bluuebunny/crossref_metadata_2025 huggingface dataset:
Advanced maternal age leads to changes within the insulin/IGF system and lipid metabolism in the reproductive tract and preimplantation embryo: insights from the rabbit model
Authors: Trohl Juliane , Schindler Maria , Buske Maximilian , de Nivelle Johanna , Toto Nienguesso Alicia , Navarrete Santos Anne
Published: November 2023

Reproductive potential in women declines with age. The impact of ageing on embryo–maternal interactions is still unclear. Rabbits were used as a reproductive model to investigate maternal age-related alterations in reproductive organs and embryos on Day 6 of pregnancy. Blood, ovaries, endometrium, and blastocysts from young (16–20 weeks) and advanced maternal age phase (>108 weeks, old) rabbits were analysed at the mRNA and protein levels to investigate the insulin-like growth factor (IGF) system, lipid metabolism, and stress defence system. Older rabbits had lower numbers of embryos at Day 6 of pregnancy. Plasma insulin and IGF levels were reduced, which was accompanied by paracrine regulation of IGFs and their receptors in ovaries and endometrium. Embryos adapted to hormonal changes as indicated by reduced embryonic IGF1 and 2 levels. Aged reproductive organs increased energy generation from the degradation of fatty acids, leading to higher oxidative stress. Stress markers, including catalase, superoxide dismutase 2, and receptor for advanced glycation end products were elevated in ovaries and endometrium from aged rabbits. Embryonic fatty acid uptake and β-oxidation were increased in both embryonic compartments (embryoblast and trophoblast) in old rabbits, associated with minor changes in the oxidative and glycative stress defence systems. In summary, the insulin/IGF system, lipid metabolism, and stress defence were dysregulated in reproductive tissues of older rabbits, which is consistent with changes in embryonic metabolism and stress defence. These data highlight the crucial influence of maternal age on uterine adaptability and embryo development.
CropGS-Hub: a comprehensive database of genotype and phenotype resources for genomic prediction in major crops
Authors: Chen Jiaxin , Tan Cong , Zhu Min , Zhang Chenyang , Wang Zhihan , Ni Xuemei , Liu Yanlin , Wei Tong , Wei XiaoFeng , Fang Xiaodong , Xu Yang , Huang Xuehui , Qiu Jie , Liu Huan
Published: November 2023

The explosive amount of multi-omics data has brought a paradigm shift both in academic research and further application in life science. However, managing and reusing the growing resources of genomic and phenotype data points presents considerable challenges for the research community. There is an urgent need for an integrated database that combines genome-wide association studies (GWAS) with genomic selection (GS). Here, we present CropGS-Hub, a comprehensive database comprising genotype, phenotype, and GWAS signals, as well as a one-stop platform with built-in algorithms for genomic prediction and crossing design. This database encompasses a comprehensive collection of over 224 billion genotype data and 434 thousand phenotype data generated from >30 000 individuals in 14 representative populations belonging to 7 major crop species. Moreover, the platform implemented three complete functional genomic selection related modules including phenotype prediction, user model training and crossing design, as well as a fast SNP genotyper plugin-in called SNPGT specifically built for CropGS-Hub, aiming to assist crop scientists and breeders without necessitating coding skills. CropGS-Hub can be accessed at https://iagr.genomics.cn/CropGS/.
A modular dCas9-based recruitment platform for combinatorial epigenome editing
Authors: Swain Tessa , Pflueger Christian , Freytag Saskia , Poppe Daniel , Pflueger Jahnvi , Nguyen Trung Viet , Li Ji Kevin , Lister Ryan
Published: November 2023

Targeted epigenome editing tools allow precise manipulation and investigation of genome modifications, however they often display high context dependency and variable efficacy between target genes and cell types. While systems that simultaneously recruit multiple distinct ‘effector’ chromatin regulators can improve efficacy, they generally lack control over effector composition and spatial organisation. To overcome this we have created a modular combinatorial epigenome editing platform, called SSSavi. This system is an interchangeable and reconfigurable docking platform fused to dCas9 that enables simultaneous recruitment of up to four different effectors, allowing precise control of effector composition and spatial ordering. We demonstrate the activity and specificity of the SSSavi system and, by testing it against existing multi-effector targeting systems, demonstrate its comparable efficacy. Furthermore, we demonstrate the importance of the spatial ordering of the recruited effectors for effective transcriptional regulation. Together, the SSSavi system enables exploration of combinatorial effector co-recruitment to enhance manipulation of chromatin contexts previously resistant to targeted editing.
The Efg1–Bud22 dimer associates with the U14 snoRNP contacting the 5′ rRNA domain of an early 90S pre-ribosomal particle
Authors: Beine-Golovchuk Olga , Kallas Martina , Kunze Ruth , Griesel Sabine , Baßler Jochen
Published: November 2023

The DEAD-box helicase Dbp4 plays an essential role during the early assembly of the 40S ribosome, which is only poorly understood to date. By applying the yeast two-hybrid method and biochemical approaches, we discovered that Dbp4 interacts with the Efg1–Bud22 dimer. Both factors associate with early pre-90S particles and smaller complexes, each characterized by a high presence of the U14 snoRNA. A crosslink analysis of Bud22 revealed its contact to the U14 snoRNA and the 5′ domain of the nascent 18S rRNA, close to its U14 snoRNA hybridization site. Moreover, depletion of Bud22 or Efg1 specifically affects U14 snoRNA association with pre-ribosomal complexes. Accordingly, we concluded that the role of the Efg1–Bud22 dimer is linked to the U14 snoRNA function on early 90S ribosome intermediates chaperoning the 5′ domain of the nascent 18S rRNA. The successful rRNA folding of the 5′ domain and the release of Efg1, Bud22, Dpb4, U14 snoRNA and associated snoRNP factors allows the subsequent recruitment of the Kre33-Bfr2-Enp2-Lcp5 module towards the 90S pre-ribosome.
The replication enhancer crtS depends on transcription factor Lrp for modulating binding of initiator RctB to ori2 of Vibrio cholerae
Authors: Doan Alexander , Chatterjee Soniya , Kothapalli Roopa , Khan Zaki , Sen Shaanit , Kedei Noemi , Jha Jyoti K , Chattoraj Dhruba K , Ramachandran Revathy
Published: November 2023

