bluuebunny/crossref_metadata_2025 huggingface dataset:
Sarcopenia is associated with worse outcomes in patients with inflammatory bowel disease: insights from US national hospitalization data
Authors: Kohli Isha , Thind Nuhar , Bhalla Akshita , Attri Amitpal , Bhupal Sahiljot Singh , Sohal Aalam , Yang Juliana
Published: October 2024

Background

Inflammatory bowel disease (IBD) is an inflammatory disorder associated with significant morbidity and mortality. Recent studies have reported sarcopenia as a significant factor affecting the quality of life and outcomes of these patients.

Methods

We used the National Inpatient Sample 2016–2020 to identify adult patients with IBD. The patients were stratified into two groups based on the presence of sarcopenia. Data were collected on patient demographics, hospital characteristics, and comorbidities. The outcomes studied were in-hospital mortality, sepsis, shock, ICU admission, and need for surgery. Multivariate logistic regression analysis was performed.

Results

A total of 1 524 820 IBD hospitalizations were included. Of these, 209 615 (9%) were noted to have sarcopenia. Patients with sarcopenia had a higher incidence of in-hospital mortality (4.2% vs. 1.2%, P < 0.001), ICU admission (6.5% vs. 2.4%, P < 0.001), and need for abdominal surgery (6.5% vs. 3.5%, P < 0.001). After adjusting for confounders, the presence of sarcopenia was associated with higher odds of in-hospital mortality (adjusted odds ratio: 2.83, 95% confidence interval: 2.66–3.02, P < 0.001) and additional worse outcomes.

Conclusion

Our study reports that the presence of sarcopenia was associated with an increased risk of death and the need for abdominal surgery. Preventative measures aimed at improving sarcopenia should be taken to prevent worse outcomes in this patient population.
Fatty liver index as an independent predictor of all-cause and disease-specific mortality
Authors: Zhang Ruixin , Ren Shuhao , Mi Hongfei , Wang Meixia , He Tingjuan , Zhang Renyan , Jiang Wei , Su Chenghao
Published: October 2024

Purpose:

This study aims to assess the prognostic value of the fatty liver index (FLI), a noninvasive tool for hepatic steatosis assessment, in predicting all-cause and disease-specific mortality.

Methods:

We linked data from the National Health and Nutrition Examination Survey III (1988–1994) with Public-Use Mortality Files, forming a cohort of 11 297 participants with a median follow-up period of 26.25 years. Cox proportional hazards models were used to evaluate the association between FLI and all-cause mortality, while Fine and Gray’s models assessed the relationship between FLI and disease-specific mortality.

Results:

The FLI ≥ 60 was independently associated with an increased risk of all-cause mortality (hazard ratio = 1.24, P < 0.001), as well as mortality from malignant neoplasms (hazard ratio = 1.18, P = 0.048), diabetes (hazard ratio = 2.62, P = 0.001), and cardiovascular diseases (CVDs) (hazard ratio = 1.18, P = 0.018), compared to FLI < 30. No significant associations were found with Alzheimer’s disease, influenza and pneumonia, chronic lower respiratory diseases, or renal disorders. Subgroup analyses indicated that individuals who were females aged 40–60 (hazard ratio = 1.67, P = 0.003), non-overweight (hazard ratio = 1.75, P = 0.007), or without abdominal obesity (hazard ratio = 1.75, P = 0.007) exhibited a stronger association between FLI ≥ 60 and all-cause mortality.

Conclusion:

These findings support the prognostic value of the FLI for predicting mortality from all causes, malignant neoplasms, diabetes, and CVDs. Targeted attention is needed in postmenopausal women, non-overweight, and non-abdominally obese populations.
Advancements in pediatric headache
Authors: Miller Richard N. , Kim Monica E. , Gunduz Muhammed Talha , Aylward Shawn C.
Published: October 2024

Purpose of review

To provide an update on advancements in pediatric headache.

Recent findings

The symptomatology associated with primary headache disorders has been compared with ICHD-3 criteria. Primary stabbing headache pain lasts longer than 3 seconds in over half of patients. Persistent posttraumatic headache or new daily persistent headache have significant overlap in pain character and nonpain-related symptoms with migraine. In a large cohort with continuous headache at first follow-up, 47% reported resolution of their continuous headache and 19.4% had a 50% or greater reduction in frequency with improvements in fluid intake, sleep, not skipping meals, and exercise. There was no correlation with improved lifestyle habits and clinical outcomes despite the overall improvement. Studies noted significant improvement in headache scores with onabotulinum toxin A and incobotulinum toxin A injections with limited side effects. Intranasal sumatriptan without concurrent intravenous therapies found a clinically meaningful decrease in pain score prior to discharge with shorter lengths of stay and lower emergency department costs compared with the those who received intravenous therapies.

