bluuebunny/crossref_metadata_2025 huggingface dataset:
Exosomal miR-485-3p derived from pancreatic ductal epithelial cells inhibits pancreatic cancer metastasis through targeting PAK1
Authors: Li Mingzhe , Zhou Jiaxin , Zhang Zhengkui , Li Jisong , Wang Feng , Ma Ling , Tian Xiaodong , Mao Zebin , Yang Yinmo
Published: December 2022

Background:

Cell competition is an important feature in pancreatic cancer (PC) progression, but the underlying mechanism remains elusive. This study aims to explore the role of exosomes derived from normal pancreatic ductal epithelial cells involved in PC progression.

Methods:

PC cells and pancreatic stellate cells (PSCs) were treated with exosomes isolated from pancreatic ductal epithelial cells. Cell proliferation was assessed by CCK8 assays. Cell migration and invasion were assessed by Transwell assays. PC and matched adjacent non-tumor tissue specimens were obtained from 46 patients pathologically diagnosed with PC at Peking University First Hospital from 2013 to 2017. Tissue miR-485-3p and p21-activated kinase-1 (PAK1) expression was examined by real-time polymerase chain reaction (RT-PCR), and the relationship of the two was analyzed using Pearman's product-moment correlation. The clinical significance of miR-485-3p was analyzed using the Chi-square test, Wilcoxon rank-sum test, and Fisher exact probability, respectively. The binding of miR-485-3p to PAK1 5′-untranslated region (5′-UTR) was examined by luciferase assay. PC cells were xenografted into nude mice as a PC metastasis model.

Results:

Exosomes from pancreatic ductal epithelial cells suppressed PC cell migration and invasion as well as the secretion and migration of PSCs. MiR-485-3p was enriched in the exosomes of pancreatic ductal epithelial cells but deficient in those of PC cells and PSCs, in accordance with the lower level in PSCs and PC cells than that in pancreatic ductal cells. And the mature miR-485-3p could be delivered into these cells by the exosomes secreted by normal pancreatic duct cells, to inhibit PC cell migration and invasion. Clinical data analysis showed that miR-485-3p was significantly decreased in PC tissues (P < 0.05) and was negatively associated with lymphovascular invasion (P = 0.044). As a direct target of miR-485-3p, PAK1 was found to exert an inhibitory effect on PC cells, and there was a significantly negative correlation between the expression levels of miR-485-3p and PAK1 (r = −0.6525, P < 0.0001) in PC tissues. Moreover, miR-485-3p could suppress PC metastasis in vivo by targeting p21-activated kinase-1.

Conclusions:

Exosomal miR-485-3p delivered by normal pancreatic ductal epithelial cells into PC cells inhibits PC metastasis by directly targeting PAK1. The restoration of miR-485-3p by exosomes or some other vehicle might be a novel approach for PC treatment.
Clinical Characteristics of Basal Cell Carcinomas of the Vulva: An Institutional Retrospective Review
Authors: Muñoz Genevieve , Singla Parteek , Hurst Eva , Council M. Laurin
Published: December 2022

BACKGROUND

There are limited data on the etiology, clinical characteristics, and optimal treatment of vulvar basal cell carcinoma (BCC).

OBJECTIVE

This retrospective review may aid in treatment decisions for vulvar BCC.

MATERIALS AND METHODS

A retrospective review of our institutional CoPath database was performed, using search terms to identify cases of vulvar BCCs from 2000 to 2018.

RESULTS

A total of 35 cases of vulvar BCC were included. Patient age ranged from 33 to 97 years with a mean age of 70 years. Of the 35 cases, 28 (80%) involved the cutaneous vulva, 6 (17%) involved the suprapubic area, and 1 (3%) involved the clitoris. Most vulvar BCCs were treated by wide local excision (46%) and vulvectomies (37%), with 3 cases treated with Mohs (11%) and 2 with electrodesiccation and curettage (6%). Preoperative tumor sizes were 0.86 cm2 for Mohs, 0.94 cm2 for excision, and 1.54 cm2 for vulvectomy. The mean margins were 3 mm for Mohs, 4.4 mm for wide local excision, and 6 mm for vulvectomy. Most cases (77%) were identified and treated by gynecology.

CONCLUSION

Mohs micrographic surgery should be considered for the advantages of being tissue sparing, evaluating the complete peripheral and deep margin, and avoiding the costs and risks of general anesthesia.
Noninvasive Hands-free Bipolar Radiofrequency Facial Remodeling Device for the Improvement of Skin Appearance
Authors: Labadie Jessica G. , Chilukuri Suneel , Cohen Joel , Kilmer Suzanne , Lupo Mary , Rohrich Rod , Dover Jeffrey S.
Published: December 2022

BACKGROUND

Aging is a multifactorial response to genetic preprogramming nuances, sun exposure, and ultraviolet radiation. Recently, there has been a paradigm shift toward minimally invasive rejuvenation.

OBJECTIVE

This prospective multicenter study aims to evaluate the efficacy and safety of a novel hands-free bipolar bulk radiofrequency (RF) device in terms of improvement in skin appearance.

PATIENTS AND METHODS

This multicenter prospective study enrolled subjects aged 35 to 75 years with visible signs of aging. The primary objective was to evaluate skin appearance pretreatment and at 1, 3, and 6 months after the final treatment. Each patient received 3 total treatments to the chin and cheeks using the hands-free RF device spaced 2 weeks apart.

