bluuebunny/crossref_metadata_2025 huggingface dataset:
Correction of Lying Ear and Aesthetic Modification of Helix and Ear Lobule With Hyaluronic Acid Filler Injection: Experience in Chinese Patients
Authors: Li Yiming , Dong Weiwei , Zhang Lingmei , Yang Ying , Song Yang , Shi Ning , Li Shiyi , Mohd Hayati Mohd Firdaus Bin , Ling Sophia Heng Si , Tang Yujun
Published: January 2024

Background

Large and long ears are regarded as symbols of wealth and health in East Asian culture, and people with lying ears often want their ears to be more exposed and prominent. Surgeries to correct lying ears have been documented.

Objectives

The aim of this study was to report the correction of lying ears and the aesthetic modification of helix and ear lobule with hyaluronic acid (HA) injections.

Methods

HA injections were performed at the auriculocephalic sulcus to increase the cranioauricular angle (CA) and correct lying ears. The injections at helix and lobule were case specific. The CA was measured and photographs were taken at baseline and at 1-, 3-, 6-, and 10-month follow-ups. Efficacy was assessed with the 5-point Global Aesthetic Improvement Scale (GAIS). Adverse events were recorded.

Results

Forty-six patients (92 ears) received HA injections and completed follow-ups. Instant correction outcomes were observed. Sixteen (34.8%) patients received 1 touch-up injection, the clinical efficacy of which persisted for 1 to 1.5 years. For over 90% of cases with touch-up treatment the GAIS was “very much improved” or “much improved” at all follow-ups. The GAIS for over 70% of cases without touch-up treatment was “very much improved” or “much improved” at 1-, 3-, and 6-month follow-ups. CA increased significantly compared with the baseline. Patients also reported “more V-shaped face shape” and “lifted jawline” effects. No serious adverse events occurred.

Conclusions

As an alternative technique to surgeries, HA filler injections at the auriculocephalic sulcus effectively corrected lying ears. This technique produced immediate, long-lasting, and aesthetically pleasing results. The side effects and downtime were minimal.

Level of Evidence: 3
Pedicle Selection and Design in Reduction Mammaplasty: The Role of Preoperative Fluorescence Imaging
Authors: Lin Yan , Li Haoran , Li Zhengyao , Chen Lin , Xing Wenshan , Zhang Xiaoyu , Mu Dali
Published: January 2024

Background

Breast reduction has a wide selection of pedicles but often relies on the surgeon’s preference and experience. Necrosis of the nipple-areola complex (NAC) is a catastrophic complication of breast reduction surgery.

Objectives

To solve the above problem objectively, we applied fluorescence imaging technology to the pedicle selection and design of breast reduction surgery for the first time, so that the dominant vessels of the NAC were included in the designed pedicle.

Methods

We retrospectively enrolled 120 patients with breast reduction (a total of 239 breasts). We compared 60 patients who underwent breast reduction without fluorescence imaging for pedicle selection (Group A) with 60 patients who underwent pedicle selection with fluorescence imaging (Group B). The NAC blood supply was monitored after the operation.

Results

In this study, 60 Group A cases (119 breasts) and 60 Group B cases (120 breasts) were analyzed. There were no statistically significant differences in patient demographic data or intraoperative resection weights. There were 7 cases of NAC necrosis in Group A (1 case of complete necrosis and 6 cases of partial necrosis), while no NAC necrosis occurred in Group B. There was a significant difference in the rate of NAC necrosis between the 2 groups.

Conclusions

Preoperative fluorescence imaging can guide the selection and design of breast reduction, significantly reducing postoperative NAC blood supply obstacles and necrosis.

Level of Evidence: 3
Expression, purification, and biological activity evaluation of cathepsin L in mammalian cells
Authors: Zhou Wenwen , You Baoqing , Zheng Yifan , Si Shuyi , Li Yan , Zhang Jing
Published: January 2024

Cathepsin L (CTSL) could cleave and activate SARS-CoV-2 Spike protein to promote viral entry, making it a hopeful therapeutic target for COVID-19 prevention and treatment. So CTSL inhibitors are considered to be a promising strategy to SARS-CoV-2 infection. CTSL has previously been expressed in inclusion body in Escherichia coli. In order to prepare CTSL with high purity and activity in soluble active form, we transformed HEK-293T cells with a recombinant mammalian expression plasmid. CTSL was purified to a purity about 95%, found to migrate at approximately 43 kDa and exhibited substrate specificity against Z-Phe-Arg-AMC with specific activity of no less than 85 081 U/mg, characteristic of active CTSL. Although eukaryotic purified CTSL is commercially available, our study for the first time reported the details of the expression, purification, and characterization of active, recombinant CTSL in eukaryocyte system, which laid an experimental foundation for the establishment of high-throughput screening model for anti-coronavirus drugs targeting CTSL.
Inhibition of melanoma cell proliferation by strobilurins isolated from mushrooms and their synthetic analogues
Authors: Tanaka Tomoya , Takahashi Kenji , Inoue Yuki , Endo Naoki , Shimoda Emiko , Ueno Kotomi , Ichiyanagi Tsuyoshi , Ohta Toshio , Ishihara Atsushi
Published: January 2024