Newer studies have suggested changes to symptomatology and duration of pediatric headache syndromes. Onabotulinum toxin A and incobotulinum toxin A injections, and emergency department intranasal sumatriptan are well tolerated therapies in pediatric headache.
The Influence of Hospital Physician Integration on Culture of Patient Safety
Authors: Upadhyay Soumya , Chien Lung-Chang
Published: October 2024

Background

Medical errors are responsible for a large number of deaths every year in the Unites States. Hospitals use various strategies including leadership, staffing, and structural changes to deal with this concerning issue. Hospital physician integration is a structural strategy to possibly improve patient safety. Using the conceptual lens of Donabedian’s Structure Process Outcome model, this study aims to investigate how hospital physician integration affects organizational, management, and communication attributes of patient safety culture.

Methods

A pooled cross sectional study design using the Hospital Survey on Patient Safety Culture, the American Hospital Association data, and Area Health Resource File was used to analyze the relationship between hospital physician integration and organizational and management patient safety culture attributes. The dataset comprised of hospital level data from 2021 and 2022 for patient safety culture and hospital characteristics and contained a final sample of 205 observations. The independent variable was levels of integration across five levels. Three attributes of safety culture were chosen-positive perceptions of communication openness, organizational learning, and hospital management support for patient safety. The control variables were organizational characteristics. Multivariable linear regression was used as the analytic method.

Results

Findings demonstrated a statistically significant correlation between higher level of hospital physician integration and positive perceptions of hospital management support for patient safety. There are 0.063 higher positive perceptions of hospital management support for patient safety for higher levels of integration compared with lower levels of integration (P < 0.05). Perceptions of communication openness and organizational learning did not demonstrate a statistically significant correlation with any level of hospital physician integration.

Conclusions

Hospital physician integration and hospital management support for patient safety were moderately but significantly related. Hospital physician integration allows resources to become available for physician. As physicians take on management roles management of resources and eventually performance can improve, there is a need for future research in this area to examine if integration is a step in the right direction to overcome the challenges of patient safety and if investments in resources and training can be beneficial to safety culture.
Clinical Characteristics and Outcomes of Patients With COVID-19 Treated in Mayo Clinic’s Advanced Care at Home Program
Authors: Gothot Rachel A. , Maniaci Michael J. , Paulson Margaret R. , Dumic Igor , Haney Amy A. , Li Zhuo , Maita Karla C. , Valles Brittane T. , Burger Charles D.
Published: October 2024

Objectives

Mayo Clinic’s hospital-at-home program, Advanced Care at Home (ACH), launched in 2020. While hospital-at-home literature reported safe and effective care for the general patient population and those with COVID, comparative outcomes between these two groups were unknown. The aim of this retrospective analysis was to compare the outcomes of COVID and non-COVID patients enrolled in ACH and evaluate if COVID patients can be safely treated in this setting.

Methods

Demographics, clinical characteristics, and safety outcomes were retrospectively analyzed to compare COVID and non-COVID patients discharged from ACH between November 2020 and May 2022. Patient characteristics analyzed included severity of illness (SOI) and risk of mortality (ROM), calculated using All Patient Refined Diagnosis Related Groups (APR-DRG). Hospitalization-specific variables included length of stay (LOS), escalation of care, and 30-day readmission rates.

Results

Of 1051 patients, 173 (16%) had COVID, and 878 (84%) were non-COVID patients. The average age in the COVID cohort was 66.6 (15.3) years, compared with 72.2 (14.0) in the non-COVID cohort. Extreme SOI was higher in the COVID group (43.3% versus 17.4%), as was extreme ROM (46.2% versus 16.2%), but LOS was shorter (5.7 versus 7 days). Escalation of care (7.5% in COVID cohort versus 8.4%) and 30-day readmission outcomes (9.2% for COVID patients versus 12.9%) were not statistically different between the groups.