Replication of Vibrio cholerae chromosome 2 (Chr2) initiates when the Chr1 locus, crtS (Chr2 replication triggering site) duplicates. The site binds the Chr2 initiator, RctB, and the binding increases when crtS is complexed with the transcription factor, Lrp. How Lrp increases the RctB binding and how RctB is subsequently activated for initiation by the crtS-Lrp complex remain unclear. Here we show that Lrp bends crtS DNA and possibly contacts RctB, acts that commonly promote DNA-protein interactions. To understand how the crtS-Lrp complex enhances replication, we isolated Tn-insertion and point mutants of RctB, selecting for retention of initiator activity without crtS. Nearly all mutants (42/44) still responded to crtS for enhancing replication, exclusively in an Lrp-dependent manner. The results suggest that the Lrp-crtS controls either an essential function or more than one function of RctB. Indeed, crtS modulates two kinds of RctB binding to the origin of Chr2, ori2, both of which we find to be Lrp-dependent. Some point mutants of RctB that are optimally modulated for ori2 binding without crtS still remained responsive to crtS and Lrp for replication enhancement. We infer that crtS-Lrp functions as a unit, which has an overarching role, beyond controlling initiator binding to ori2.
Fibrates and the risk of cardiovascular outcomes in chronic kidney disease patients
Authors: Goto Hirohito , Iseri Ken , Hida Noriko
Published: November 2023

Background

The high risk of major adverse cardiovascular events (MACE) in patients with chronic kidney disease (CKD) has been well described. However, the efficacy of fibrates on the risk of MACE in patients with CKD remains unclear.

Methods

We conducted a nested case–control study using data from a large administrative database that included more than 1.5 million Japanese patients. We defined cases as CKD patients with incidences of MACE and matched them with controls based on age, sex, calendar year of cohort entry and CKD stage. Fibrate exposure timing was categorized as current, recent or past. A conditional logistic regression analysis was used to investigate the association between fibrate use and the risk of MACE.

Results

Our study included 47 490 patients with CKD, with 15 830 MACE identified during a median follow-up of 9.4 months. The numbers of fibrates used during the study period were 556 (3.5%) in the case group and 1109 (3.5%) in the control group. Fibrate use was significantly associated with a decreased risk of MACE [odds ratio (OR) 0.84; 95% confidence interval (CI) 0.75–0.94], particularly for current (OR 0.81; 95% CI 0.68–0.97) and recent use (OR 0.65; 95% CI 0.48–0.90). Regarding the class effect of fibrates, pemafibrate use, but not bezafibrate or fenofibrate use, was significantly associated with a decreased risk of MACE (OR 0.73; 95% CI 0.528–0.997).

Conclusion

Recent and current fibrate use, especially pemafibrate use, was associated with a reduced risk of MACE in patients with CKD. This suggests the potential benefits of continuous fibrate therapy and the possible superiority of pemafibrate over other fibrates. However, further investigations in different populations are required to confirm the generalizability of these findings.
Patient-derived glioblastoma organoids reflect tumor heterogeneity and treatment sensitivity
Authors: Verduin Maikel , Hoosemans Linde , Vanmechelen Maxime , van Heumen Mike , Piepers Jolanda A F , Astuti Galuh , Ackermans Linda , Schijns Olaf E M G , Kampen Kim R , Tjan-Heijnen Vivianne C G , de Barbanson Buys A , Postma Alida A , Eekers Danielle B P , Broen Martijn P G , Beckervordersandforth Jan , Staňková Katerina , de Smet Frederik , Rich Jeremy , Hubert Christopher G , Gimenez Gregory , Chatterjee Aniruddha , Hoeben Ann , Vooijs Marc A
Published: November 2023

Background

Treatment resistance and tumor relapse are the primary causes of mortality in glioblastoma (GBM), with intratumoral heterogeneity playing a significant role. Patient-derived cancer organoids have emerged as a promising model capable of recapitulating tumor heterogeneity. Our objective was to develop patient-derived GBM organoids (PGO) to investigate treatment response and resistance.

Methods

GBM samples were used to generate PGOs and analyzed using whole-exome sequencing (WES) and single-cell karyotype sequencing. PGOs were subjected to temozolomide (TMZ) to assess viability. Bulk RNA sequencing was performed before and after TMZ.

Results

WES analysis on individual PGOs cultured for 3 time points (1–3 months) showed a high inter-organoid correlation and retention of genetic variants (range 92.3%–97.7%). Most variants were retained in the PGO compared to the tumor (range 58%–90%) and exhibited similar copy number variations. Single-cell karyotype sequencing demonstrated preservation of genetic heterogeneity. Single-cell multiplex immunofluorescence showed maintenance of cellular states. TMZ treatment of PGOs showed a differential response, which largely corresponded with MGMT promoter methylation. Differentially expressed genes before and after TMZ revealed an upregulation of the JNK kinase pathway. Notably, the combination treatment of a JNK kinase inhibitor and TMZ demonstrated a synergistic effect.