Strobilurins A and X, isolated from Mucidula venosolamellata culture extracts, demonstrated potent inhibition of human melanoma G-361 cell proliferation. Strobilurin X exhibited milder inhibitory effects on human fibroblast cells (NB1RGB) compared to strobilurin A. Additional strobilurin-related compounds were isolated from the other mushroom species. Oudemansins A and B displayed weaker activities on G-361 cells than strobilurins A and B, respectively, emphasizing the importance of a conjugated double-bond structure. Among isolated compounds, strobilurin G showed the lowest IC50 value for G-361 cells. Additional strobilurins bearing various substituents on the benzene ring were synthesized. Synthetic intermediates lacking the methyl β-methoxyacrylate group and a strobilurin analogue bearing modified β-methoxyacrylate moiety showed almost no inhibitory activity against G-361 cells. The introduction of long or bulky substituents at the 4′ position of the benzene ring of strobilurins enhanced the activity and selectivity, suggesting differential recognition of the benzene ring by G-361 and NB1RGB cells.
epidecodeR: a functional exploration tool for epigenetic and epitranscriptomic regulation
Authors: Joshi Kandarp , Wang Dan O
Published: January 2024

Recent technological advances in sequencing DNA and RNA modifications using high-throughput platforms have generated vast epigenomic and epitranscriptomic datasets whose power in transforming life science is yet fully unleashed. Currently available in silico methods have facilitated the identification, positioning and quantitative comparisons of individual modification sites. However, the essential challenge to link specific ‘epi-marks’ to gene expression in the particular context of cellular and biological processes is unmet. To fast-track exploration, we generated epidecodeR implemented in R, which allows biologists to quickly survey whether an epigenomic or epitranscriptomic status of their interest potentially influences gene expression responses. The evaluation is based on the cumulative distribution function and the statistical significance in differential expression of genes grouped by the number of ‘epi-marks’. This tool proves useful in predicting the role of H3K9ac and H3K27ac in associated gene expression after knocking down deacetylases FAM60A and SDS3 and N6-methyl-adenosine-associated gene expression after knocking out the reader proteins. We further used epidecodeR to explore the effectiveness of demethylase FTO inhibitors and histone-associated modifications in drug abuse in animals. epidecodeR is available for downloading as an R package at https://bioconductor.riken.jp/packages/3.13/bioc/html/epidecodeR.html.
High-throughput mRNA-seq atlas of human placenta shows vast transcriptome remodeling from first to third trimester
Authors: Gonzalez Tania L , Wertheimer Sahar , Flowers Amy E , Wang Yizhou , Santiskulvong Chintda , Clark Ekaterina L , Jefferies Caroline A , Lawrenson Kate , Chan Jessica L , Joshi Nikhil V , Zhu Yazhen , Tseng Hsian-Rong , Karumanchi S Ananth , Williams III John , Pisarska Margareta D
Published: January 2024

The placenta, composed of chorionic villi, changes dramatically across gestation. Understanding differences in ongoing pregnancies are essential to identify the role of chorionic villi at specific times in gestation and develop biomarkers and prognostic indicators of maternal–fetal health. The normative mRNA profile is established using next-generation sequencing of 124 first trimester and 43 third trimester human placentas from ongoing healthy pregnancies. Stably expressed genes (SEGs) not different between trimesters and with low variability are identified. Differential expression analysis of first versus third trimester adjusted for fetal sex is performed, followed by a subanalysis with 23 matched pregnancies to control for subject variability using the same genetic and environmental background. Placenta expresses 14,979 polyadenylated genes above sequencing noise (transcripts per million > 0.66), with 10.7% SEGs across gestation. Differentially expressed genes (DEGs) account for 86.7% of genes in the full cohort [false discovery rate (FDR) < 0.05]. Fold changes highly correlate between the full cohort and subanalysis (Pearson = 0.98). At stricter thresholds (FDR < 0.001, fold change > 1.5), there remains 50.1% DEGs (3353 upregulated in first and 4155 upregulated in third trimester). This is the largest mRNA atlas of healthy human placenta across gestation, controlling for genetic and environmental factors, demonstrating substantial changes from first to third trimester in chorionic villi. Specific differences and SEGs may be used to understand the specific role of the chorionic villi throughout gestation and develop first trimester biomarkers of placental health that transpire across gestation, which can be used for future development of biomarkers for maternal–fetal health.
Bearing Witness: The Impact of Lived Experience Educators Participating in Social Work Student Supervision during Placement
Authors: Duncanson Kate , Kingston Phoebe , Tran Patricia , Blundell Barbara , Gillieatt Sue , Mahboub Lyn , Martin Robyn
Published: January 2024

Social work student supervision during field education is a mandated requirement where students review their activities and learning in the workplace with field educators (FEs). Inevitably service users will be discussed in supervision but will have little or no opportunity to represent their perspectives during sessions. In order to explore how service user perspectives might be integrated into supervision, this qualitative study examined the participation of two Lived Experience Educators in supervision sessions between six social work students and their FEs during final placement. Despite some initial trepidation, participants reported a significant and overwhelmingly positive impact based on more equalised power differentials, greater depth of reflection and the emergence of new ideas on increasing accountability to service users. These results have implications for the practice of supervision, with both students and staff, and for how people with lived experience expertise may contribute to improving service culture for the intended beneficiaries of social work services.
A Common Purpose? Social Work Students’ Social Justice Related Views in Finland and the island of Ireland
Authors: McFadden Paula , Bloomberg Helena , Kallio Johanna , Kroll Christian , McCartan Claire , Flanagan Niamh , Kirwin Gloria , Pentaraki Maria , Wilson Elaine
Published: January 2024