Conclusions

Despite higher SOI and ROM, COVID patients had shorter LOS with outcomes that were not statistically different from non-COVID patients. COVID patients can be safely and efficiently cared for in ACH.
Older Adult Misuse of Over-the-Counter Medications: Effectiveness of a Novel Pharmacy-Based Intervention to Improve Patient Safety
Authors: Gilson Aaron M. , Chladek Jason S. , Stone Jamie A. , Watterson Taylor L. , Lehnbom Elin C. , Hoffins Emily L. , Berbakov Maria E. , Moon Jukrin , Jacobson Nora A. , Holden Richard J. , Gangnon Ronald E. , Walbrandt Pigarelli Denise L. , Welch Lauren L. , Portillo Edward C. , Shiyanbola Olayinka O. , Gollhardt Joel , Walker Kenneth , Chui Michelle A.
Published: October 2024

Objectives

Older adults’ (ages ≥65) inappropriate over-the-counter medications (OTC) use is prevalent, comprising Drug-Age, Drug-Drug, Drug-Disease, and Drug-Label types. Given that pharmacies sell many OTCs, structurally redesigning pharmacy aisles for improving patient safety (Senior Safe) was conceived to mitigate older adult OTC misuse, using Stop Signs and Behind-the-Counter Signs for high-risk OTCs. This study determined whether Senior Safe reduced high-risk OTCs misuse, while secondarily evaluating misuse changes for all OTCs.

Methods

A randomized controlled trial design matched and randomly allocated 20 health system community pharmacies to control or intervention groups. All 288 study participants completed an OTC choice task in which they chose a hypothetical symptom scenario (pain, sleep, cough/cold/allergy), selected an OTC, and described how they would use it at symptom onset and if symptoms persisted or worsened. Reported OTC use was evaluated for each misuse type. Intervention and control sites were compared for each misuse type using multivariate modeling.

Results

For high-risk OTCs, Drug-Age and Drug-Drug misuse were more likely in control sites (OR = 2.752, P = 0.004; OR = 6.199, P = 0.003, respectively), whereas Drug-Disease and Drug-Label misuse had too few occurrences in intervention sites for statistical comparisons. For all OTCs, only Drug-Age misuse was more likely for control sites (OR = 5.120, P = 0.001). Adults aged 85+ years had the greatest likelihood of all misuse types.

Conclusions

Results demonstrated that older adults frequently reported multiple misuse types, highlighting safety concerns. Senior Safe reduced high-risk OTC misuse, especially for older adults younger than 85 years. Cumulatively, these findings provide insights into practice recommendations supported through regulatory guidance.
Hypoxia-Inducible Factor-1α Potentiates Multiterritory Perforator Flap Survival by Augmenting Vascular Endothelial Growth Factor Expression in the Choke II Zone
Authors: Zeng Xiuan , Xie Yunfei , Guo Tao , Gao Zhenyang , Wang Kejing , Yang Qibing , Li Meng
Published: October 2024

Background

Hypoxia-inducible factor-1α (HIF-1α), regulated by prolyl hydroxylase, plays a central role in tissue adaptation to ischemia. This study investigates the impact of HIF-1α on angiogenesis in the Choke II zone of multiterritory perforator flaps.

Methods

Ninety male Wistar rats were allocated into 3 groups, with 30 rats in each group: the dimethyloxalylglycine (DMOG) group, the 3-(5-hydroxymethyl-2-furyl)-1-benzylindazole (YC-1) group, and the normal saline (NS) group. All rats underwent multiterritory perforator flap surgeries on their dorsal side. Subsequently, they received intraperitoneal injections of DMOG (40 mg/kg), YC-1 (10 mg/kg), and normal saline on postoperative days 1, 2, and 3, respectively. After treatment, angiogenesis in the Choke II zone of the flap on day 7 was observed through transillumination tests and lead oxide/gelatin x-ray angiography. Histological features were determined using hematoxylin and eosin staining, and the expression of HIF-1α and vascular endothelial growth factor (VEGF) in the Choke II region of the flap was assessed via immunohistochemistry and western blotting.

Results

Compared to the YC-1 and NS groups, the DMOG group exhibited significant angiogenesis, resulting in a denser vascular network in the Choke II zone of the flap. The DMOG group showed significantly higher microvessel density in the Choke II zone than the YC-1 and NS groups (7.10 ± 0.99 vs 24.30 ± 3.65; 14.30 ± 2.40 vs 24.30 ± 3.65, both P<0.05). Additionally, the DMOG group demonstrated higher expression of VEGF and HIF-1α in the flaps than the other groups (P < 0.05).