Conclusions

Overall, these findings demonstrate the robustness of PGOs in retaining the genetic and phenotypic heterogeneity in culture and the application of measuring clinically relevant drug responses. These data show that PGOs have the potential to be further developed into avatars for personalized adaptive treatment selection and actionable drug target discovery and as a platform to study GBM biology.
Effect of Inhaled Ciclesonide in Non–Critically Ill Hospitalized Patients With Coronavirus Disease 2019: A Multicenter Observational Study in Japan
Authors: Suzuki Jun , Endo Shiro , Suzuki Takayuki , Sasahara Teppei , Hatakeyama Shuji , Morisawa Yuji , Hayakawa Mineji , Yamakawa Kazuma , Endo Akira , Ogura Takayuki , Hirayama Atsushi , Yasunaga Hideo , Tagami Takashi
Published: November 2023

Background

Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic. Although systemic steroids play an important role in treating patients with severe COVID-19, the role of inhaled corticosteroids in non–critically ill, hospitalized patients with COVID-19 remains unclear.

Methods

We analyzed findings in non–critically ill, hospitalized patients with COVID-19 who were >18 years old and were admitted to 64 Japanese hospitals between January and September 2020. We performed propensity score matching analysis to evaluate 28-day and in-hospital mortality rates with or without inhaled ciclesonide within 2 days of admission. Sensitivity analyses using inverse probability weighting analysis, and generalized estimating equation method were also performed.

Results

Eligible patients (n = 3638) were divided into ciclesonide (n = 290) and control (n = 3, 393) groups. The 1-to-4 propensity score matching analysis included 271 ciclesonide users and 1084 nonusers. There were no significant differences between the 2 groups for 28-day (3.3% vs 2.3%; risk difference, 1.0% [95% confidence interval, −1.2 to 3.3]) or in-hospital (4.8% vs 2.6%; risk difference, 2.2 [−.5 to 4.9]) mortality rates. The sensitivity analysis showed similar outcomes.

Conclusions

From this multicenter observational study in Japan, inhaled ciclesonide did not decrease 28-day or in-hospital mortality rates in non–critically ill, hospitalized patients with COVID-19. Future large, multinational, randomized trials are required to confirm our results.
Comparison of Adjuvant Clindamycin vs Linezolid for Severe Invasive Group A Streptococcus Skin and Soft Tissue Infections
Authors: Heil Emily L , Kaur Harpreet , Atalla Anthony , Basappa Sapna , Mathew Minu , Seung Hyunuk , Johnson J Kristie , Schrank Gregory M
Published: November 2023

Background

Linezolid may be an option for severe group A Streptococcus (GAS) infections based on its potent in vitro activity and antitoxin effects, but clinical data supporting its use over clindamycin are limited. This study evaluated treatment outcomes in patients with severe GAS skin and soft tissue infections who received either linezolid or clindamycin.

Methods

This retrospective single-center cohort study examined patients with GAS isolated from blood and/or tissue cultures with invasive soft tissue infection or necrotizing fasciitis who underwent surgical debridement and received linezolid or clindamycin for at least 48 hours. The primary outcome was percentage change in Sequential Organ Failure Assessment (SOFA) score from baseline through 72 hours of hospitalization.

Results

After adjustment for time to first surgical intervention among patients with a baseline SOFA score >0 (n = 23 per group), there was no difference in reduction of SOFA score over the first 72 hours in patients receiving clindamycin vs linezolid. In the entire cohort (n = 26, clindamycin; n = 29, linezolid), there was no difference in inpatient mortality (2% vs 1%) or any secondary outcomes, including duration of vasopressor therapy, intensive care unit length of stay, and antibiotic-associated adverse drug events.

Conclusions

There was no difference in reduction of critical illness as measured by SOFA score between baseline and 72 hours among patients treated with clindamycin vs linezolid. Given its more favorable side effect profile, linezolid may be a viable option for the treatment of serious GAS infections and should be further studied.
Hepatitis E Virus Infection Epidemiology in Recipients of Allogeneic Hematopoietic Cell Transplant
Authors: Courjon Johan , Portillo Vera , Yerly Sabine , Vetter Pauline , Schibler Manuel , Mappoura Maria , Morin Sarah , Giannotti Federica , Mamez Anne-Claire , van Delden Christian , Kaiser Laurent , Chalandon Yves , Masouridi-Levrat Stavroula , Neofytos Dionysios
Published: November 2023

Among 292 recipients of allogeneic hematopoietic cell transplant (2018–2022), 64 (21.9%) tested positive for anti–hepatitis E virus (HEV) immunoglobulin G. Among 208 recipients tested by plasma/serum HEV polymerase chain reaction (2012–2022), 3 (1.4%) primary HEV infections were diagnosed; in 1 patient, plasma HEV polymerase chain reaction relapsed positive for 100 days. HEV infection remains rare albeit associated with persistent viral replication.
Treatment of Hypercalcemic Hyperparathyroidism After Kidney Transplantation Is Associated With Improved Allograft Survival
Authors: Wang Rongzhi , Reed Rhiannon D , Price Griffin , Abraham Peter , Lewis Marshall , McMullin Jessica Liu , MacLennan Paul , Killian Cozette , Locke Jayme E , Ong Song , Kumar Vineeta , Gillis Andrea , Lindeman Brenessa , Chen Herbert , Fazendin Jessica
Published: November 2023

Background

Hyperparathyroidism (HPT) and malignancy are the most common causes of hypercalcemia. Among kidney transplant (KT) recipients, hypercalcemia is mostly caused by tertiary HPT. Persistent tertiary HPT after KT is associated with allograft failure. Previous studies on managing tHPT were subjected to survivor treatment selection bias; as such, the impact of tertiary HPT treatment on allograft function remained unclear. We aim to assess the association between hypercalcemic tertiary HPT treatment and kidney allograft survival.