RESULTS

In total, data from 87 patients were assessed from 6 treatment sites. The average age was 54 years (range 35–75 years). Most patients were female (97%), and Fitzpatrick skin types I to V were represented. Overall, patients found the procedures to be relatively pain-free, and both patients and investigators felt they noted some improvement in their skin appearance. Histological sections demonstrated an increase in collagen or elastic fibers within the papillary dermis.

CONCLUSION

This study supports the use of this novel noninvasive hands-free bipolar facial remodeling device for the improvement of skin appearance.
Application of Resuspension Data of Respirable Particles for Early Phase Inhalation Following Deposition Contamination in Radiological Emergencies
Authors: Lange Florentin , Koch Wolfgang
Published: December 2022

In model experiments, wind resuspension rates, Rr, of respirable particles (<10 μm, aerodynamic diameter) and their time dependence after deposition on representatively contaminated urban surfaces were measured under real-life conditions, taking into account different weather conditions (wind velocities, precipitation) as well as countermeasures (fixation). For contamination by dry deposition of particles, short-term resuspension rates averaged over the first half hour,

after exposure to wind with a friction velocity, u*, of 0.8 m s−1 ranged between 0.1% h−1 and 2% h−1 depending on the surface material, whereas after wet deposition, resuspension rates were two orders of magnitude lower. The time pattern of the resuspension rates followed a power law decrease, Rr
∝ t
−μ
, with values of μ close to 1. The measurements revealed a strong dependence on friction velocity,

. For a larger area of 200 × 800 m2 contaminated with 106 Bq m−2 of particles in the respirable size range, applying a simple Gaussian dispersion model airborne activity concentration (Bq m−3) was calculated. On this basis, for an initial time of high windspeed, a cautious resuspension factor of Rf = 5 10−6 m−1 is derived for the first day, which diminishes inversely with time. The exposure of persons to external radiation and to inhaled airborne radioactivity is compared with examples for three radionuclides representing strong beta-, gamma- and alpha-radiation.
Post-traumatic growth in family members of childhood cancer survivors—an updated systematic review
Authors: Halldorsdottir Berglind , Michel Gisela , Baenziger Julia
Published: December 2022

Background:

Childhood cancer affects not only the patients, but their entire family. We systematically reviewed recent evidence of post-traumatic growth (PTG) among family members of childhood cancer survivors (CCS).

Methods:

We updated a systematic review of PTG among family members of CCS (including new evidence from March 2010 to December 2021). We screened 4 databases (PubMed, PsycINFO, CINAHL, and SCOPUS). Key study information and results were extracted for the quality appraisal. We narratively synthesized the evidence for reported levels and domains of PTG in caregivers (aim 1) and siblings (aim 2) and associated sociodemographic and psychosocial characteristics (aim 3) in families of CCS.

Results:

Of the 646 identified articles, 16 met eligibility criteria. Eleven studies used quantitative (all cross-sectional), 3 qualitative, and 2 mixed methods. Participants included parents and other primary caregivers (11 studies), grandparents (1 study), and siblings (5 studies). Most caregivers reported high levels of PTG, most often involving personal growth and stronger/closer family relationships. Siblings reported low-to-moderate PTG, with an emphasis on appreciating life and becoming more independent and mature. While sociodemographic and clinical characteristics were not associated with PTG, psychosocial factors such as personal resources, including social support and coping strategies, were associated with PTG outcomes.

Conclusion:

In the past decade, few studies have assessed PTG among families of CCS despite the call to focus on families in a previous review. We found that social support and proactive coping strategies may be the most helpful in promoting PTG.
The Impact of Exogenous Testosterone on Breast Cancer Risk in Transmasculine Individuals
Authors: Gurrala Rakesh R. , Kumar Taruni , Yoo Aran , Mundinger Gerhard S. , Womac Daniel J. , Lau Frank H.
Published: December 2022

Background

Exogenous testosterone is vital to gender-affirming therapy for transmasculine individuals. Testosterone may be implicated in breast cancer (BCa) because it can activate androgen and estrogen receptors. To further explore this risk, we performed a systematic review to investigate the impact of exogenous testosterone on BCa risk in transmasculine individuals.

Methods

We searched PubMed/MEDLINE and Ovid/Embase for clinical and preclinical studies assessing BCa and testosterone therapy and screened 6125 articles independently. We ascertained level of evidence using a modified tool from Cook et al (Chest. 1992;102:305S–311S) and risk of bias using a modified Joanna Briggs Institute's Critical Appraisal Tool.

Results

Seventy-six studies were included. Epidemiological data suggested that BCa incidence was higher in transmasculine individuals compared with cisgender men but lower compared with cisgender women. Histological studies of transmasculine breast tissue samples also demonstrated a low incidence of precancerous lesions. Interestingly, cases demonstrated that BCa occurred at a younger average age in transmasculine individuals and was predominantly hormone receptor positive. The mechanism for BCa in transmasculine individuals may be related to androgen receptor stimulation or conversion to estradiol. Serum studies reported varied estradiol levels associated with exogenous testosterone. Animal and in vitro studies demonstrated that testosterone was growth inhibitory but may induce proliferation at higher doses or with low estradiol levels.