Exploring social work students’ views to understand how equipped they are to pursue the social justice mission of the profession should be of central academic and practical interest. There are, however, surprisingly few empirical studies focussing on social work students’ views on social justice-related issues from a comparative viewpoint. Such knowledge is thought to be of a wider international interest from a number of perspectives, including social work education and student exchange and, in a wider context, for the development of social work as a profession and for discussing the prerequisites for shared international notions of social work. This article explores the views of social work students studying in different socio-economic contexts and welfare regimes in relation to some key aspects assumed to be vital for the profession. The results based on survey data from student cohorts in Finland (N = 608) and the island of Ireland (N = 279) support the general conclusion that there are important, similar patterns of motivations and understandings amongst the students, despite substantial differences in histories, welfare state developments, current policies and social conditions in various jurisdictions. The results are of interest to educators across countries internationally and provide an important basis for future similar studies.
TRIM14 suppressed the progression of NSCLC via hexosamine biosynthesis pathway
Authors: Wei Sisi , Ai Meiling , Zhan Yuan , Yu Jieqing , Xie Tao , Hu Qinghua , Fang Yang , Huang Xuan , Li Yong
Published: January 2024

Tripartite Motif 14 (TRIM14) is an oncoprotein that belongs to the E3 ligase TRIM family, which is involved in the progression of various tumors except for non-small cell lung carcinoma (NSCLC). However, little is currently known regarding the function and related mechanisms of TRIM14 in NSCLC. Here, we found that the TRIM14 protein was downregulated in lung adenocarcinoma tissues compared with the adjacent tissues, which can suppress tumor cell proliferation and migration both in vitro and in vivo. Moreover, TRIM14 can directly bind to glutamine fructose-6-phosphate amidotransferase 1 (GFAT1), which in turn results in the degradation of GFAT1 and reduced O-glycosylation levels. GFAT1 is a key enzyme in the rate-limiting step of the hexosamine biosynthetic pathway (HBP). Replenishment of N-acetyl-d-glucosamine can successfully reverse the inhibitory effect of TRIM14 on the NSCLC cell growth and migration as expected. Collectively, our data revealed that TRIM14 suppressed NSCLC cell proliferation and migration through ubiquitination and degradation of GFAT1, providing a new regulatory role for TRIM14 on HBP.
Towards improving community detection in complex networks using influential nodes
Authors: Zheng Henghe , Zhao Haitao , Ahmadi Gholamreza
Published: January 2024

Complex network analysis is inspired by empirical studies of real-world networks such as computer networks, technology networks and social networks. The analysis of community structure in complex networks is understood as an important issue by the research society. A community is a set of nodes in a network where the density of connections is high. The insight in the literature shows many approaches to identify influential nodes, but these approaches only lead to finding community centres. Meanwhile, clustering techniques are effectively used for community detection, where they can reveal group structure and hidden connections by considering topological and demographic information. This article presents an ensemble clustering algorithm based on influential nodes to improve community detection in complex networks. Considering different characteristics of the network, the proposed method seeks to discover common interests between users and their behaviours to identify the most suitable communities. First, a set of influential nodes are identified as community centres. Then, these centres are considered as cluster centres. After that, primary clusters are created based on the determined centres. Finally, the primary clusters are reclustered to form the final clusters. Here, the final clusters are considered as communities of users in the network. The simulation has been performed on real-world networks and the results confirm the effectiveness of the proposed method. Specifically, the communities identified by the proposed method are 2.1% better than the best existing state-of-the-art method in terms of modularity. Keywords: complex network; community detection; influential nodes; ensemble clustering.
Why is early-onset atrial fibrillation uncommon in patients with Duchenne muscular dystrophy? Insights from the mdx mouse
Authors: Nguyen My-Nhan , Hooper Charlotte , Stefanini Matilde , Vrellaku Besarte , Carnicer Ricardo , Wood Matthew J , Simon Jillian N , Casadei Barbara
Published: January 2024

Aims

A reduction in both dystrophin and neuronal nitric oxide synthase (NOS1) secondary to microRNA-31 (miR-31) up-regulation contributes to the atrial electrical remodelling that underpins human and experimental atrial fibrillation (AF). In contrast, patients with Duchenne muscular dystrophy (DMD), who lack dystrophin and NOS1 and, at least in the skeletal muscle, have raised miR-31 expression, do not have increase susceptibility to AF in the absence of left ventricular (LV) dysfunction. Here, we investigated whether dystrophin deficiency is also associated with atrial up-regulation of miR-31, loss of NOS1 protein, and increased AF susceptibility in young mdx mice.

Methods and results

Echocardiography showed normal cardiac structure and function in 12–13 weeks mdx mice, with no indication by assay of hydroxyproline that atrial fibrosis had developed. The absence of dystrophin in mdx mice was accompanied by an overall reduction in syntrophin and a lower NOS1 protein content in the skeletal muscle and in the left atrial and ventricular myocardium, with the latter occurring alongside reduced Nos1 transcript levels (exons 1–2 by quantitative polymerase chain reaction) and an increase in NOS1 polyubiquitination [assessed using tandem polyubiquitination pulldowns; P < 0.05 vs. wild type (WT)]. Neither the up-regulation of miR-31 nor the substantial reduction in NOS activity observed in the skeletal muscle was present in the atrial tissue of mdx mice. At difference with the skeletal muscle, the mdx atrial myocardium showed a reduction in the constitutive NOS inhibitor, caveolin-1, coupled with an increase in NOS3 serine1177 phosphorylation, in the absence of differences in the protein content of other NOS isoforms or in the relative expression NOS1 splice variants. In line with these findings, transoesophageal atrial burst pacing revealed no difference in AF susceptibility between mdx mice and their WT littermates.