Materials and Methods

We identified 280 KT recipients (2015-2019) with elevated post-KT adjusted serum calcium and parathyroid hormone (PTH). KT recipients were characterized by treatment: cinacalcet, parathyroidectomy, or no treatment. Time-varying Cox regression with delayed entry at the time of first elevated post-KT calcium was conducted, and death-censored and all-cause allograft failure were compared by treatment groups.

Results

Of the 280 recipients with tHPT, 49 underwent PTx, and 98 received cinacalcet. The median time from KT to first elevated calcium was 1 month (IQR: 0-4). The median time from first elevated calcium to receiving cinacalcet and parathyroidectomy was 0(IQR: 0-3) and 13(IQR: 8-23) months, respectively. KT recipients with no treatment had shorter dialysis vintage (P = .017) and lower PTH at KT (P = .002), later onset of hypercalcemia post-KT (P < .001). Treatment with PTx (adjusted hazard ratio (aHR) = 0.18, 95%CI 0.04-0.76, P = .02) or cinacalcet (aHR = 0.14, 95%CI 0.004-0.47, P = .002) was associated with lower risk of death-censored allograft failure. Moreover, receipt of PTx (aHR = 0.28, 95%CI 0.12-0.66, P < .001) or cinacalcet (aHR = 0.38, 95%CI 0.22-0.66, P < .001) was associated with lower risk of all-cause allograft failure.

Conclusions

This study demonstrates that treatment of hypercalcemic tertiary HPT post-KT is associated with improved allograft survival. Although these findings are not specific to hypercalcemia of malignancy, they do demonstrate the negative impact of hypercalcemic tertiary HPT on kidney function. Hypercalcemic HPT should be screened and aggressively treated post-KT.
Expansin SlExp1 and endoglucanase SlCel2 synergistically promote fruit softening and cell wall disassembly in tomato
Authors: Su Guanqing , Lin Yifan , Wang Chunfeng , Lu Jiao , Liu Zimeng , He Zhiren , Shu Xiu , Chen Wenbo , Wu Rongrong , Li Baijun , Zhu Changqing , Rose Jocelyn K C , Grierson Donald , Giovannoni James J , Shi Yanna , Chen Kunsong
Published: November 2023

Fruit softening, an irreversible process that occurs during fruit ripening, can lead to losses and waste during postharvest transportation and storage. Cell wall disassembly is the main factor leading to loss of fruit firmness, and several ripening-associated cell wall genes have been targeted for genetic modification, particularly pectin modifiers. However, individual knockdown of most cell wall–related genes has had minimal influence on cell wall integrity and fruit firmness, with the notable exception of pectate lyase. Compared to pectin disassembly, studies of the cell wall matrix, the xyloglucan–cellulose framework, and underlying mechanisms during fruit softening are limited. Here, a tomato (Solanum lycopersicum) fruit ripening–associated α-expansin (SlExpansin1/SlExp1) and an endoglucanase (SlCellulase2/SlCel2), which function in the cell wall matrix, were knocked out individually and together using clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated nuclease 9-mediated genome editing. Simultaneous knockout of SlExp1 and SlCel2 enhanced fruit firmness, reduced depolymerization of homogalacturonan-type pectin and xyloglucan, and increased cell adhesion. In contrast, single knockouts of either SlExp1 or SlCel2 did not substantially change fruit firmness, while simultaneous overexpression of SlExp1 and SlCel2 promoted early fruit softening. Collectively, our results demonstrate that SlExp1 and SlCel2 synergistically regulate cell wall disassembly and fruit softening in tomato.
Transcription factors PuPRE6/PuMYB12 and histone deacetylase PuHDAC9-like regulate sucrose levels in pear
Authors: Gao Siyang , Yin Mingxin , Xu Mingyang , Zhang He , Li Shuai , Han Yinxiao , Ji Shujuan , Li Xinyue , Du Guodong
Published: November 2023

The improvement of fruit quality, in particular sugar content, has been a major goal of plant breeding programmes for many years. Here, 2 varieties of the Ussurian pear (Pyrus ussuriensis), Nanguo, and its high-sucrose accumulation bud sport, Nanhong, were used to study the molecular mechanisms regulating sucrose transport in fruits. Comparative transcriptome analysis showed that in Nanhong fruit, an MYB transcription factor, PuMYB12, and a sucrose transporter protein, PuSUT4-like, were expressed at higher levels, while a paclobutrazol resistance transcription factor, PuPRE6, and a histone deacetylase (HDAC), PuHDAC9-like, were expressed at lower levels in Nanguo fruit. PuSUT4-like silencing and overexpression experiments in Nanguo pear showed that PuSUT4-like is essential for sucrose transportation. PuPRE6 and PuMYB12 act as antagonistic complexes to regulate PuSUT4-like transcription and sucrose accumulation. The histone deacetylation levels of the PuMYB12 and PuSUT4-like promoters were higher in Nanguo fruit than in Nanhong fruit, and Y1H assays showed that HDAC PuHDAC9-like bound directly to the promoters of PuMYB12 and PuSUT4-like. Our results uncovered transcription regulation and epigenetic mechanisms underlying sucrose accumulation in pears.
Temporal origin of nestedness in interaction networks
Authors: Staniczenko Phillip P A , Panja Debabrata
Published: November 2023