Conclusions

Plastic surgeons play a critical role in providing gender-affirming care for transmasculine patients. The limited studies available suggest that this patient population has decreased risk for BCa when compared with cisgender women; however, any BCa that does occur may have different clinical presentations and underlying mechanisms compared with cisgender women and men. Overall, the limitations for clinical studies and discrepancies among preclinical studies warrant further investigation.
First Composite Woman-to-Woman Facial Transplantation in Turkey
Authors: Ozmen Selahattin , Findikcioglu Kemal , Sibar Serhat , Tuncer Serhan , Ayhan Suhan , Guz Galip , Unal Yusuf , Aslan Selcuk
Published: December 2022

After the first face transplantation from woman to woman we performed in our clinic, it was aimed to eliminate the lack of knowledge about the subject in the literature by transferring our experiences and long-term results to the problems we had with the patient. A 20-year-old patient underwent partial osteomyocutaneous facial transplant (22nd facial transplant), which included 2 functional units of the face. The patient had no major problems in the early period and had a good aesthetic appearance. In the postoperative period, the patient ended her social isolation and adopted the transplanted face.

In the late period, secondary surgical interventions, management of the problems caused by immunosuppression, and the patient's living in a remote location to our clinic were the difficulties encountered. Six revision surgeries were performed after the transplantation. Due to immunosuppression, opportunistic infections and metabolic problems required intermittent hospitalization. The patient died at the end of 56 months because of complications secondary to immunosuppression.

A successful transplant involves the management of long-term problems rather than a successful tissue transfer in the early period. In today's conditions, long-term success can be achieved with a good patient compliance, as well as each team member should take an active role in the team at the transplantation centers. More case series are needed to adapt the standard treatment and follow-up protocols for solid organ transplantations for composite tissue allotransplantations. This will be possible by sharing the results and experiences transparently in the centers where face transplantation is performed worldwide.
Long-Term Outcomes in Patients With Peripheral Arterial Disease Who Undergo Free Flap Reconstruction for Chronic Lower Extremity Wounds
Authors: Bovill John D. , Huffman Samuel S. , Deldar Romina , Sayyed Adaah A. , Gupta Nisha J. , Truong Brian N. , Bekeny Jenna C. , Attinger Christopher E. , Akbari Cameron N. , Evans Karen K.
Published: December 2022

Background

Free tissue transfer (FTT) is critical for limb salvage of chronic lower extremity (LE) wounds. In patients with peripheral arterial disease (PAD), FTT LE reconstruction can be challenging due to limited vessel selection for anastomosis. The study aims to evaluate our surgical and functional outcomes after FTT to LE in patients with PAD.

Methods

A retrospective review identified patients who underwent LE free flap reconstruction between 2011 and 2021. All patients underwent preoperative arteriogram and subsequent FTT. Patients were classified into PAD or non-PAD cohorts, based on the presence of LE arterial stenoses or occlusions identified on arteriogram. Primary outcomes included complications, flap success, need for post-FTT vascular reintervention, limb salvage, and ambulatory status.

Results

A total of 253 patients underwent FTT to LE, with 84 patients (33.2%) in the PAD cohort. Patients with PAD had a higher prevalence of diabetes (83.3% vs 39.1%,P< 0.001) and end-stage renal disease (8.3% vs 2.4%,P= 0.028). Osteomyelitis was more common in the PAD group (73.8% vs 55.0%,P= 0.004). Free tissue transfer donor sites and flap composition were similar between cohorts. At a mean follow-up of 21.1 months, limb salvage rates were similar between non-PAD and PAD cohorts (90.5% vs 84.5%,P= 0.158), with no significant differences in ambulatory status or mortality. Higher complication rates occurred in the PAD cohort (38.1% vs 20.7%,P= 0.003), of which partial flap necrosis was more prevalent in the PAD group (6.0% vs 0.6%,P= 0.016). There was no difference in flap success rates between groups (P= 0.430). More postflap angiograms were performed in the PAD group (29.8% vs 7.1%,P< 0.001), with repeat percutaneous endovascular intervention performed in 68.0% of the PAD group versus 33.3% of the non-PAD group (P< 0.001).

Conclusions

This is the largest study to demonstrate excellent long-term limb salvage outcomes in patients with PAD who undergo FTT to LE. Percutaneous endovascular intervention and FTT are effective methods to achieve limb salvage in vasculopathic patients with chronic LE wounds.
Pseudorabies virus infection induces endoplasmic reticulum stress and unfolded protein response in suspension-cultured BHK-21 cells
Authors: Chen Li , Ni Minshu , Ahmed Waqas , Xu Yue , Bao Xi , Zhuang Tenghan , Feng Lei , Guo Meijin
Published: December 2022

Viral infections cause endoplasmic reticulum (ER) stress and subsequently unfolded protein response (UPR) which restores ER homeostasis. In this study, levels of proteins or transcription of three UPR pathways were examined in suspension-cultured BHK-21 cells to investigate Pseudorabies virus (PRV) infection-induced ER stress, in which glucose-related proteins 78 kD and 94 kD (GRP78 and GRP94) were upregulated. The downstream double-stranded RNA-activated protein kinase-like ER kinase (PERK) pathway was activated with upregulation of ATF4, CHOP, and GADD34, and the inositol requiring kinase 1 (IRE1) pathway was triggered by the splicing of X box-binding protein 1 (XBP1) mRNA and the enhanced expression of p58IPK and EDEM. Furthermore, our results showed that the ER stress, induced by 0.005 µM thapsigargin, promoted PRV replication in suspension-cultured BHK-21 cells, and that PRV glycoprotein B (gB) overexpression triggered the PERK and IRE1 pathways.
De novoassembly and annotation of the Patagonian toothfish (Dissostichus eleginoides) genome
Authors: Ryder David , Stone David , Minardi Diana , Riley Ainsley , Avant Justin , Cross Lisa , Soeffker Marta , Davidson Deborah , Newman Andrew , Thomson Peter , Darby Chris , van Aerle Ronny
Published: December 2022

