and the Accreditation Council for Graduate Medical Education was performed. Data on graduating residents and applicants to fellowship were collected. ANOVA and t-tests were used to compare differences between groups.

Results:

Significant disparities were observed in applicants and matched applicants to aesthetic fellowships among the four residencies (p<0.001). Aesthetic fellowship was the most popular option after otolaryngology residency (12.5%-27% depending on the year) and second most popular choice after PRS (8%-17%) and dermatology (2%-5%). A comparison between PRS and otolaryngology demonstrated a significantly higher percent of the latter choosing aesthetic fellowship over time (p<0.001). However, no significant difference in applicants to aesthetic fellowship was found between dermatology and ophthalmology (t-test, p=0.060).

Conclusions:

The number of applicants to aesthetic fellowship has increased over time across all eligible residencies with the more surgical heavy specialties (ENT and PRS) having the highest percent of applicants. Differences in aesthetic training between fields was also observed, which may reflect underlying variations in training and residency exposure.
Overlooked and misunderstood: can glutathione conjugates be clues to understanding plant glutathione transferases?
Authors: Micic Nikola , Holmelund Rønager Asta , Sørensen Mette , Bjarnholt Nanna
Published: September 2024

Plant glutathione transferases (GSTs) constitute a large and diverse family of enzymes that are involved in plant stress response, metabolism and defence, yet their physiological functions remain largely elusive. Consistent with the traditional view on GSTs across organisms as detoxification enzymes,in vitromost plant GSTs catalyse glutathionylation, conjugation of the tripeptide glutathione (GSH; γ-Glu-Cys-Gly) onto reactive molecules. However, when it comes to elucidating GST functions, it remains a key challenge that the endogenous plant glutathione conjugates (GS-conjugates) that would result from such glutathionylation reactions are rarely reported. Furthermore, GSTs often display high substrate promiscuity, and their proposed substrates are prone to spontaneous chemical reactions with GSH; hence, single-gene knockouts rarely provide clear chemotypes or phenotypes. In a few cases, GS-conjugates are demonstrated to be biosynthetic intermediates that are rapidly further metabolized towards a pathway end product, explaining their low abundance and rare detection. In this review, we summarize the current knowledge of plant GST functions and how and possibly why evolution has resulted in a broad and extensive expansion of the plant GST family. Finally, we demonstrate that endogenous GS-conjugates are more prevalent in plants than assumed and suggest they are overlooked as clues towards the identification of plant GST functions.

This article is part of the theme issue ‘The evolution of plant metabolism’.
The transcriptomic response of cells of the thermophilic bacteriumGeobacillus icigianusto terahertz irradiation
Authors: Peltek Sergey , Bannikova Svetlana , Khlebodarova Tamara , Uvarova Yulia , Mukhin Aleksey , Vasiliev Gennady , Scheglov Mikhail , Shipova Aleksandra , Vasilievа Asya , Oshchepkov Dmitry , Bryanskaya Alla , Popik Vasiliy
Published: September 2024

As areas of application of terahertz (THz) radiation expand in science and practice, evidence is accumulating that this type of radiation can affect not only biological molecules directly but also cellular processes as a whole. In this study, the transcriptome in cells of the thermophilic bacteriumGeobacillus icigianuswas analyzed immediately after THz irradiation (0.23 W/cm2, 130 μm, 15 min) and at 10 min after its completion. THz irradiation does not affect the activity of heat shock protein genes and diminishes the activity of genes whose products involved in peptidoglycan recycling, participate in redox reactions and in protection of DNA and proteins from damage, including genes of chaperone protein ClpB and of DNA repair protein RadA as well as genes of catalase and kinase McsB, which play an essential role in the regulation of the cellular response to oxidative stress. Gene systems responsible for the homeostasis of transition metals (copper, iron, and zinc) proved to be the most sensitive to THz irradiation; downregulation of these systems increased significantly 10 min after the end of the irradiation. Blockage of the expression of genes responsible for copper export and iron import systems under the influence of THz irradiation may be a harbinger of toxic stress inG. icigianuscells, which leads to destabilization of the function of proteins containing Fe/S clusters. It was also hypothesized that some negative effects of THz radiation on metabolism inG. icigianuscells are related to disturbances in activities of gene systems controlled by metal-sensitive transcription factors.
Distinct regulatory mechanisms by the nuclear Argonautes HRDE-1 and NRDE-3 in the soma ofCaenorhabditis elegans
Authors: Mendoza Hector , Jash Eshna , Davis Michael B. , Haines Rebecca A. , Van Diepenbos Sarah , Csankovszki Györgyi
Published: September 2024