Nestedness is a common property of communication, finance, trade, and ecological networks. In networks with high levels of nestedness, the link positions of low-degree nodes (those with few links) form nested subsets of the link positions of high-degree nodes (those with many links), leading to matrix representations with characteristic upper triangular or staircase patterns. Recent theoretical work has connected nestedness to the functionality of complex systems and has suggested that it is a structural by-product of the skewed degree distributions often seen in empirical data. However, mechanisms for generating nestedness remain poorly understood, limiting the connections that can be made between system processes and observed network structures. Here, we show that a simple probabilistic model based on phenology—the timing of copresences among interaction partners—can produce nested structures and correctly predict around two-thirds of interactions in two fish market networks and around one-third of interactions in 22 plant–pollinator networks. Notably, the links most readily explained by frequent actor copresences appear to form a backbone of nested interactions, with the remaining interactions attributable to opportunistic interactions or preferences for particular interaction partners that are not routinely available.
Police engagement with rural communities on Facebook
Authors: Bullock Karen , Harkness Alistair , Mellberg Jacques , Christmas Hilary
Published: November 2023

Police organizations in Western liberal democracies are under increasing pressure to generate effective means of engaging with the communities that they serve. Established as a contemporary means of communication engagement, many police organizations have turned to social media to interact with citizens. A growing body of work examines the nature of public engagement with police social media. However, it tends not to differentiate by the features of place. This article starts to fill this gap by examining the effectiveness of the police use of Facebook as an engagement tool with rural communities, reporting on research conducted in the United Kingdom and in Australia. The aim here is to identify what type of content rural police Facebook pages are posting and whether certain post types and post-characteristics are associated with higher levels of engagement. We argue that certain characteristics of Facebook posts assist in gaining ‘cut through’ and thus effective engagement with rural communities. Implications for community engagement are discussed.
Implementation of Physical Therapist Services for Men Undergoing Radical Prostatectomy: An Administrative Case Report
Authors: Wolden Mitchell , Brown Scott , Carlsson Sigrid V , Noah Thomas A , Mungovan Sean F
Published: November 2023

Objective

Prostate cancer is the most commonly diagnosed cancer among men in the USA, and radical prostatectomy (RP) is the primary surgical treatment option. With an increasing number of men undergoing RP and surviving prostate cancer, clinical management strategies have broadened to improve the preoperative and postoperative patient experience and minimize treatment-related functional consequences. Urinary incontinence is a predictable functional consequence of RP. Recent reviews recommend preoperative and postoperative physical therapist services as the standard of care for men undergoing RP to decrease the severity of urinary incontinence and improve patients’ quality of life. Despite compelling evidence, the routine provision of physical therapist services preoperatively and postoperatively for men undergoing RP is limited. The purpose of this case report is to describe the implementation of preoperative and postoperative physical therapist services for men undergoing RP in a US health care system using the knowledge-to-action process and the Consolidated Framework for Implementation Research frameworks.

Case Description

The implementation process included 4 steps: (1) development of a preoperative and postoperative physical therapist services program; (2) identification of barriers and enablers for implementation; (3) implementation of the program; and (4) evaluation of the effectiveness of the implemented program.

Results

Outcomes from the implementation of a physical therapist services program for men undergoing RP included lower urinary incontinence rates, improved patient satisfaction, and increased physical therapist utilization.

Conclusion

This case report documents the implementation of physical therapist services for men undergoing RP. The use of implementation frameworks enabled the identification of unique enablers, barriers, and strategies for the implementation of physical therapist services for men undergoing RP.

Impact

Implementing preoperative and postoperative physical therapist services for men undergoing RP improves patient outcomes. The implementation process and outcomes can be considered by other health care systems when developing preoperative and postoperative physical therapist services for men undergoing RP.
Sol–gel derived B2O3–CaO borate bioactive glasses with hemostatic, antibacterial and pro-angiogenic activities
Authors: Zheng Kai , Bider Faina , Monavari Mahshid , Xu Zhiyan , Janko Christina , Alexiou Christoph , Beltrán Ana M , Boccaccini Aldo R
Published: November 2023

Sol–gel borate bioactive glasses (BGs) are promising ion-releasing biomaterials for wound healing applications. Here, we report the synthesis of a series of binary B2O3–CaO borate BGs (CaO ranging from 50 to 90 mol%) using a sol–gel-based method. The influence of CaO content in B2O3–CaO borate BG on morphology, structure and ion release behavior was investigated in detail. Reduced dissolution (ion release) and crystallization could be observed in borate BGs when CaO content increased, while the morphology was not significantly altered by increasing CaO content. Our results evidenced that the ion release behavior of borate BGs could be tailored by tuning the B2O3/CaO molar ratio. We also evaluated the in vitro cytotoxicity, hemostatic, antibacterial and angiogenic activities of borate BGs. Cytocompatibility was validated for all borate BGs. However, borate BGs exhibited composition-dependent hemostatic, antibacterial and angiogenic activities. Generally, higher contents of Ca in borate BGs facilitated hemostatic activity, while higher contents of B2O3 were beneficial for pro-angiogenic activity. The synthesized sol–gel-derived borate BGs are promising materials for developing advanced wound healing dressings, given their fast ion release behavior and favorable hemostatic, antibacterial and angiogenic activities.
Multimorbidity in systemic lupus erythematosus in a population-based cohort: the Lupus Midwest Network
Authors: Figueroa-Parra Gabriel , Meade-Aguilar Jose A , Hulshizer Cassondra A , Gunderson Tina M , Chamberlain Alanna M , Thanarajasingam Uma , Greenlund Kurt J , Barbour Kamil E , Crowson Cynthia S , Duarte-García Alí
Published: November 2023

Objectives

The objectives of this study were to assess the prevalence and incidence of multimorbidity and its association with the SLICC/ACR damage index (SDI) among patients with SLE.