Patagonian toothfish (Dissostichus eleginoides) is an economically and ecologically important fish species in the family Nototheniidae, found at depths between 70 and 2,500 meters on the southern shelves and slopes around the sub-Antarctic islands of the Southern Ocean. Genomic sequence data for this species is limited. Here, we report a high-quality assembly and annotation of theD. eleginoidesgenome, generated using a combination of Illumina, PacBio and Omni-C sequencing technologies. To aid the genome annotation, the transcriptome derived from a variety of toothfish tissues was also generated using both short and long read sequencing methods. The final genome assembly was 797.8 Mb with a N50 scaffold length of 3.5 Mb. Approximately 31.7% of the genome consisted of repetitive elements. A total of 35,543 putative protein-coding regions were identified, of which 50% have been functionally annotated. Transcriptomics analysis showed that approximately 64% of the predicted genes (22,617 genes) were found to be expressed in the tissues sampled. Comparative genomics analysis revealed that the anti-freeze glycoprotein (AFGP) locus ofD. eleginoidesdoes not contain any AFGP proteins compared to the same locus in the Antarctic toothfish (Dissostichus mawsoni). This is in agreement with previously published results looking at hybridization signals and confirms that Patagonian toothfish do not possess AFGP coding sequences in their genome. The high-quality genome assembly of the Patagonian toothfish will provide a valuable genetic resource for ecological and evolutionary studies on this and other closely related species.
Zn2+potentiation of OTOP proton channels identifies structural elements of the gating apparatus
Authors: Teng Bochuan , Kaplan Joshua P. , Liang Ziyu , Goldschen-Ohm Marcel , Liman Emily R.
Published: December 2022

Otopetrin proteins (OTOPs) form proton-selective ion channels that are expressed in diverse cell types where they may mediate detection of acids or regulation of pH. In vertebrates there are three family members: OTOP1 is required for formation of otoconia in the vesibular system and it forms the receptor for sour taste, while the functions of OTOP2, and OTOP3 are not yet known. Importantly, the gating mechanisms of any of the OTOP channels are not well-understood, and until recently, it was not even known if the channels were gated. Here we show that Zn2+, as well as other transition metals including copper (Cu2+), potently activate murine OTOP3. Zn2+pre-exposure increases the magnitude of OTOP3 currents to a subsequent acid stimulus by as much as 10-fold. In contrast, OTOP2 currents are insensitive to potentiation by Zn2+. Swapping the extracellular tm 11-12 linker between OTOP3 and OTOP2 was sufficient to eliminate Zn2+potentiation of OTOP3 and confer Zn2+potentiation on OTOP2. We also show that H531 within the tm 11-12 linker is essential for potentiation of OTOP3 by Zn2+, likely by forming part of its binding site. Kinetic modeling of the data is consistent with Zn2+stabilizing the open state of the channel, possibly competing with H+for activation of the channels. These results establish the tm 11-12 linker as part of the gating apparatus of OTOP channels and a target for drug discovery. Zinc is an essential micronutrient and its regulation of OTOP channels will undoubtedly have important physiological sequelae.

Significance Statement

A family of proton-activated H+ion channels was recently identified that includes the sour receptor OTOP1. Here we show that members of the OTOP channel family are differentially sensitive to Zn2+, which strongly activates OTOP3 but not OTOP2. By studying chimeric channels, we identify structural elements in the extracellular linker between transmembrane domains 11-12 that are necessary and sufficient for Zn2+activation of OTOP channels. In addition to the taste system, OTOP channels play important roles in biomineralization in both vertebrate and invertebrates and are expressed in the digestive tract where their expression is a predictor of cancer prognosis. Our identification of the tm 11-12 linker as part of the gating apparatus makes it a promising target for pharmaceutical discovery.
Mechanical resistance of the environment affects root hair growth and nucleus dynamics
Authors: Pereira David , Alline Thomas , Lin Emilie , Asnacios Atef
Published: December 2022

Root hair (RH) cells are important for the growth and survival of seedlings. They favor plant-microbe interactions, nutrients, and water uptake. RH cells increase drastically the surface of exchange of the root system with the surrounding environment. To be able to invade the soil, RH cells have to penetrate a dense and porous medium exhibiting a variety of physical properties. The soil’s physical properties, such as mechanical resistance, impact the growth and survival of plants. Consequently, studying the effect of soil resistance on the growth of RH is essential to improve our understanding of plant growth. Here we investigate the effect of the mechanical resistance of the culture medium on RH-physical and phenotypical parameters such as length, time, and speed of growth. We also analyze the impact of the environment on the positioning, and movement of the nucleus inside the growing cells. To do so, Arabidopsis Thaliana seedlings were cultured in a custom-made microfluidic-like system, in solid media with agar concentrations ranging from 0.5% to 1.25%. We show that the time of growth of RH cells is independent of the mechanical resistance of the surrounding environment, while the RH speed decreases when the mechanical resistance increases. As a consequence, the RH cells are shorter in stiffer environments. Moreover, we show that the speed of the nucleus adapts to the mechanical resistance of the environment and follows the same trend as the average speed of the RH tip. Eventually, during RH growth, the nucleus-to-tip distance was found to decrease when the stiffness of the environment was increased, indicating mechanotransduction from the cell surface to the nucleus.
The first fossil replete ant worker establishes living food storage in the Eocene
Authors: Sawh Indira , Bae Eunice , Camilo Luciana , Lanan Michele , Lucky Andrea , Morais Menezes Henrique , Fiorentino Gianpiero , Sosiak Christine , Khadempour Lily , Barden Phillip
Published: December 2022