Conclusion

Dystrophin depletion is not associated with atrial miR-31 up-regulation, reduced NOS activity, or increased AF susceptibility in the mdx mouse. Compared with the skeletal muscle, the milder atrial biochemical phenotype may explain why patients with DMD do not exhibit a higher prevalence of atrial arrhythmias despite a reduction in NOS1 content.
Long-term simulated microgravity fosters carotid aging-like changes via Piezo1
Authors: Zhang Jiaxin , Wang Xinpei , Fu Zihao , Xing Changyang , Wang Zhen , Yang Hongyan , Li Jiahui , Liu Meijie , Dong Ling , Zhang Xing , Li Yongzhi , Wang Jiaping , Long Jiangang , Liu Jiankang , Wang Shengpeng , Li Jia , Gao Feng
Published: January 2024

Aims

Elucidating the impacts of long-term spaceflight on cardiovascular health is urgently needed in face of the rapid development of human space exploration. Recent reports including the NASA Twins Study on vascular deconditioning and aging of astronauts in spaceflight are controversial. The aims of this study were to elucidate whether long-term microgravity promotes vascular aging and the underlying mechanisms.

Methods and results

Hindlimb unloading (HU) by tail suspension was used to simulate microgravity in rats and mice. The dynamic changes of carotid stiffness in rats during 8 weeks of HU were determined. Simulated microgravity led to carotid artery aging-like changes as evidenced by increased stiffness, thickness, fibrosis, and elevated senescence biomarkers in the HU rats. Specific deletion of the mechanotransducer Piezo1 in vascular smooth muscles significantly blunted these aging-like changes in mice. Mechanistically, mechanical stretch-induced activation of Piezo1 elevated microRNA-582-5p in vascular smooth muscle cells, with resultant enhanced synthetic cell phenotype and increased collagen deposition via PTEN/PI3K/Akt signalling. Importantly, inhibition of miRNA-582-5p alleviated carotid fibrosis and stiffness not only in HU rats but also in aged rats.

Conclusions

Long-term simulated microgravity induces carotid aging-like changes via the mechanotransducer Piezo1-initiated and miRNA-mediated mechanism.
Toxigenic Clostridium perfringens Isolated from At-Risk Paediatric Inflammatory Bowel Disease Patients
Authors: Kuo James , Uzunovic Jasmina , Jacobson Amanda , Dourado Michelle , Gierke Sarah , Rajendram Manohary , Keilberg Daniela , Mar Jordan , Stekol Emily , Curry Joanna , Verstraete Sofia , Lund Jessica , Liang Yuxin , Tamburini Fiona B , Omattage Natalie S , Masureel Matthieu , Rutherford Steven T , Hackos David H , Tan Man-Wah , Byrd Allyson L , Keir Mary E , Skippington Elizabeth , Storek Kelly M
Published: January 2024

Background and Aims

This study aimed to identify microbial drivers of inflammatory bowel disease [IBD], by investigating mucosal-associated bacteria and their detrimental products in IBD patients.

Methods

We directly cultured bacterial communities from mucosal biopsies from paediatric gastrointestinal patients and examined for pathogenicity-associated traits. Upon identifying Clostridium perfringens as toxigenic bacteria present in mucosal biopsies, we isolated strains and further characterized toxicity and prevalence.

Results

Mucosal biopsy microbial composition differed from corresponding stool samples. C. perfringens was present in eight of nine patients’ mucosal biopsies, correlating with haemolytic activity, but was not present in all corresponding stool samples. Large IBD datasets showed higher C. perfringens prevalence in stool samples of IBD adults [18.7–27.1%] versus healthy controls [5.1%]. In vitro, C. perfringens supernatants were toxic to cell types beneath the intestinal epithelial barrier, including endothelial cells, neuroblasts, and neutrophils, while the impact on epithelial cells was less pronounced, suggesting C. perfringens may be particularly damaging when barrier integrity is compromised. Further characterization using purified toxins and genetic insertion mutants confirmed perfringolysin O [PFO] toxin was sufficient for toxicity. Toxin RNA signatures were found in the original patient biopsies by PCR, suggesting intestinal production. C. perfringens supernatants also induced activation of neuroblast and dorsal root ganglion neurons in vitro, suggesting C. perfringens in inflamed mucosal tissue may directly contribute to abdominal pain, a frequent IBD symptom.

Conclusions

Gastrointestinal carriage of certain toxigenic C. perfringens may have an important pathogenic impact on IBD patients. These findings support routine monitoring of C. perfringens and PFO toxins and potential treatment in patients.
Impact of atherosclerosis imaging-quantitative computed tomography on diagnostic certainty, downstream testing, coronary revascularization, and medical therapy: the CERTAIN study
Authors: Nurmohamed Nick S , Cole Jason H , Budoff Matthew J , Karlsberg Ronald P , Gupta Himanshu , Sullenberger Lance E , Quesada Carlos G , Rahban Habib , Woods Kevin M , Uzzilia Jeffrey R , Purga Scott L , Aquino Melissa , Hoffmann Udo , Min James K , Earls James P , Choi Andrew D
Published: January 2024

Aims

The incremental impact of atherosclerosis imaging-quantitative computed tomography (AI-QCT) on diagnostic certainty and downstream patient management is not yet known. The aim of this study was to compare the clinical utility of the routine implementation of AI-QCT versus conventional visual coronary CT angiography (CCTA) interpretation.