Conclusions

In summary, HIF-1α enhances the expression of VEGF, promoting angiogenesis in the Choke II zone of the multiterritory perforator flap, thus increasing the survival area.
The Efficacy of Naso-Alveolar Molding on Premaxilla Pushback and Dentoalveolar Changes in Patients With Bilateral Cleft Lip and Palate
Authors: Bangun Kristaninta , Tania Vika , Kreshanti Prasetyanugraheni , Pancawati Julieta , Mihardjanti Marini , Halim Jessica , Cendrick Windy
Published: October 2024

Objective:

To evaluate the extent of naso-alveolar molding (NAM) in pushing the premaxilla posteriorly in patients with bilateral cleft lip and palate (BCLP).

Background:

Naso-alveolar molding application in cleft lip and palate cases bridges the cleft gap and increases nasal tip projection. In BCLP, NAM potentially mobilizes the premaxilla posteriorly to allow tension-free primary lip closure. However, some patients with BCLP with NAM history still necessitate osteotomy during labioplasty, questioning the efficacy of NAM for BCLP management.

Methods:

This single-center retrospective study was conducted using medical records of nonsyndromic patients with BCLP. Twenty-six patients with BCLP were enrolled over a 5-year period with a history of NAM application before primary labioplasty. The changes in premaxilla width (P), anterior arch width (A), posterior arch width (R), and anteroposterior projection of the premaxilla (P’-A’) were statistically analyzed at 2 time points: (1) at the start of NAM application (T1) and (2) after completion of NAM before surgery (T2).

Results:

The average age at NAM initiation was 46.2 ± 40.4 days, and the average duration of NAM usage was 125.14 ± 62.94 days. A and P-A showed significant differences between T1 and T2 (P < 0.0001), whereas the rest did not show significant differences in value following NAM application (P > 0.05). Naso-alveolar molding successfully pushed back the premaxilla portion about 4.68 ± 2.83 mm on average.

Conclusion:

Naso-alveolar molding can push back the premaxillary protrusion up to 5 mm, which can serve as a cutoff point for the consideration of combined modalities. Prenatal diagnosis, counseling, and cleft education should be the benchmark in cleft centers to improve overall patient outcomes.
First Moroccan Case of Infective Endocarditis Due to NDM-Type Carbapenemase-Producing Serratia marcescens in a Preterm Infant: A Case Report
Authors: Malihy Zakaria , El Abdallaoui Ikram , Abassor Tilila , Sghir Salah , Ben lahlou Yassine , Abilkassem Rachid , Benaissa Elmostafa , Chadli Mariama
Published: October 2024

Serratia marcescens (S. marcescens) is a Gram-negative rod-shaped bacterium belonging to the Enterobacteriaceae family, commonly found in various environments. This opportunistic pathogen can cause urinary tract infections, respiratory infections, and septicemia, but endocarditis is particularly rare and concerning due to its rapid and devastating progression. We report the second case in the world of infective endocarditis (IE) caused by S. marcescens in a preterm infant born at 34 weeks of gestation. The patient was a preterm male infant born at 34 weeks of gestation, from a triplet pregnancy, admitted to the neonatal intensive care unit on day 2 of life for respiratory distress. The mother, aged 39, had undiagnosed gestational diabetes. Premature rupture of membranes had occurred 10 days before delivery, necessitating prophylactic treatment with amoxicillin. On day 4 of life, the newborn developed a fever with elevated CRP levels and leukocytosis, leading to antibiotic therapy with colistin, imipenem, and amikacin. Blood cultures revealed the presence of carbapenemase-producing S. marcescens sensitive to fluoroquinolones. A cardiac ultrasound showed vegetations on the mitral valve, confirming the diagnosis of IE. Despite intensive treatment, the newborn died on day 16 of life due to septic shock. This rare case of endocarditis caused by S. marcescens highlights the severity of this infection in preterm infants. Treatment relies on appropriate antibiotic therapy. Prevention requires strict hygiene measures. Further research is needed to establish optimal therapeutic recommendations.
Does PERM1 Regulate Systolic Cardiac Function? A Game of Numbers
Authors: Zaitsev Alexey V. , Sreedevi Karthi , Goode Brianna , Warren Junco S.
Published: October 2024