Worker specialization extends the behavioral and ecological repertoire of ant colonies. Specialization may relate to colony defense, brood care, foraging, and, in some taxa, storage. Replete workers swell the crop and gaster to store liquid food, which can be accessed by other colony members through trophallaxis. This storage ability, known as repletism, has independently evolved across several ant lineages, but the temporal history of this trait has not yet been investigated. Here, we describe the first fossil replete in the extinct speciesLeptomyrmex neotropicusBaroni Urbani, 1980 preserved in Miocene-age Dominican amber. Together with new evidence of repletism inL. neotropicus’extant sister species,L. relictusBoudinot et al., 2016, we reconstruct the pattern of acquisition and descent in this storage-linked trait. Our ancestral state reconstruction suggests thatLeptomyrmexacquired replete workers in the Eocene and may therefore represent the earliest instance of so-called “honeypot” ants among all known ants, both living and extinct.
Dissecting the Human Leptomeninges at single-cell resolution
Authors: Kearns Nicola , Iatrou Artemis , Flood Danny , De Tissera Sashini , Mullaney Zachary M. , Xu Jishu , Gaiteri Chris , Bennett David A. , Wang Yanling
Published: December 2022

Emerging evidence shows that the meninges conduct essential immune surveillance and immune defense at the brain border, and the dysfunction of meningeal immunity contributes to aging and neurodegeneration. However, no study exists on the molecular properties of cell types within human leptomeninges. Here, we provide the first single nuclei profiling of dissected postmortem leptomeninges from aged individuals. We detect diverse cell types, including unique meningeal endothelial, mural, and fibroblast subtypes. For immune cells, we show that most T cells express CD8 and bear characteristics of tissue-resident memory T cells. We also identify distinct subtypes of border-associated macrophages (BAMs) that display differential gene expressions from microglia and express risk genes for Alzheimer’s Disease (AD), as nominated by genome-wide association studies (GWAS). We discover cell-type-specific differentially expressed genes in individuals with Alzheimer’s dementia, particularly in fibroblasts and BAMs. Indeed, when cultured, leptomeningeal cells display the signature ofex vivoAD fibroblasts upon amyloid-β treatment. We further explore ligand-receptor interactions within the leptomeningeal niche and computationally infer intercellular communications in AD. Thus, our study establishes a molecular map of human leptomeningeal cell types, providing significant insight into the border immune and fibrotic responses in AD.
Evaluation of the causal associations between brain imaging-derived phenotypes and type 2 diabetes: a bidirectional Mendelian randomization study
Authors: Dong Shan-Shan , Yu Ke , Tang Shi-Hao , Guo Jing , Guo Yan , Yang Tie-Lin
Published: December 2022

OBJECTIVE

To investigate whether the association between brain imaging-derived phenotypes (IDPs) and Type 2 diabetes (T2D) related traits is causal.

DESIGN

Two sample, bidirectional Mendelian randomization study.

SETTING

Genome wide association study (GWAS) summary data taken from various cohorts comprised of the general population (mainly composed of Europeans).

PARTICIPANTS

Summary data were used from previous GWAS. For IDPs, the data included up to 33,224 European individuals from the UK Biobank. For T2D-related traits, the number of participants ranged from 63,396 to 455,313.

MAIN OUTCOME MEASURES

A total of 587 reliable IDPs and five T2D-related traits (T2D, fasting glucose, 2h-glucose post-challenge, glycated hemoglobin, and fasting insulin).

RESULTS

We identified 3 IDPs with potential causal effects on T2D or fasting insulin. For example, we observed that the area of the right rostral middle frontal cortex was negatively associated with the T2D risk (OR = 0.74, 95% CI 0.65 to 0.85,P= 1.31 × 10−5). In addition, we identified potential causal effects of T2D-related traits on 6 IDPs. For example, T2D was negatively associated with the volumes of the right superior frontal gyrus (β = -0.05, 95% CI -0.08 to -0.03,P= 2.17 × 10−5) and the right paracentral lobule (β = -0.05, 95% CI -0.07 to -0.02,P= 1.74 × 10−4).

CONCLUSIONS

Our results revealed strong genetic evidence for the bidirectional causal associations between brain neuroimaging phenotypes and T2D-related traits. This will contribute to better prediction and intervention for the risk of T2D.
An International Consensus Definition for Contextual Factors: Findings from a Nominal Group Technique
Authors: Cook Chad E , Bailliard Antoine , Bent Jennifer , Bialosky Joel , Carlino Elisa , Colloca Luana , Esteves Jorge E , Newell Dave , Palese Alvisa , Reed William R. , Vilardaga Jennifer Plumb , Rossettini Giacomo
Published: December 2022

Emerging literature suggests contextual factors are important components of therapeutic encounters and may substantially influence clinical outcomes of a treatment intervention. At present, a single consensus definition of contextual factors, which is universal across all health-related conditions is lacking. The objective of this study was to create a consensus definition of contextual factors to better refine this concept for clinicians and researchers. The study used a multi-stage virtual Nominal Group Technique (vNGT) to create and rank contextual factor definitions. Nominal group techniques are a form of consensus-based research, and are beneficial for identifying problems, exploring solutions and establishing priorities. The 10 international vNGT participants had a variety of clinical backgrounds and research specializations and were all specialists in contextual factors research. The initial stages of the vNGT resulted in the creation of 14 independent contextual factor definitions. After a prolonged discussion period, the initial definitions were heavily modified, and 12 final definitions were rank ordered by the vNGT participants from first to last. A sixth round was used to identify a final consensus, which reflected the complexity of contextual factors and included three primary domains: 1) an overall definition; 2) qualifiers that serve as examples of the key areas of the definition; and 3) how contextual factors may influence clinical outcomes. Our consensus definition of contextual factors seeks to improve the understanding and communication between clinicians and researchers. These are especially important in recognizing their potential role in moderating/mediating clinical outcomes.
Haemochromatosis genetic variants and musculoskeletal outcomes: 11.5 year follow-up in the UK Biobank cohort study
Authors: Banfield Lucy R , Knapp Karen M , Pilling Luke C , Melzer David , Atkins Janice L
Published: December 2022

Background

The iron overload disorder haemochromatosis is primarily caused by the homozygousHFEp.C282Y variant, but the scale of excess related musculoskeletal morbidity is uncertain.