RNA interference is a conserved silencing mechanism that depends on the generation of small RNA molecules that disrupt synthesis of their corresponding transcripts. Nuclear RNA interference is a unique process that triggers regulation through epigenetic alterations to the genome. This pathway has been extensively characterized inCaenorhabditis elegansand involves the nuclear recruitment of H3K9 histone methyltransferases by the Argonautes HRDE-1 and NRDE-3. The coordinate regulation of genetic targets by H3K9 methylation and the nuclear Argonautes is highly complex and has been mainly described based on the small RNA populations that are involved.

Recent studies have also linked the nuclear RNAi pathway to the compaction of the hermaphrodite X chromosomes during dosage compensation, a mechanism that balances genetic differences between the biological sexes by repressing X chromosomes in hermaphrodites. This chromosome-wide process provides an excellent opportunity to further investigate the relationship between H3K9 methylation and the nuclear Argonautes from the perspective of the transcriptome. Our work suggests that the nuclear RNAi and the H3K9 methylation pathways each contribute to the condensation of the X chromosomes during dosage compensation but the consequences on their transcriptional output are minimal. Instead, nuclear RNAi mutants exhibit global transcriptional differences, in which HRDE-1 and NRDE-3 affect expression of their native targets through different modes of regulation and different relationships to H3K9 methylation.

ARTICLE SUMMARY

This study examines the transcriptional consequences during the disruption of the nuclear RNAi silencing mechanism inC. elegans. Through microscopy and bioinformatic work, we demonstrate that although nuclear RNAi mutants exhibit significantly decondensed X chromosomes, chromosome-wide transcriptional de-repression is not detectable. Downstream analyses further explore the global influence of the nuclear RNAi pathway, indicating that the nuclear Argonautes HRDE-1 and NRDE-3 function through two distinct mechanisms.
PP mediated the relationship between METS-IR and AIS in non-diabetic patients
Authors: Li Zhaoyang , Jia Ruirui , Chen Dong , Wang Hui , Zhang Youyou
Published: September 2024

Background

The correlation between metabolic score for insulin resistance (METS-IR) and high insulin normal glucose clamp test is stronger than other non-insulin-based insulin resistance scores. Insulin resistance was related to the occurrence and development of hypertension and stroke, however, the association between METS-IR and hypertension, as well as ischemic stroke is lack of evidence. This study aimed to determine the association between METS-IR and acute ischemic stroke in non-diabetic patients, and the mediating role of blood pressure parameters on it.

Methods

This hospital-based study included 557 non-diabetic subjects diagnosed with premature acute ischemic stroke. Logistic regression models and mediation analyses were conducted to assess the role of blood pressure parameters (systolic blood pressure, diastolic blood pressure, pulse pressure and mean arterial pressure) in the associations between METS-IR and risk of acute ischemic stroke.

Results

After adjusting for potential covariates, each SD increment of METS-IR was associated with 26% higher odds (OR = 1.26, 95% CI: 1.06-1.52) increment in ORs of acute ischemic stroke. The OR for acute ischemic stroke in patients with highest quartile of METS-IR was 1.73 hold (OR = 1.73, 95% CI: 1.12-2.70) higher than that in those with the lowest quartile of METS-IR. Furthermore, mediation analyses indicated that pulse pressure partially mediate the detrimental effect of insulin resistance (assessed by the METS-IR) on acute ischemic stroke (mediation percentage: 11.70%).

Conclusions

Our study suggests a relationship between METS-IR and acute ischemic stroke, and the association of METS-IR with acute ischemic stroke was partially mediated by pulse pressure.
Rapid prediction of thermodynamically destabilizing tyrosine phosphorylations in cancers
Authors: Woodard Jaie , Liu Zhengqing , Chegini Atena Malemir , Tian Jian , Bhowmick Rupa , Pennathur Subramanium , Mashaghi Alireza , Brender Jeffrey , Chandrasekaran Sriram
Published: September 2024