Methods

Using prevalent and incident population–based cohorts of patients with SLE and their matched comparators, we assessed 57 chronic conditions. Chronic conditions were categorized as SDI-related or SDI-unrelated. Multimorbidity was defined as the presence of two or more chronic conditions. The prevalence of multimorbidity for both cohorts was compared using logistic regression. Cox models were used to examine the development of multimorbidity after SLE incidence.

Results

The prevalent cohort included 449 patients with established SLE on 1 January 2015. They were three times more likely to have multimorbidity compared with non-SLE comparators [odds ratio (OR) 2.98, 95% CI 2.18–4.11]. The incident cohort included 270 patients with new-onset SLE. At SLE incidence, patients with SLE were more likely to have multimorbidity than comparators (OR 2.27, 95% CI 1.59–3.27). After incidence, the risk of developing multimorbidity was 2-fold higher among patients with SLE than among comparators [hazard ratio (HR) 2.11, 95% CI 1.59–2.80]. The development of multimorbidity was higher in patients with SLE based on SDI-related conditions (HR 2.91, 95% CI 2.17–3.88) than on SDI-unrelated conditions (HR 1.73, 95% CI, 1.32–2.26).

Conclusion

Patients with SLE had a higher burden of multimorbidity, even before the onset of the disease. The risk disparity continued after SLE classification and was also seen in a prevalent SLE cohort. Multimorbidity was driven both by SDI-related and unrelated conditions.
Twin-screw melt granulation for high-dose paracetamol tablets
Authors: Ross Steven A , Mithu Md Sadeque , Douroumis Dennis
Published: November 2023

Objectives

In this study twin-screw melt granulation (TSMG) was used to produce sustained release formulations and improve the poor compressibility of paracetamol (PMOL).

Methods

By using various amounts of polyethylene glycol (PEG), a low melting point binder and ethyl cellulose (EC) as insoluble carrier, the formation of high content of PMOL granules occurred at low processing temperatures (55°C).

Key findings

X-ray diffraction and differential scanning calorimetry analysis showed the presence of partially crystalline PMOL in the extruded granules. Compressed caplet tablets comprising of TSMG granules presented sustained release profiles for 3-4 h depending on the EC concentration. The tablets showed excellent tabletability and low compaction forces were applied.

Conclusions

TSMG can be used for the processing of drugs with poor compressibility actives for the compression of high-dose tablets.
Sleep features and long-term incident neurodegeneration: a polysomnographic study
Authors: Ibrahim Abubaker , Cesari Matteo , Heidbreder Anna , Defrancesco Michaela , Brandauer Elisabeth , Seppi Klaus , Kiechl Stefan , Högl Birgit , Stefani Ambra
Published: November 2023

Study Objectives

Sleep is altered early in neurodegenerative diseases (NDDs) and may contribute to neurodegeneration. Long-term, large sample-size studies assessing NDDs association with objective sleep measures are scant. We aimed to investigate whether video-polysomnography (v-PSG)-based sleep features are associated with long-term NDDs incidence.

Methods

Retrospective cohort study of patients referred 2004–2007 to the Sleep Disorders Unit, Neurology, Medical University Innsbruck, Austria. All patients ≥ 18 years undergoing v-PSG and without NDDs at baseline or within 5 years were included. Main outcome was NDDs diagnosis ≥5 years after v-PSG.

Results

Of 1454 patients assessed for eligibility, 999 (68.7%) met inclusion criteria (68.3% men; median age 54.9 (IQR 33.9–62.7) years). Seventy-five patients (7.5%) developed NDDs and 924 (92.5%) remained disease-free after a median of 12.8 (IQR 9.9–14.6) years. After adjusting for demographic, sleep, and clinical covariates, a one-percentage decrease in sleep efficiency, N3-, or rapid-eye-movement (REM)-sleep was associated with 1.9%, 6.5%, or 5.2% increased risk of incident NDDs (HR 1.019, 1.065, and 1.052). One-percentage decrease in wake within sleep period time represented a 2.2% reduced risk of incident NDDs (HR 0.978). Random-forest analysis identified wake, followed by N3 and REM-sleep percentages, as the most important feature associated with NDDs diagnosis. Additionally, multiple sleep features combination improved discrimination of incident NDDs compared to individual sleep stages (concordance-index 0.72).

Conclusions

These findings support contribution of sleep changes to NDDs pathogenesis and provide insights into the temporal window during which these differences are detectable, pointing to sleep as early NDDs marker and potential target of neuroprotective strategies.
Cell Therapy Improves Quality-of-Life in Heart Failure: Outcomes From a Phase III Clinical Trial
Authors: Yamada Satsuki , Bartunek Jozef , Povsic Thomas J , Cotter Gad , Davison Beth A , Edwards Christopher , Behfar Atta , Metra Marco , Filippatos Gerasimos S , Vanderheyden Marc , Wijns William , Terzic Andre
Published: November 2023