Methods

We estimated haemochromatosis-genotype associations with clinically diagnosed musculoskeletal outcomes and joint replacement surgeries in the UK Biobank community cohort. 451,143 European ancestry participants (40-70 years at baseline) were followed in hospital records (mean 11.5 years). Cox proportional hazards models estimatedHFEp.C282Y and p.H63D associations with incident outcomes.

Results

Male p.C282Y homozygotes (n=1,294) had increased incidence of osteoarthritis (n=52, HR: 2.12 [95% CI:1.61-2.80]; p=8.8*10-8), hip replacement (n=88, HR:1.84 [95% CI: 1.49-2.27]; p=1.6*10-8), knee replacement (n=61, HR:1.54 [95% CI:1.20-1.98]; p=8.4*10-4), ankle and shoulder replacement, compared to males with noHFEmutations. Cumulative incidence analysis, using Kaplan-Meier lifetable probabilities demonstrated 10.4% of male homozygotes were projected to develop osteoarthritis and 15.5% to have hip replacements by age 75, versus 5.0% and 8.7% respectively without mutations. Male p.C282Y homozygotes also had increased incidence of femoral fractures (n=15, HR:1.72 [95% CI: 1.03-2.87]; p=0.04) and osteoporosis (n=21, HR:1.71 [95% CI: 1.11-2.64, p=0.02), although the latter association was limited to those with liver fibrosis/cirrhosis diagnoses. Female p.C282Y homozygotes had increased incidence of osteoarthritis only (n=57, HR:1.46, [95% CI: 1.12-1.89]; p=0.01). Male p.C282Y/p.H63D compound heterozygotes experienced a modest increased risk of hip replacements (n= 234, HR: 1.17 [95% CI: 1.02–1.33] p=0.02), but this did not pass multiple testing corrections.

Conclusions

In this large community cohort, the p.C282Y homozygote genotype was associated with substantial excess musculoskeletal morbidity in males. WiderHFEgenotype testing may be justified, including in orthopaedic clinics serving higherHFEvariant prevalence populations.

Abstract Figure
Effects of Pod-Based Electronic Cigarette Use on Vascular Health and Relation to Volatile Organic Compound Exposure in Young Adults
Authors: Majid Sana , Fetterman Jessica L. , Weisbrod Robert M. , Behrooz Leili , Stokes Andrew , Blaha Michael J. , Conklin Daniel , Srivastava Sanjay , Robertson Rose Marie , Bhatnagar Aruni , Keith Rachel J. , Hamburg Naomi M.
Published: December 2022

Background

Pod-based electronic cigarettes (e-cigarettes) use that contain nicotine salts is frequent among youth and young adults; thus, we compared the vascular health effects of pod-based e-cigarette use to combustible cigarette use.

Methods and Results

We performed a two center observational, cross-sectional study of healthy adults recruited from the community (aged 18-45, N=106) in 3 groups: pod-based e-cigarette users (N=48); combustible cigarette users (N=21); and tobacco nonusers (N=37) and assessed the acute (following structured use) and chronic (resting state after 6 hour tobacco abstinence) effects of pod-based e-cigarette use on endothelial function (brachial artery flow-mediated dilation), blood pressure, and heart rate. Among the pod-based e-cigarette users, 64% were exclusive users including 37% who had never used combustible cigarettes. Pod-based e-cigarette users and combustible cigarette users had higher systolic blood pressure compared to non-users (121±11mmHg, 121±13mmHg, 112±10 mmHg, P=0.0004). Structured pod-based e-cigarette use acutely decreased flow-mediated dilation (−3.2±2.7%), raised systolic and diastolic blood pressure (6±8mmHg, 4±5mmHg) and heart rate (5±7bpm), similar to combustible cigarette use (−2.6±2.6%, 9±8mmHg, 6±5mmHg, 6±6bpm P=0.83, 0.3, 0.4, 0.56 vs pod-based), and to a greater extent than nonuse (0.3±4.1%, 0.7±5mmHg, 0.3±3mmHg, -3±4bpm, P=1.0x10−7, 0.002, 0.003, 2.6x10−7). Differences remained robust in models adjusted for age, sex, and race. The effect of pod-based cigarette use was similar in adults who had never used combustible cigarettes. Levels of acrolein, acrylamide, acrylonitrile, and crotonaldehyde were associated with the changes in vascular health measures.