Methods and results

In this multi-centre cross-over study in 5 expert CCTA sites, 750 consecutive adult patients referred for CCTA were prospectively recruited. Blinded to the AI-QCT analysis, site physicians established patient diagnoses and plans for downstream non-invasive testing, coronary intervention, and medication management based on the conventional site assessment. Next, physicians were asked to repeat their assessments based upon AI-QCT results. The included patients had an age of 63.8 ± 12.2 years; 433 (57.7%) were male. Compared with the conventional site CCTA evaluation, AI-QCT analysis improved physician’s confidence two- to five-fold at every step of the care pathway and was associated with change in diagnosis or management in the majority of patients (428; 57.1%; P < 0.001), including for measures such as Coronary Artery Disease-Reporting and Data System (CAD-RADS) (295; 39.3%; P < 0.001) and plaque burden (197; 26.3%; P < 0.001). After AI-QCT including ischaemia assessment, the need for downstream non-invasive and invasive testing was reduced by 37.1% (P < 0.001), compared with the conventional site CCTA evaluation. Incremental to the site CCTA evaluation alone, AI-QCT resulted in statin initiation/increase an aspirin initiation in an additional 28.1% (P < 0.001) and 23.0% (P < 0.001) of patients, respectively.

Conclusion

The use of AI-QCT improves diagnostic certainty and may result in reduced downstream need for non-invasive testing and increased rates of preventive medical therapy.
Accuracy of diagnostic tests for acute diverticulitis that are feasible in primary care: a systematic review and meta-analysis
Authors: Vijfschagt Natasja D , de Boer Michiel R , Berger Marjolein Y , Burger Huibert , Holtman Gea A
Published: January 2024

Background

Recognition of acute diverticulitis is important to determine an adequate management strategy. Differentiating it from other gastrointestinal disorders is challenging as symptoms overlap. Clinical tests might assist the clinician with this diagnostic challenge. Previous reviews have focussed on prognostic questions and imaging examinations in secondary care.

Objective

To evaluate the diagnostic accuracy of clinical tests feasible in primary care for acute diverticulitis in suspected patients.

Method

We have systematically searched multiple databases for diagnostic accuracy studies of tests feasible in primary care compared to a reference standard in suspected patients. Two reviewers independently selected studies, extracted data, and assessed study quality with the QUADAS-2 tool. We have meta-analysed the results in the case of more than four studies per index test.

Results

Seventeen studies were included, all studies were performed in secondary care (median prevalence 48%). Individual signs and symptoms showed a wide range in sensitivity (range 0.00–0.98) and specificity (range 0.08–1.00). Of the four laboratory tests evaluated, CRP >10 mg/l had the highest sensitivity (range 0.89–0.96) with specificity ranging from 0.28 to 0.61. Ultrasound had the highest pooled sensitivity and specificity of 0.92 (95% CI 0.86–0.96) and 0.94 (95% CI 0.88–0.97), respectively.

Conclusion

None of the studies were performed in primary care. Individual signs and symptoms alone are insufficiently informative for acute diverticulitis diagnosis. CRP showed potential for ruling out and ultrasound had a high diagnostic accuracy. More research is needed about the diagnostic accuracy of these tests in primary care.

PROSPERO registration number

CRD42021230622
Mill and Landbase Attributes Condition Response Rates to Timber Product Output Surveys in the Western United States
Authors: Affleck David L R , Gaines George C
Published: January 2024

Since the 1940s, the USDA Forest Service has surveyed roundwood receiving facilities to report on timber products output (TPO). The TPO program provides information on forest removals, processing capacity, and wood product markets, complementing inventory estimates of status and change. The program adopted an annual state-level probability sampling design in 2019 and this research evaluates rates of unit nonresponse (UN) in surveys of eleven western states over reference years 2019–2021. The overall response rate for this region and period was 43.7%, which appears low relative to prior western surveys. Response rates also differed significantly by state, facility type, and facility size class. Furthermore, distributions of forestland ownership and harvest levels over potential facility feedstock areas differed significantly between respondents and nonrespondents for an important class of large sawmills. Taken together, these results suggest UN is substantially degrading the precision of western TPO surveys and may be inducing appreciable bias in current estimators. At the same time, response rates were significantly higher where responses were obtained in previous years, suggesting a positive facilitation effect. The implications of these rates and patterns in UN for TPO survey design and estimation are discussed.