Patients with heart failure experience limitations in daily activity and poor quality-of-life. Prospective surveillance of health-related quality-of-life supplemented traditional death and hospitalization outcomes in the multinational, randomized, double-blinded CHART-1 clinical trial that assessed cardiopoiesis-guided cell therapy in ischemic heart failure patients with reduced left ventricular ejection fraction. The Minnesota Living with Heart Failure Questionnaire (MLHFQ), a Food and Drug Administration qualified instrument for evaluating therapeutic effectiveness, was applied through the 1-year follow-up. Cell treated (n = 109) and sham procedure (n = 140) cohorts reported improved MLHFQ scores comparable between the 2 study arms (mean treatment difference with baseline adjustment −3.2 points, P = .107). Superiority of cell treatment over sham in betterment of the MLHFQ score was demonstrated in patients with pre-existing advanced left ventricular enlargement (baseline-adjusted mean treatment difference −6.4 points, P = .009). In this highly responsive subpopulation, benefit on the MLHFQ score paralleled reduction in death and hospitalization post-cell therapy (adjusted Mann-Whitney odds 1.43, 95% CI, 1.01-2.01; P = .039). The potential of cell therapy in addressing the quality-of-life dimension of heart failure requires further evaluation for disease relief.
Kangaroo mother care utilization at stepdown ward of a tertiary care teaching hospital: a quality improvement study
Authors: Patel Dipen V , Sameer K , Pujara Reshma K , Nimbalkar Somashekhar M , Patel Paresha Y , Makwana Jayshreeben B , Patel Smita N
Published: November 2023

Purpose

India has the highest burden of preterm/low birth weight newborns. To tackle this, Kangaroo Mother Care (KMC) needs to be scaled up. We did a quality improvement (QI) study to increase KMC coverage to 80% and its utilization to at least 4 h/infant/day.

Methods

This study was conducted at a stepdown ward (KMC ward) of a tertiary care teaching institute over a period of four months. All babies with birth weight <2.5 kg were eligible. The QI team included faculty in-charge, one senior resident and three senior staff nurses. Potential barriers were listed using fish-bone analysis. Four possible interventions were identified (daily documentation of total KMC hours by doctor, providing KMC during all the nursing duty shifts, counseling and education to mothers and family members), introduced, and then subsequently tested by four Plan-Do-Study-Act (PDSA) cycles and sustenance was assessed over three months.

Results

A total of 93 infants were included in this QI study. During baseline phase, the KMC coverage was 50% which increased to 100% by the end of fourth PDSA cycle and remained 100% during the sustenance phase. During baseline period, KMC was given for ≥ 4 h in 18.8% (28 of 149) patient days which increased to 88.96% (137 of 154) during the sustenance phase. The mean KMC utilization increased from 1.97 (1.57) h/infant/day to 5.65 (1.20) h/infant/day in the sustenance phase.

Conclusion

QI study incorporating PDSA cycles helped improve coverage and utilization of KMC.
Mitochondrial phylogenomics of bumblebees, Bombus (Hymenoptera: Apidae): a tale of structural variation, shifts in selection constraints, and tree discordance
Authors: Gonçalves Leonardo Tresoldi , Françoso Elaine , Deprá Maríndia
Published: November 2023

The mitochondrial DNA (mtDNA) of bumblebees (Bombus) has been widely used for phylogenetic studies, but its evolution is still underexplored. Here we report a comprehensive analysis of 60 bumblebee mitogenomes, including 40 newly assembled ones, to investigate bumblebee mtDNA structure, composition, and informativeness under a phylogenetic framework. Our mtDNA dataset supports the monophyly of Bombus and its subgenera, although we found a high degree of tree discordance in deeper nodes when using different inference methods or matrix composition. Concerning mitogenome structure, our results show that tRNA genes were often rearranged, with unique rearrangements indicating shared ancestry across bumblebee subgenera, illustrating their potential for subgeneric classification. Our results also challenge the notion that faster evolving mtDNA exhibits higher gene rearrangement rates. Finally, we explicitly assessed shifts in selection constraints of mtDNA genes in obligate social parasites of subgenus Psithyrus and found that their mtDNA evolved under relaxed selective constraints. Our findings show the utility of mtDNA in providing insights into bumblebee phylogenetics, evolution, and genome trait diversification. We also highlight the potential for comparative mitogenomics to uncover previously unknown aspects of bumblebee evolution, offering exciting opportunities for future research in this field.
Higher matrix stiffness promotes VSMC senescence by affecting mitochondria–ER contact sites and mitochondria/ER dysfunction
Authors: He Haipeng , Zeng Baozhu , Wu Xinxiang , Hou Jianfeng , Wang Yannan , Wang Yanheng , Lin Yuqing , Wu Peng , Zheng Changyu , Yin Henghui , Wang Nan
Published: November 2023

Abdominal aortic aneurysm (AAA) is a prevalent condition characterized by the weakening and bulging of the abdominal aorta. This study aimed to investigate the impact of a stiff matrix on vascular smooth muscle cells (VSMCs) in AAA development. Bioinformatics analysis revealed that differentially expressed genes (DEGs) in VSMCs of an AAA mouse model were enriched in cellular senescence and related pathways. To simulate aging‐related changes, VSMCs were cultured on stiff matrices, and compared to those on soft matrices, the VSMCs cultured on stiff matrices exhibited cellular senescence. Furthermore, the mutual distance between mitochondria and endoplasmic reticulum (ER) in VSMCs was increased, indicating altered mitochondria–endoplasmic reticulum contacts (MERCs). The observed upregulation of reactive oxygen species (ROS) levels, antioxidant gene expression, and decreased mitochondrial membrane potential suggested the presence of mitochondrial dysfunction in VSMCs cultured on a stiff matrix. Additionally, the induction of ER stress‐related genes indicated ER dysfunction. These findings collectively indicated impaired functionality of both mitochondria and ER in VSMCs cultured on a stiff matrix. Moreover, our data revealed that high lipid levels exacerbated the effects of high matrix stiffness on VSMCs senescence, MERC sites, and mitochondria/ER dysfunction. Importantly, treatment with the antilipemic agent CI‐981 effectively reversed these detrimental effects. These findings provide insights into the role of matrix stiffness, mitochondrial dysfunction, ER stress, and lipid metabolism in AAA development, suggesting potential therapeutic targets for intervention.
Prodromal Parkinson's disease and the catecholaldehyde hypothesis: Insight from olfactory bulb organotypic cultures
Authors: Bagnoli Enrico , Trotier Alexandre , McMahon Jill , Quinlan Leo R. , Biggs Manus , Pandit Abhay , FitzGerald Una
Published: November 2023