Conclusions

Overall, our findings suggest that pod-based e-cigarette use has acute and chronic vascular effects in healthy young adults including those who never used combustible cigarettes. Select metabolites derived from volatile organic compounds were associated with the vascular changes suggesting relevance to vascular health.
A plant virus causes symptoms through the deployment of a host-mimicking protein domain to attract the insect vector
Authors: Gao Man , Aguilar Emmanuel , Garnelo Gómez Borja , Medina-Puche Laura , Fan Pengfei , Ontiveros Irene , Pan Shaojun , Tan Huang , von Roepenack-Lahaye Edda , Chen Na , Wang Xiao-Wei , Baulcombe David C , Bejarano Eduardo R , Díaz-Pendón Juan Antonio , Furutani Masahiko , Morita Miyo Terao , Lozano-Durán Rosa
Published: December 2022

Viruses are obligate intracellular parasites with limited proteomes that heavily rely on the cell molecular machinery for their multiplication and spread. Plant viruses frequently cause symptoms through interference with host developmental programs. Despite the agricultural relevance of symptom development in virus-infected crops, the molecular mechanisms underlying these viral effects remain elusive. Here, we show that the symptoms triggered by tomato yellow leaf curl virus (TYLCV) depend on the physical interaction between the host-mimicking domain of a virus-encoded protein, C4, and a plant-specific family of RCC1-like domain-containing (RLD) proteins. C4 outcompetes endogenous interactors of RLDs, disrupting RLD function in the regulation of endomembrane trafficking and polar auxin transport, ultimately leading to the developmental alterations recognized as symptoms of the viral infection. Importantly, symptoms do not have a detectable effect on the performance of the virus in the plant host, but they serve as attractants for the viral insect vector, the whiteflyBemisia tabaci, hence promoting pathogen spread. Our work uncovers the molecular underpinnings of the viral manipulation that leads to symptom development in the TYLCV-tomato pathosystem, and suggests that symptoms have evolved as a strategy to promote viral transmission by the insect vector. Given that most plant viruses are insect-transmitted, the principles described here might have broad applicability to crop-virus interactions.
Reductive Enzyme Cascades for Valorization of PET Deconstruction Products
Authors: Gopal Madan R. , Dickey Roman M. , Butler Neil D. , Talley Michael R. , Mohapatra Ashlesha , Watson Mary P. , Chen Wilfred , Kunjapur Aditya M.
Published: December 2022

To better incentivize the collection of plastic wastes, new chemical transformations must be developed that add value to plastic deconstruction products. Polyethylene terephthalate (PET) is a common plastic whose deconstruction through chemical or biological means has received much attention. However, a limited number of alternative products have been formed from PET deconstruction, and only a small share could serve as building blocks for alternative materials or therapeutics. Here, we demonstrate the production of useful mono-amine and diamine building blocks from known PET deconstruction products. We achieve this by designing one-pot biocatalytic transformations that are informed by the substrate specificity of an ω-transaminase and diverse carboxylic acid reductases (CAR) towards PET deconstruction products. We first establish that an ω-transaminase fromChromobacterium violaceum(cvTA) can efficiently catalyze amine transfer to potential PET-derived aldehydes to form the mono-aminepara-(aminomethyl)benzoic acid (pAMBA) or the diaminepara-xylylenediamine (pXYL). We then identified CAR orthologs that could perform the bifunctional reduction of TPA to terephthalaldehyde (TPAL) or the reduction ofmono-(2-hydroxyethyl) terephthalic acid (MHET) to its corresponding aldehyde. After characterizing 17 CARsin vitro, we show that the CAR fromSegniliparus rotundus(srCAR) had the highest observed activity on TPA. Given these newly elucidated substrate specificity results, we designed modular enzyme cascades based on coupling srCAR and cvTA in one-pot with enzymatic co-factor regeneration. When we supply TPA, we achieve a 69 ± 1% yield of pXYL, which is useful as a building block for materials. When we instead supply MHET and subsequently perform base-catalyzed ester hydrolysis, we achieve 70 ± 8% yield of pAMBA, which is useful for therapeutic applications and as a pharmaceutical building block. This work expands the breadth of products derived from PET deconstruction and lays the groundwork for eventual valorization of waste PET to higher-value chemicals and materials.

GRAPHICAL ABSTRACT
RNA binding protein PRRC2B mediates translation of specific mRNAs and regulates cell cycle progression
Authors: Jiang Feng , Hedaya Omar M. , Khor EngSoon , Wu Jiangbin , Auguste Matthew , Yao Peng
Published: December 2022

Accumulating evidence suggests that posttranscriptional control of gene expression, including RNA splicing, transport, modification, translation, and degradation, primarily relies on RNA binding proteins (RBPs). However, the functions of many RBPs remain understudied. Here, we characterized the function of a novel RBP, Proline-Rich Coiled-coil 2B (PRRC2B). Through photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation and sequencing (PAR-CLIP-seq), we identified transcriptome-wide CU- or GA-rich PRRC2B binding sites near the translation initiation codon on a specific cohort of mRNAs in HEK293T cells. These mRNAs, including oncogenes and cell cycle regulators such asCCND2(cyclin D2), exhibited decreased translation upon PRRC2B knockdown as revealed by polysome-associated RNA-seq, resulting in reduced G1/S phase transition and cell proliferation. Antisense oligonucleotides blocking PRRC2B interactions withCCND2mRNA decreased its translation, thus inhibiting G1/S transition and cell proliferation. Mechanistically, PRRC2B interactome analysis revealed RNA-independent interactions with eukaryotic translation initiation factors 3 (eIF3) and 4G2 (eIF4G2). The interaction with translation initiation factors is essential for PRRC2B function since the eIF3/eIF4G2-interacting defective mutant, unlike wild-type PRRC2B, failed to rescue the translation deficiency or cell proliferation inhibition caused by PRRC2B knockdown. Altogether, our findings reveal that PRRC2B is essential for efficiently translating specific proteins required for cell cycle progression and cell proliferation.