Study Implications: The USDA Forest Service estimates timber products output (TPO) from US forests using sample surveys of roundwood receiving facilities. In TPO samples of western states for the period 2019–2021, the average response rate was only 43.7%. The level of unit nonresponse will substantially degrade the precision of TPO estimates at state and regional levels, while the observed patterns may induce bias. Further research is needed to identify the bias and precision of current and alternative estimators and to investigate survey implementation factors or design enhancements that would allow more intensive follow-up efforts to focus on a smaller number of nonrespondents.
The unfolded protein response of the endoplasmic reticulum protects Caenorhabditis elegans against DNA damage caused by stalled replication forks
Authors: Xu Jiaming , Sabatino Brendil , Yan Junran , Ermakova Glafira , Doering Kelsie R S , Taubert Stefan
Published: January 2024

All animals must maintain genome and proteome integrity, especially when experiencing endogenous or exogenous stress. To cope, organisms have evolved sophisticated and conserved response systems: unfolded protein responses (UPRs) ensure proteostasis, while DNA damage responses (DDRs) maintain genome integrity. Emerging evidence suggests that UPRs and DDRs crosstalk, but this remains poorly understood. Here, we demonstrate that depletion of the DNA primases pri-1 or pri-2, which synthesize RNA primers at replication forks and whose inactivation causes DNA damage, activates the UPR of the endoplasmic reticulum (UPR-ER) in Caenorhabditis elegans, with especially strong activation in the germline. We observed activation of both the inositol-requiring-enzyme 1 (ire-1) and the protein kinase RNA-like endoplasmic reticulum kinase (pek-1) branches of the (UPR-ER). Interestingly, activation of the (UPR-ER) output gene heat shock protein 4 (hsp-4) was partially independent of its canonical activators, ire-1 and X-box binding protein (xbp-1), and instead required the third branch of the (UPR-ER), activating transcription factor 6 (atf-6), suggesting functional redundancy. We further found that primase depletion specifically induces the (UPR-ER), but not the distinct cytosolic or mitochondrial UPRs, suggesting that primase inactivation causes compartment-specific rather than global stress. Functionally, loss of ire-1 or pek-1 sensitizes animals to replication stress caused by hydroxyurea. Finally, transcriptome analysis of pri-1 embryos revealed several deregulated processes that could cause (UPR-ER) activation, including protein glycosylation, calcium signaling, and fatty acid desaturation. Together, our data show that the (UPR-ER), but not other UPRs, responds to replication fork stress and that the (UPR-ER) is required to alleviate this stress.
Challenges and approaches to calibrating patient phenotype as evidence for cancer gene variant classification under ACMG/AMP guidelines
Authors: Fortuno Cristina , Michailidou Kyriaki , Parsons Michael , Dolinsky Jill S , Pesaran Tina , Yussuf Amal , Mester Jessica L , Hruska Kathleen S , Hiraki Susan , O’Connor Robert , Chan Raymond C , Kim Serra , Tavtigian Sean V , Goldgar David , James Paul A , Spurdle Amanda B
Published: January 2024

Since first publication of the American College of Medical Genetics and Genomics/Association for Medical Pathology (ACMG/AMP) variant classification guidelines, additional recommendations for application of certain criteria have been released (https://clinicalgenome.org/docs/), to improve their application in the diagnostic setting. However, none have addressed use of the PS4 and PP4 criteria, capturing patient presentation as evidence towards pathogenicity. Application of PS4 can be done through traditional case–control studies, or “proband counting” within or across clinical testing cohorts. Review of the existing PS4 and PP4 specifications for Hereditary Cancer Gene Variant Curation Expert Panels revealed substantial differences in the approach to defining specifications. Using BRCA1, BRCA2 and TP53 as exemplar genes, we calibrated different methods proposed for applying the “PS4 proband counting” criterion. For each approach, we considered limitations, non-independence with other ACMG/AMP criteria, broader applicability, and variability in results for different datasets. Our findings highlight inherent overlap of proband-counting methods with ACMG/AMP frequency codes, and the importance of calibration to derive dataset-specific code weights that can account for potential between-dataset differences in ascertainment and other factors. Our work emphasizes the advantages and generalizability of logistic regression analysis over simple proband-counting approaches to empirically determine the relative predictive capacity and weight of various personal clinical features in the context of multigene panel testing, for improved variant interpretation. We also provide a general protocol, including instructions for data formatting and a web-server for analysis of personal history parameters, to facilitate dataset-specific calibration analyses required to use such data for germline variant classification.
PMAT: an efficient plant mitogenome assembly toolkit using low-coverage HiFi sequencing data
Authors: Bi Changwei , Shen Fei , Han Fuchuan , Qu Yanshu , Hou Jing , Xu Kewang , Xu Li-an , He Wenchuang , Wu Zhiqiang , Yin Tongming
Published: January 2024

Complete mitochondrial genomes (mitogenomes) of plants are valuable resources for nucleocytoplasmic interactions, plant evolution, and plant cytoplasmic male sterile line breeding. However, the complete assembly of plant mitogenomes is challenging due to frequent recombination events and horizontal gene transfers. Previous studies have adopted Illumina, PacBio, and Nanopore sequencing data to assemble plant mitogenomes, but the poor assembly completeness, low sequencing accuracy, and high cost limit the sampling capacity. Here, we present an efficient assembly toolkit (PMAT) for de novo assembly of plant mitogenomes using low-coverage HiFi sequencing data. PMAT has been applied to the de novo assembly of 13 broadly representative plant mitogenomes, outperforming existing organelle genome assemblers in terms of assembly accuracy and completeness. By evaluating the assembly of plant mitogenomes from different sequencing data, it was confirmed that PMAT only requires 1× HiFi sequencing data to obtain a complete plant mitogenome. The source code for PMAT is available at https://github.com/bichangwei/PMAT. The developed PMAT toolkit will indeed accelerate the understanding of evolutionary variation and breeding application of plant mitogenomes.
Allele-specific DNA methylation and gene expression during shoot organogenesis in tissue culture of hybrid poplar
Authors: Guo Ying , Feng Yang-Fan , Yang Gang-Gui , Jia Yan , He Jie , Wu Ze-Yu , Liao Hao-Ran , Wei Qi-Xuan , Xue Liang-Jiao
Published: January 2024