Parkinson's disease (PD) is a progressive, neurodegenerative disorder with an increasing incidence, unknown etiology, and is currently incurable. Advances in understanding the pathological mechanisms at a molecular level have been slow, with little attention focused on the early prodromal phase of the disease. Consequently, the development of early‐acting disease‐modifying therapies has been hindered. The olfactory bulb (OB), the brain region responsible for initial processing of olfactory information, is particularly affected early in PD at both functional and molecular levels but there is little information on how the cells in this region are affected by disease. Organotypic and primary OB cultures were developed and characterized. These platforms were then used to assess the effects of 3,4‐dihydroxyphenylacetylaldehyde (DOPAL), a metabolite of dopamine present in increased levels in post‐mortem PD tissue and which is thought to contribute to PD pathogenesis. Our findings showed that DOPAL exposure can recapitulate many aspects of PD pathology. Oxidative stress, depolarization of mitochondrial membranes, and neurodegeneration were all induced by DOPAL addition, as were measured transcriptomic changes consistent with those reported in PD clinical studies. These olfactory models of prodromal disease lend credence to the catecholaldehyde hypothesis of PD and provide insight into the mechanisms by which the OB may be involved in disease progression.
Lipid raft interacting galectin 8 regulates primary ciliogenesis
Authors: Syu Jhan‐Jhang , Chang Chieh‐Hsiang , Chang Pei‐Yu , Liu Chia‐Hsiung , Yu Chia‐Jung , Jou Tzuu‐Shuh
Published: November 2023

Primary cilium is a specialized sensory organelle that transmits environmental information into cells. Its length is tightly controlled by various mechanisms such as the frequency or the cargo size of the intraflagellar transport trains which deliver the building materials such as tubulin subunits essential for the growing cilia. Here, we show the sialoglycan interacting galectin 8 regulates the process of primary ciliogenesis. As the epithelia become polarized, there are more galectin 8 being apically secreted and these extracellular galectin 8 molecules apparently bind to a lipid raft enriched domain at the base of the primary cilia through interacting with lipid raft components, such as GD3 ganglioside and scaffold protein caveolin 1. Furthermore, the binding of galectin 8 at this critical region triggers rapid growth of primary cilia by perturbing the barrier function of the transition zone (TZ). Our study also demonstrates the functionality of this barrier depends on intact organization of lipid rafts at the cilia as genetically knockout of Cav1 and pharmacologically inhibition of lipid raft both phenocopy the effect of apical addition of recombinant galectin 8; that is, rapid elongation of primary cilia and redistribution of cilia proteins from TZ to the growing axoneme. Indeed, as cilia elongated, endogenous galectin 8, caveolin 1, and TZ component, TMEM231, also transited from the TZ to the growing axoneme. We also noted that the interaction between caveolin 1 and TMEM231 could be perturbed by exogenous galectin 8. Taken together, we proposed that galectin 8 promoted primary cilia elongation through impeding the barrier function of the TZ by interfering with the interaction between caveolin 1 and TMEM231.
Rapid evaluation of habitat connectivity change to safeguard multispecies persistence in human-transformed landscapes
Authors: Oehri Jacqueline , Wood Sylvia L.R. , Touratier Eluna , Leung Brian , Gonzalez Andrew
Published: November 2023

Protecting habitat connectivity in fragmented landscapes is essential for safeguarding biodiversity and nature’s contributions to people. Following the Post-2020 Kunming-Montreal Global Biodiversity Framework (KM-GBF) of the Convention on Biological Diversity (CBD) there is a clear science-policy need to assess habitat connectivity and track its change over time to inform conservation planning.

In response to this need we describe an analytical, multi-indicator and multispecies approach for the rapid assessment of habitat connectivity at fine spatial grain and at the extent of an entire ecoregion. Out of 69 connectivity indicators we found through a literature review, we identified a key-set of nine indicators that align with the Essential Biodiversity Variables framework and that are suitable to guide rapid action for connectivity and conservation targets in the KM-GBF. Using these selected indicators, we mapped and evaluated connectivity change from 2011 to 2021 across the ecoregion of the St-Lawrence Lowlands in Quebec (∼30,000 km2) for seven ecoprofile species representing regional forest habitat needs. For the majority of these ecoprofile species, trends over the last decade indicate a decline in effective connected area and metapopulation carrying capacity, mainly via a division of large contiguous habitat into smaller fragments, whereas total habitat area largely remained unchanged.

These results highlight that trends in habitat area and connectivity are not necessarily correlated and the urgent need to conserve and restore connectivity in the St-Lawrence Lowlands, in order to meet regional targets under the KM-GBF. Our general approach enables a comprehensive evaluation of connectivity for regional spatial planning for biodiversity. We develop an R-tool to support this analysis and that can be extended to other conservation planning efforts for connectivity.