Graphic Abstract
Heightened efficacy of anidulafungin when used in combination with manogepix or 5-flucytosine againstCandida auris in vitro
Authors: John Larissa L.H. , Thomson Darren D. , Bicanic Tihana , Hoenigl Martin , Brown Alistair J.P. , Harrison Thomas S. , Bignell Elaine
Published: December 2022

Candida aurisis an emerging, multi-drug resistant fungal pathogen that causes refractory colonisation and life-threatening invasive nosocomial infections. The high proportion ofC. aurisisolates that display antifungal resistance severely limits treatment options. Combination therapies provide a possible strategy to enhance antifungal efficacy and prevent the emergence of further resistance. Therefore, we examined drug combinations using antifungals that are already in clinical use or undergoing clinical trials. Using checkerboard assays we screened combinations of 5-flucytosine and manogepix (the active form of the novel antifungal drug fosmanogepix) with anidulafungin, amphotericin B or voriconazole against drug resistant and susceptibleC. aurisisolates from clades I and III. Fractional inhibitory concentration indices (FICI values) of 0.28-0.75 and 0.36-1.02 were observed for combinations of anidulafungin with manogepix or 5-flucytosine, respectively, indicating synergistic activity. The high potency of these anidulafungin combinations was confirmed using live-cell microfluidics-assisted imaging of fungal growth. In summary, combinations of anidulafungin with manogepix or 5-flucytosine show great potential against both resistant and susceptibleC. aurisisolates.
Joint association of daytime sleep behaviors and dietary quality with the risk of dementia: A large prospective cohort study
Authors: Cao Xingqi , Zhang Jingyun , Li Xin , Yang Zhenqing , Sun Kaili , Chen Weiran , Zhu Yubo , Xu Qinglin , Xu Jiahui , He Liu , Li Xueqin , Tan Xiao , Zhang Lisan , Liu Zuyun
Published: December 2022

Background

Identifying modifiable risk factors of dementia is crucial for its early prevention. Daytime sleep behaviors (DSB) and diet are synergetic factors, both potentially important in maintaining cognitive health. However, whether they may jointly influence the risk of dementia in the general population remains unclear.

Methods

This study included 187,078 participants from the UK Biobank. DSB burden (low, medium, and high) was assessed through two questions regarding daytime sleepiness and napping. The Recommended Food Score (RFS) was calculated to assess dietary quality (by tertile). We ascertained incident dementia through linkage to hospital inpatient records. We used Cox proportional hazards regression models to estimate the associations.

Results

During a median follow-up of 10 years, we documented 1,351 cases with incident dementia. Compared with participants with low DSB burden, those with high DSB burden had a 21% (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 1.06, 1.38) higher risk of incident dementia. Dietary quality was negatively associated with dementia risk (HR for tertile 1 versus tertile 3: 1.42; 95% CI: 1.24, 1.63). There was a significant interaction between DSB burden and RFS (P for interaction = 0.027). Compared with participants with low DSB burden & high RFS, those with high DSB burden had higher risks of incident dementia, regardless of RFS level.

Conclusions

High DSB burden and low dietary quality separately or in joint were significantly associated with higher risks of incident dementia, while high DSB burden seems to play a decisive role. Our findings imply that programs targeting the two behavioral factors, particularly the DSB, may help to prevent dementia.
Effectiveness of the Coronavirus Disease 2019 (COVID-19) Bivalent Vaccine
Authors: Shrestha Nabin K. , Burke Patrick C. , Nowacki Amy S. , Simon James F. , Hagen Amanda , Gordon Steven M.
Published: December 2022

Background

The purpose of this study was to evaluate whether a bivalent COVID-19 vaccine protects against COVID-19.

Methods

Employees of Cleveland Clinic in employment when the bivalent COVID-19 vaccine first became available, were included. Cumulative incidence of COVID-19 over the following 26 weeks was examined. Protection provided by vaccination (analyzed as a time-dependent covariate) was evaluated using Cox proportional hazards regression, with change in dominant circulating lineages over time accounted for by time-dependent coefficients. The analysis was adjusted for the pandemic phase when the last prior COVID-19 episode occurred, and the number of prior vaccine doses.

Results

Among 51017 employees, COVID-19 occurred in 4424 (8.7%) during the study. In multivariable analysis, the bivalent vaccinated state was associated with lower risk of COVID-19 during the BA.4/5 dominant (HR, .71; 95% C.I., .63-.79) and the BQ dominant (HR, .80; 95% C.I., .69-.94) phases, but decreased risk was not found during the XBB dominant phase (HR, .96; 95% C.I., .82-.1.12). Estimated vaccine effectiveness (VE) was 29% (95% C.I., 21%-37%), 20% (95% C.I., 6%-31%), and 4% (95% C.I., -12%-18%), during the BA.4/5, BQ, and XBB dominant phases, respectively. Risk of COVID-19 also increased with time since most recent prior COVID-19 episode and with the number of vaccine doses previously received.

Conclusions

The bivalent COVID-19 vaccine given to working-aged adults afforded modest protection overall against COVID-19 while the BA.4/5 lineages were the dominant circulating strains, afforded less protection when the BQ lineages were dominant, and effectiveness was not demonstrated when the XBB lineages were dominant.

Among 51017 working-aged Cleveland Clinic employees, the bivalent COVID-19 vaccine was 29% effective in preventing infection while the BA.4/5 lineages were dominant, and 20% effective while the BQ lineages were. Effectiveness was not demonstrated when the XBB lineages were dominant.