Tyrosine phosphorylations are a prominent characteristic of numerous cancers, necessitating the use of computational tools to comprehensively analyze phosphoproteomes and identify potentially (dys)functional phosphorylations. Here we propose a machine learning-based method to predict the thermodynamic stability change resulting from tyrosine phosphorylation. Our approach, based on prediction of phosphomimetic delta-delta-G from structural features, strongly correlates with experimental mutational scanning cDNA proteolysis data (R = 0.71). We predicted the destabilizing effects of all 384,857 tyrosine residues from the Alphafold2 database. We then applied our approach to a pan-cancer phosphoproteomics dataset, comprising over 600 unique tyrosine phosphorylations across 11 cancer subtypes. We predict destabilizing phosphorylations in both oncogenes and tumor suppressors, where the former likely reflects a generalized relief of auto-inhibition or activating conformational change. We find that the number of circuit topological parallel relations with respect to residues contacting the phosphorylated site is greater for autoinhibited oncogenes than for other proteins (Wilcoxon p = 0.03). Utilizing an extreme gradient-boosting machine learning approach, we obtain an AUC of 0.85 for the prediction of autoinhibited phosphorylation states from circuit topological features. The top destabilized proteins from the pan-cancer data are enriched for chemical and oxidative stress pathways. Among metabolic proteins, highly destabilizing phosphorylations tend to occur in more peripheral proteins with lower network centrality measures (Wilcoxon p = 0.005). We predict 58% of recurrent tyrosine cancer phosphorylations to be destabilizing at the 1 kcal/mol threshold. Our approach can enable rapid screening of destabilizing phosphorylations and phosphomimetic mutations.
mTORC1 and STAT3 signalings are indispensable for in vitro TGFβ1-dependent Three-Dimensional (3D) tendon construct
Authors: Koo Bon-hyeock , Smith Aiden , Joeng Kyu Sang
Published: September 2024

The Transforming Growth Factor-β 1 (TGFβ1) is a well-known growth factor involved in tenocytes differentiation, extracellular matrix production, and cell fate regulation. We previously demonstrated that TGFβ1 has a critical role in the formation ofin vitro3D tendon constructs using mouse primary tendon cells. In this study, we investigated the function of Mammalian target of rapamycin complex 1 (mTORC1) and Signal transducer and activator of transcription 3 (STAT3) signaling in the formation of TGFβ1-inducedin vitro3D tendon constructs using specific inhibitors, rapamycin (mTORC1 inhibitor) and stattic (stat3 inhibitor). TGFβ1 treatment activated both mTORC1 and STAT3 in 3D tendon constructs. The treatment of rapamycin or stattic partly attenuated TGFβ1-dependent cellular, molecular, and matrix changes in the 3D tendon constructs. Overall, this study demonstrates that mTORC1-STAT3 signaling axis is a downstream mediator of TGFβ1 signaling in the formation of 3D tendon constructs.
Potentiation of active locomotor state by spinal-projecting serotonergic neurons
Authors: Fenstermacher Sara J. , Vonasek Ann , Gattuso Hannah , Chaimowitz Corryn , Dymecki Susan M. , Jessell Thomas M. , Dasen Jeremy S.
Published: September 2024

Animals produce diverse motor actions that enable expression of context-appropriate behaviors. Neuromodulators facilitate behavioral flexibility by altering the temporal dynamics and output of neural circuits. Discrete populations of serotonergic (5-HT) neurons target circuits in the brainstem and spinal cord, but their role in the control of motor behavior is unclear. Here we define the pre- and post-synaptic organization of the spinal-projecting serotonergic system and define a role in locomotor control. We show that while forebrain-targeting 5-HT neurons decrease their activity during locomotion, subpopulations of spinal projecting neurons increase their activity in a context-dependent manner. Optogenetic activation of ventrally projecting 5-HT neurons does not trigger initiation of movement, but rather enhances the speed and duration of ongoing locomotion over extended time scales. These findings indicate that the descending serotonergic system potentiates locomotor output and demonstrate a role for serotonergic neurons in modulating the temporal dynamics of motor circuits.
Untargeted CUT&Tag and BG4 CUT&Tag are both enriched at G-quadruplexes and accessible chromatin
Authors: Thompson Matthew , Byrd Alicia
Published: September 2024