Plant tissue regeneration is critical for genetic transformation and genome editing techniques. During the regeneration process, changes in epigenetic modifications accompany the cell fate transition. However, how allele-specific DNA methylation in two haplotypes contributes to the transcriptional dynamics during regeneration remains elusive. Here we applied an inter-species hybrid poplar (Populus alba × P. glandulosa cv. 84 K) as a system to characterize the DNA methylation landscape during de novo shoot organogenesis at allele level. Both direct and indirect shoot organogenesis showed a reduction in genome-wide DNA methylation. At gene level, non-expressed genes were hypermethylated in comparison with expressed genes. Among the genes exhibiting significant correlations between levels of DNA methylation and gene expression, the expression patterns of 75% of genes were negatively correlated with DNA methylation in the CG context, whereas the correlation patterns in the CHH context were the reverse. The allele-biased DNA methylation was consistent during shoot organogenesis, with fewer than one-thousandth of allele-specific methylation regions shifted. Analysis of allele-specific expression revealed that there were only 1909 genes showing phase-dependent allele-biased expression in the regeneration process, among which the allele pairs with greater differences in transcription factor binding sites at promoter regions exhibited greater differences in allele expression. Our results indicated a relatively independent transcriptional regulation in two subgenomes during shoot organogenesis, which was contributed by cis-acting genomic and epigenomic variations.
Climate Change and the Modern Slavery Conundrum in Africa: Reimagining the Relevance of Human Rights Law
Authors: Ogunniyi Daniel
Published: January 2024

Although climate change is among the main ecological crisis the world is grappling with today, relevant discourses on the subject often focus exclusively on the existential threats it presents ignoring other associated risks, including how it exacerbates modern slavery vulnerabilities. Despite already constituting a major human rights challenge, climate change promises to further exacerbate the modern slavery conundrum in Africa. Thus, in this paper, two interconnected questions are engaged with. Firstly, the climate crisis is interrogated vis-à-vis the way it induces modern slavery vulnerabilities in Africa and undermines human rights. The second aspect assesses the utility of the human rights framework in climate change action and its potential to protect modern slavery victims. While African countries are obligated to implement mitigation and adaptation strategies within their jurisdictions, to effectively address the modern slavery challenge, the paper suggests a stronger focus on global climate action via international cooperation and debt-for-nature swap.
A NOVEL MOUSE MODEL OF CROHN’S DISEASE DRIVEN BY THE INTERACTION OF CD4 T CELLS AND GUT MICROBIOTA-RESPONSIVE γδ T CELLS
Authors: Anderson Nicole , Olson Matthew
Published: January 2024

Inflammatory bowel disease (IBD) is a spectrum of disorders, namely Crohn’s Disease (CD) and Ulcerative Colitis (UC), characterized by distinct patterns of intestinal inflammation, a dysregulated intestinal immune response, and an altered gut microbiota. Given the growing number of new IBD diagnoses (70,000 new cases reported each year) and the inconsistent results of current treatment options, there is a major unmet need to understand IBD pathophysiology to develop more effective treatments. Previous reports indicate that IBD patients have an altered gut microbiota that can influence the development of inflammatory innate and adaptive immune cells that cause intestinal tissue damage and drive IBD pathogenesis. In particular, innate-like γδ T cells have been shown to accumulate within lesional tissue of CD patients and exhibit an inflammatory profile. However, the role of γδ T cells in promoting CD is not well understood, partially due to a lack of mouse models that accurately mimic human γδ T cell phenotypes. Thus, there is a critical need to more deeply understand conventional-γδ cross-talk in the intestine and develop novel animal models that accurately recapitulate these interactions during disease.

We have previously shown that the transcription factors (TFs) STAT3 and BATF play critical roles in pathogenic CD4 T cell differentiation, but their roles in modulating interactions between adaptive and innate-like T cells are less clear. In our preliminary work, we surprisingly found that mice with conventional T cell-specific deletions in STAT3 and BATF, but not each individual TF, developed an aggressive spontaneous colitis with pathology that mimics the intestinal damage seen in Crohn’s disease patients. This spontaneous colitis was hallmarked by elevated numbers of inflammatory (i.e., high IFN-γ producing) γδ T cells in the intestines, which mimic those found in a subset of IBD patients. Importantly, depletion of γδ T cells in this model resulted in diminished disease, implicating these cells as key mediators of CD-like intestinal inflammation. γδ T cells in our model were largely localized between colonic crypts and in close proximity to the gut microbiota, suggesting that they may be influenced by changes in gut microbes. Indeed, we observed that STAT3/BATF-deficient mice exhibited an altered gut microbiota which was required for the dysregulated γδ T cell response. Taken together, our data indicate that STAT3/BATF-expressing conventional CD4 T cells regulate gut microbes that would otherwise drive the generation of inflammatory γδ T cells that contribute to CD-like disease. Therefore, a better understanding of microbe-γδ T cell interactions is imperative for understanding intestinal homeostasis and for defining therapies that may prevent the onset of IBD.