G-quadruplex DNA structures (G4s) form within single-stranded DNA in nucleosome-free chromatin. As G4s modulate gene expression and genomic stability, genome-wide mapping of G4s has generated strong research interest. Recently, the Cleavage Under Targets and Tagmentation (CUT&Tag) method was performed with the G4-specific BG4 antibody to target Tn5 transposase to G4s. While this method generated a novel high-resolution map of G4s, we unexpectedly observed a strong correlation between the genome-wide signal distribution of BG4 CUT&Tag and accessible chromatin. To examine whether untargeted Tn5 cutting at accessible chromatin contributes to BG4 CUT&Tag signal, we examined the genome-wide distribution of signal from untargeted (i.e. negative control) CUT&Tag datasets. We observed that untargeted CUT&Tag signal distribution was highly similar to both that of accessible chromatin and of BG4 CUT&Tag. We also observed that BG4 CUT&Tag signal increased at mapped G4s, but this increase was accompanied by a concomitant increase in untargeted CUT&Tag at the same loci. Consequently, enrichment of BG4 CUT&Tag over untargeted CUT&Tag was not increased at mapped G4s. These results imply that either the vast majority of accessible chromatin regions contain mappable G4s or that the presence of G4s within accessible chromatin cannot reliably be determined using BG4 CUT&Tag alone.

GRAPHICAL ABSTRACT
Selection promotes age-dependent degeneration of the mitochondrial genome
Authors: Korotkevich Ekaterina , Conrad Daniel N. , Gartner Zev J. , O’Farrell Patrick H.
Published: September 2024

Somatic mutations in mitochondrial genomes (mtDNA) accumulate exponentially during aging. Using single cell sequencing, we characterize the spectrum of age-accumulated mtDNA mutations in mouse and human liver and identify directional forces that accelerate the accumulation of mutations beyond the rate predicted by a neutral model. “Driver” mutations that give genomes a replicative advantage rose to high cellular abundance and carried along “passenger” mutations, some of which are deleterious. In addition, alleles that alter mtDNA-encoded proteins selectively increased in abundance overtime, strongly supporting the idea of a “destructive” selection that favors genomes lacking function. Overall, this combination of selective forces acting in hepatocytes promotes somatic accumulation of mutations in coding regions of mtDNA that are otherwise conserved in evolution. We propose that these selective processes could contribute to the population prevalence of mtDNA mutations, accelerate the course of heteroplasmic mitochondrial diseases and promote age-associated erosion of the mitochondrial genome.
DNA polymerase ζ is a robust reverse transcriptase
Authors: Mayle Ryan , Holloman William K. , O’Donnell Michael E.
Published: September 2024

Cell biology and genetic studies have demonstrated that DNA double strand break (DSB) repair can be performed using an RNA transcript that spans the site of the DNA break as a template for repair. This type of DSB repair requires a reverse transcriptase to convert an RNA sequence into DNA to facilitate repair of the break, rather than copying from a DNA template as in canonical DSB repair. Translesion synthesis (TLS) DNA polymerases (Pol) are often more promiscuous than DNA Pols, raising the notion that reverse transcription could be performed by a TLS Pol. Indeed, several studies have demonstrated that human Pol η has reverse transcriptase activity, while others have suggested that the yeast TLS Pol ζ is involved. Here, we purify all seven known nuclear DNA Pols ofSaccharomyces cerevisiaeand compare their reverse transcriptase activities. The comparison shows that Pol ζ far surpasses Pol η and all other DNA Pols in reverse transcriptase activity. We find that Pol ζ reverse transcriptase activity is not affected by RPA or RFC/PCNA and acts distributively to make DNA complementary to an RNA template strand. Consistent with priorS. cerevisiaestudies performedin vivo, we propose that Pol ζ is the major DNA Pol that functions in the RNA templated DSB repair pathway.
A Genetically Encoded Fluorescent Biosensor for Intracellular Measurement of Malonyl-CoA
Authors: Ranzau Brodie L. , Robinson Tiffany D. , Scully Jack M. , Kapelczack Edmund D. , Dean Teagan S. , TeSlaa Tara , Schmitt Danielle L.
Published: September 2024

Malonyl-CoA is the essential building block of fatty acids and regulates cell function through protein malonylation and allosteric regulation of signaling networks. Accordingly, the production and use of malonyl-CoA is finely tuned by the cellular energy status. Most studies of malonyl-CoA dynamics rely on bulk approaches that take only a snapshot of the average metabolic state of a population of cells, missing out on dynamic changes in malonyl-CoA and fatty acid biosynthesis that could be occurring within a single cell. To overcome this limitation, we have developed a genetically encoded fluorescent protein-based biosensor for malonyl-CoA that can be used to capture malonyl-CoA dynamics in single cells. This biosensor, termed Malibu (malonyl-CoAintracellular biosensor to understand dynamics), exhibits an excitation-ratiometric change in response to malonyl-CoA binding. We first used Malibu to monitor malonyl-CoA dynamics during inhibition of fatty acid biosynthesis using cerulenin inE. coli, observing an increase in Malibu response in a time- and dose-dependent manner. In HeLa cells, we used Malibu to monitor the impact of fatty acid biosynthesis inhibition on malonyl-CoA dynamics in single cells, finding that two inhibitors of fatty acid biosynthesis, cerulenin and orlistat, which inhibit different steps of fatty acid biosynthesis, increase malonyl-CoA levels. Altogether, we have developed a new genetically encoded biosensor for malonyl-CoA, which can be used to sensitively study malonyl-CoA dynamics in single cells, providing an unparalleled view into fatty acid biosynthesis.
The extraordinarily long lead times of screen-detected lung cancer in never-smokers
Authors: Gao Wayne , Welch H Gilbert
Published: September 2024

Background

The randomized trials of low-dose computed tomography (LDCT) screening enrolled individuals at high risk of lung cancer: heavy cigarette smokers. Nevertheless, opportunistic screening of never smokers has become commonplace in certain regions of East Asia. Lung cancer detection rates reported for this low risk group regularly exceed those reported in the randomized trials. We sought to determine the lead time – the length of time between screen detection and when symptoms would manifest (clinical presentation) – associated with LDCT detection rates reported in Taiwan.

Objective

To estimate the lead time for LDCT lung cancer detection in never smoking Taiwanese females, under the assumption that all detected cancers progress.

Methods

We analyzed data from the Taiwan Lung Cancer Screening in Never-Smoker Trial (TALENT), a prospective cohort of ≈12000 never smokers aged 55–75, and compared age-specific screen detection rates to lung cancer incidence rates in the pre-screening period. Lead time was estimated using Morrison’s approximation: one-half the ratio of screen detection to pre-screening incidence.

Results

Invasive lung cancer detection rates in never smoking females were 18 (age 70-74) to 37 (age 55-59) times higher than the respective age-specific lung cancer incidence rates prior to widespread screening. The estimated lead times for invasive lung cancers thus ranged from 9 (age 70-74) to 18.5 years (age 55-59). Had we included in situ lung cancer detection, the estimated lead time of screening would range from approximately 10 to 20 years.

Conclusion

If all detected cancers progress, the lead times for LDCT lung cancer detection in never-smokers would be 5 to 20 times longer than that reported in the randomized trials of heavy smokers (1 to 2 years). Such extended lead times are not only undesirable (Why label and treat a patient for a cancer not destined to clinically present in the next 1 or 2 decades?), but also a major source of overdiagnosis – providing plenty of time for a patient to die from other causes before developing a symptomatic cancer (Type 1 overdiagnosis). Furthermore, some screen-detected cancers may not progress and thus have an infinite lead time (Type 2 overdiagnosis). Regardless, it appears that substantial overdiagnosis has occurred in screening low-risk, never smoking individuals.
Common pathogenic mechanisms for COVID-19 and differentiated thyroid cancer: a proteomic analysis
Authors: Liu Hanqing , Wang Jiaxi , Yang Dan , Chen Chuang
Published: September 2024

Background

Previous studies have proved that viral infection might have potential associations with differentiated thyroid cancer. COVID-19 has spread to hundreds of millions of individuals since Dec 2019. This study aimed to investigate the common pathogenic mechanisms of differentiated thyroid cancer and SARS-CoV-2 infection in thyroid tissues.

Methods

The proteomic profiles of COVID-19 and differentiated thyroid cancer were downloaded from iProx database and were analyzed for differentially expressed proteins. After the common proteins were identified using the Venn diagram, gene ontology and pathway enrichment analysis were performed. Subsequently, a protein-protein interaction network was constructed and hub genes were identified with eight algorithms. The diagnostic performance of hub genes was tested with the receiver operator characteristics curve. The associations between hub genes and diseases were evaluated with the Comparative Toxicogenomics Database.