Figure 1 Graphical abstract. This project seeks to identify the interactions between T cells and gut microbiota in driving IBD, more specifically Crohn’s disease.
EVALUATING THE PRE-CLINICAL EFFICACY OF VT1021 (A CLINICAL STAGE DRUG CANDIDATE) IN MULTIPLE EXPERIMENTAL MODELS OF INFLAMMATORY BOWEL DISEASE
Authors: Wang Suming , Clossey Donna , Zota Victor , Li Wendy , Chen Jenny , Cieslewicz Michael , Watnick Randolph , Mahoney Jim , Watnick Jing
Published: January 2024

Inflammatory bowel disease (IBD) is characterized symptomatically by chronic inflammation in the colonic tract. Despite the increased understanding of the physiological symptoms of Crohn’s Disease, and IBD in general, there have been no significant breakthroughs in understanding its etiology or improving treatment. As such, there is an urgent need for efficacious therapies that are aimed specifically at preventing or curing IBD. Bolstering the need for better therapies is the fact that patients with IBD have increased risk of developing intestinal cancers. One of the pathological traits of IBD that heightens the risk of cancer is the increased level of angiogenesis that accompanies the inflammation. As the biological processes of angiogenesis and inflammation are intricately linked, we believe increasing the levels of thrombospondin-1 (TSP-1), an anti-angiogenic and anti-inflammatory protein, can reprogram immune and inflammatory cells to inhibit angiogenesis and induce the resolution of inflammation.

Vigeo has developed VT1021 which stimulates the expression of TSP-1 in inflammatory myeloid derived suppressor cells (MDSCs) systemically. VT1021 achieved proof of concept in a Phase 1/2 clinical trial with multiple cohorts and is currently in Phase 2/3 trials for oncology indications. IBD patients have increased MDSCs in both lesions and peripheral blood. MDSCs are genomically stable and not mutated in IBD patients and thus represent ideal therapeutic targets. Two dextran sulfate sodium (DSS)-induced colitis models were used to evaluate the pre-clinical efficacy of VT1021. In the preventative model, mice were treated with 4% DSS from Day 0 to Day 6 and either saline or VT1021 from Day 0 to Day 8, then sacrificed on Day 8 to collect colon tissue and plasma samples. In the rescue model, mice were treated with 4% DSS from Day 0 to Day 4, then treated with either saline, VT1021 (25, 50, 100 mg/kg) or anti-TNFa from Day 5 to Day 10. Mice were sacrificed on Day 11; colon tissue and plasma samples were collected. In both models, VT1021 treatment significantly prevented the mouse weight loss and bloody stool compared to the saline treatment. VT1021 treatment also decreased the colon inflammation by the measurement of both plasma myeloperoxidase (MPO) level and colon tissue histopathology score. Immunohistochemistry staining of colon tissue samples confirmed that VT1021 treatment stimulated TSP-1 expression in the MDSCs.

Altogether, these findings show that VT1021 treatment has equivalent efficacy to anti-TNFa treatment, while significantly reducing damage to colon tissue. We believe VT1021 will show significantly greater efficacy in patients with longer term use, while avoiding the systemic deleterious side effects common to current approved therapies.
POLYMER-BASED INTERFACE TARGETING INFLAMMATION IN ULCERATIVE COLITIS
Authors: Zhang Sufeng , Jin Amy , Lennerz Jochen , Korzenik Joshua , Traverso Carlo
Published: January 2024

A major hurdle in the treatment of inflammatory bowel disease (IBD) is the lack of effective drug carriers that can precisely deliver the required amount of drug to the sites of inflammation. Available therapies have limited efficacy or severe side effects, largely because of the low concentration of active drugs at the disease sites and non-specific systemic absorption of the administered drugs. Drug delivery targeting the sites of intestinal inflammation offers an approach to maximize therapeutic efficacy while minimizing adverse side effects.

We focus on developing formulations that can provide improved local drug administration in the treatment of ulcerative colitis (UC), one of the two main types of IBD. Targeting sites of inflammation in the gastrointestinal tract can be achieved using drug delivery systems that exploit pathophysiological features of the inflamed intestine. Our previous study showed preferential adhesion of a negatively charged small-molecule-based hydrogel to the inflamed colon in murine models of colitis and biopsies from UC patients; further, a corticosteroid drug delivered by this hydrogel demonstrated an improved efficacy compared to the drug alone. Based on our previous experience, we expanded the small-molecule-based hydrogel to polymer-based hydrogels for enhanced selective targeting. We designed the material so that it has a strong affinity towards ulcers. Through molecular structure design, we functionalized thermo-responsive poly(N-isopropylacrylamide) (PNIPAM)-based polymers to modulate the physicochemical properties of the materials and compared the resultant polymers’ gelation and adhesion to the inflamed colon in dextran sulfate sodium (DSS)-induced colitis in mice. We showed that both the types of chemical modification and polymer molecular weight affected the adhesion of the resultant hydrogels to the inflamed colon. We further quantified the disease parameters of colitis for individual mice and correlated the colitis parameters with polymers’ adhesion. Our study suggests a new strategy for targeting the inflamed colon through harnessing charge-mediated interaction and thermo-responsiveness of PNIPAM-based polymers. By adhering to the inflamed mucosa, our delivery system has the potential to maintain the drug locally at the active ulcer sites where it is needed, thereby minimizing the adverse effects of drugs on the healthy tissue. The examination of these polymeric hydrogels’ mucosal binding provides a further understanding of interactions between the polymers and the biological interface in colitis. These studies were performed in preclinical models of UC that develop colitis similar to human UC, as a prerequisite for future studies.