Results

Forty-nine common differentially expressed proteins were identified. Functional analysis revealed that the metabolism and transport of lipid and cholesterol and coagulation process were the main common biological activities affected by the two diseases. In addition, twelve genes, including AGT, AHSG, APOA2, APOM, C3, GC, ITIH2, KNG1, SERPINA1, SERPINC1, TF and TTR, were identified as the hub genes. These genes could serve as diagnostic markers for COVID-19 and differentiated thyroid cancers.

Conclusion

The current study revealed common pathogenic mechanisms of COVID-19 and differentiated thyroid cancer. The concomitant infection of SARS-CoV-2 might exert adverse effects on patients with thyroid cancers.
The effect of trauma quality improvement programme implementation on quality of life among trauma patients in urban India
Authors: Kapitan Eelika , Berg Johanna , David Siddarth , Mohan L N , Felländer-Tsai Li , Chatterjee Shamita , Ekelund Ulf , Roy Nobhojit , Petzhold Max , Von Schreeb Johan , Soni Kapil Dev , Rajan Sendhil , Khajanchi Monty , Gerdin Wärnberg Martin
Published: September 2024

Trauma accounts for around 4.4 million deaths annually and is among the leading causes of death, disproportionately affecting low- and middle-income countries. Trauma quality improvement programmes may reduce adverse patient outcomes but lack robust evidence. This study assessed the effect of implementing a trauma quality improvement programme using audit filters on health-related quality of life in adult trauma patients in urban India.

We conducted a controlled interrupted time series study (ClinicalTrials.govIDNCT03235388) across four tertiary care university hospitals. Adult (≥18 years) trauma patients, who were alive at 90 days post-admission, were included. After a 14-month observation phase, two hospitals were randomized to the intervention arm and implemented the trauma quality improvement programme, while two control hospitals did not implement any interventions. The study spanned from 2017 to 2022.

Health-related quality of life was assessed 90 days post-admission using the EuroQol 5-dimensions (EQ-5D) questionnaire. The main outcome was EQ-5D health status, scaled from 0 to 100, analyzed using a difference-in-differences (DiD) approach. Descriptive analysis was performed for the five individual EQ-5D dimensions.

2307 participants were eligible for the analyses. The DiD analysis showed a statistically significant reduction in the EQ-5D health status score in the intervention arm (DiD estimate −4.07 [95% CI: −7.00; −1.15]). For the 819 patients with major trauma, there was a more pronounced, but statistically insignificant reduction (DiD estimate −4.86 [95% CI: −9.87; 0.15]). In the intervention arm, mobility, self-care, and pain/discomfort improved, while usual activities and anxiety/depression worsened.

Implementing trauma quality improvement programmes using audit filters may reduce the average health-related quality of life of trauma patients if more severely injured patients survive, highlighting the importance of assessing quality of life after the implementation of such programmes and ensuring adequate rehabilitation resources to support long-term recovery.
Spatial learning in feature-impoverished environments inDrosophila
Authors: Chen Yang , Alfredson Robert , Motevalli Dorsa , Fogleman Sydney , Stern Ulrich , Yang Chung-Hui
Published: September 2024

The ability to return to memorized goal locations is essential for animal survival. While it is well documented that animals use visual landmarks to locate goals1,2, how they navigate spatial learning tasks in environments lacking such landmarks remains poorly understood. Here, using a high-throughput spatial learning task we developed to investigate this question inDrosophila, we found thatDrosophilacan simultaneously use self-generated olfactory cues and self-motion cues to learn a spatial goal under visually challenging conditions. Specifically, flies mark a rewarded goal location with self-deposited scents, to which they assign a positive value, and use these scents and their self-motion cues to guide them back to the goal. This learning process is mediated by the mushroom body (MB) – an olfactory learning center responsible for associating odors with reinforcement3– and by PFN neurons, which encode egocentric translational velocity4,5, a self-motion cue. Intriguingly, when the environment is enriched with prominent external olfactory landmarks, flies shift to prioritizing landmarks over self-generated cues – a strategy adjustment reflected in both the critical circuit involved and an altered transcriptome in the brain. Our findings demonstrate thatDrosophilacan dynamically adapt to environmental complexities when solving spatial learning tasks by creating and integrating internal and external cues, revealing an unexpected level of sophistication in their cognitive capacities.
Unfolding the relationship between change management, employee engagement and productivity: resistance to change and emotional intelligence as moderators
Authors: Shaik Shamshad Ahamed , Batta Ankaiah , Parayitam Satyanarayana
Published: September 2024

Purpose

The objective of this study is to investigate the effect of change management (CM) on employee productivity (EP). A double-layered conceptual model involving resistance to change and emotional intelligence (EI) as moderators and employee engagement (EE) as a mediator between CM and EP.

Design/methodology/approach

Four industries from India (education, healthcare, information technology and manufacturing) are selected to test the hypothesized relationships. The data from 406 respondents were collected through a survey instrument and was analyzed using Hayes’s PROCESS macros.

Findings

The results reveal that CM is a precursor to EE and EP. The findings also indicate that resistance to change (first moderator) and EI (second moderator) significantly influenced the relationship between CM and EP mediated through EE.

Research limitations/implications

As with any social science research, this study suffers from the limitations of common method bias and social desirability bias. However, the researchers have taken adequate care to minimize these biases. This study has several theoretical and practical implications.

Originality/value

The moderated-mediated model concerning CM is the first of its kind to study in the Indian context and hence makes a substantial contribution to the literature on CM. The implications for theory and practice are discussed.
ChatGPT is likely reducing opportunity for support, friendship and learned kindness in research
Authors: Millard Joseph , Christie Alec P. , Dicks Lynn V. , Isip Justin E. , Johnson Thomas F. , Skinner Grace , Spake Rebecca
Published: October 2024

Large language models (LLM) have proved to be highly popular since the release of ChatGPT, leading many researchers to explore their potential across multiple fields of scientific research. In a recent Perspective, Cooper et al. (2024) highlight a set of benefits and challenges for the use of LLMs in ecology, emphasising their value to coding in research and education.

While we agree that the ability of LLMs to assist in the coding process is remarkable, researchers should be conscious that this capability is likely changing the lived experience of primarily computational researchers, especially early career ecologists between Masters and Postdoctoral career stages.

In particular, since the release of ChatGPT, the authors of this paper have noticed a marked reduction in the frequency of social interactions emergent from coding and statistics queries. These questions are highly likely still being asked, but now often exclusively to a LLM.

Further research is needed to fully understand the effect of LLMs on the lived‐experience of researchers and students. For primarily computational researchers, ChatGPT is likely reducing emergent opportunity for support, friendship and learned kindness. Group leaders should recognise this and foster deliberate within‐group communication and collaboration.
The Australian Frailty Network: Development of a consumer‐focussed national response to frailty
Authors: Reid Natasha , Young Adrienne , Baldassar Loretta , Christoffersen Anja , Comans Tracy , Conroy Simon , Etherton‐Beer Christopher , Ferris Jason , Singh Maria Fiatarone , Fox Sarah , Gordon Emily H. , Ghosh Manonita , Guha Chandana , Hilmer Sarah , Kouladjian O’Donnell Lisa , Logan Benignus , Ludlow Kristiana , Miller Michelle , Morgan Mark , Mudge Alison , Muscedere John , Reidlinger Donna , Rockwood Kenneth , Saunders Rosemary , Ward David , Yates Paul , Hubbard Ruth E.
Published: September 2024

Frailty is an important concept in the care of older adults. Over the past two decades, significant advances have been made in measuring frailty. While it is now well‐recognised that frailty status is an important determinant of outcomes from medical illnesses or surgical interventions, frailty measurement is not currently routinely integrated into clinical practice. In the community setting, it is uncommon for general practitioners to deliver frailty‐optimised care. In hospitals, there is substantial variability in how people living with frailty are managed. This variability is notable between and even within disciplines. Furthermore, gains from understanding frailty mechanisms and risk factors are not yet applied/implemented at scale to delay the progression of frailty in community‐dwellers. The Australian Frailty Network (AFN) is a national collaborative group of researchers, clinicians, non‐government organisations, consumers and policymakers, in which the engagement and active involvement of consumers has been embedded from the outset. The AFN aims to generate new knowledge to improve health outcomes, to ensure evidence‐based management is translated into clinical practice and to build capacity in multidisciplinary and translational frailty research. Here, we describe the development of the AFN, highlighting important milestones: (i) securing funding for the network and flagship elements; (ii) an inaugural summit to establish the strategic vision, values and scope with end‐users; (iii) sabbatical visits to learn from international examples; and (iv) developing the governance structure and an actionable plan encompassing consumer engagement, research, education and policy and practice to maximise impact.