We and others demonstrated that PERM1 is a positive regulator of mitochondrial bioenergetics in the heart. However, discrepant results have emerged with regard to whether PERM1 loss-of-function affect cardiac contractility. In order to exclude the possibility that the reported negative results can be due to insufficient power of statistical test, we conducted a more robust echocardiography (Echo) analysis by increasing the sample size. We usedPerm1-KO and their respective wildtype (WT) littermates, which were destined to tissue harvest. This yielded 84 WT mice and 88Perm1-KO mice. We analyzed Echo-derived parameters of left ventricular (LV) systolic function. At the end of the study, ejection fraction (EF) was 65.43 ± 7.13 in WT vs. 53.98 ± 8.80 in Perm1-KO yielding p < 0.00000000000000004. Other parameters which reached statistically significant difference between WT andPerm1-KO (at p < 0.05) included LV fractional shortening (FS), LV diastolic and systolic diameters, LV anterior and posterior systolic wall thickness, LV posterior wall systolic thickening, stroke volume, and cardiac output (CO). Retrospectively, a p value < 0.05 was consistently achieved in assessment of EF only after average N per group reached 13. Larger minimal N per group were required for other parameters. Of interest, in both groups there were no correlation between EF% and CO. At the same time, in both groups EF strongly inversely correlated with LV diastolic diameter. This led us to a speculation that low EF may be in part compensated by an increased LV circumference, for the purpose of maintaining invariant CO. Indeed, the intergroup difference in CO (6%) was much smaller than the intergroup difference in EF (18%). We conclude that PERM1 does regulate cardiac mechanics. Changes caused by constitutivePerm1-KO can be conceptualized as reduced contractility partially compensated by increased LV circumference. This study underscores the importance of sufficiently large sample size for detecting significant differences in Echo data.
Bio-engineering a common probiotic to exploit colonic inflammation promotes reliable efficacy in translational models of colitis
Authors: Verdugo-Meza Andrea , Gill Sandeep K. , Godovannyi Artem , Adur Malavika K. , Barnett Jacqueline A. , Estaki Mehrbod , Ye Jiayu , Haskey Natasha , Mehain Hannah , Josephson Jessica K. , Ishida Ray , Ghesquiere Chanel , Sly Laura M. , Gibson Deanna L.
Published: October 2024

The intricate balance between the gut microbiome and host health inspires innovations in drug development. Commensal bacteria provide a multi-targeted approach ideal for treating complex medical conditions, like inflammatory bowel disease (IBD). These bacteria are self-replicating factories with broad targets that promote balanced intestinal inflammation, mucosal barrier function, and eubiosis. Yet, the lack of superiority to gold-standard treatments and their clinical inconsistency makes most probiotics unreliable for disease treatments. Intestinal inflammation, a driving factor in many diseases, often overwhelms commensal bacteria, which lack the stress-resistance mechanisms necessary to withstand host immune defenses. To address this, we introduced a persistence platform BioPersist™ intoE. coliNissle 1917. We hypothesized that a bio-engineered probiotic, or genetically engineered microbial medicine (GEMM™), designed to persist during inflammation would enhance probiotic bioavailability during colitis, leading to sustained therapeutic outcomes. We evaluated BioPersist in multiple translational colitis models such as in mice and pigs. BioPersist delayed the onset and reduced the severity of both chronic and acute colitis, proving more effective than 5-aminosalicylate. BioPersist thrived during inflammation promoting tolerogenic immune responses that limited infiltrating leukocyte activity and decreased TNF-α from resident myeloid cells in the mesentery. The persistence feature of BioPersist allowed the probiotic to overcome the damaging inflammatory response, eliciting mucosal healing evident by the increase in microbially-derived butyric acid. Based on these preclinical results, BioPersist may be a novel therapeutic option for both human and veterinary applications that sustains efficacy during colitis.

One Sentence Summary

Adding a persistence feature to a probiotic enhances its efficacy for colitis treatment, enhancing future human and veterinary therapeutic applications.
Gut microbial metabolic flux disorder in hypertension
Authors: Lai Wenkai , Zhang Yuchen , Wang Meiling , Lai Shirong , Liu Qing , Luo Qi , Zou Quan , Yang Fenglong
Published: October 2024

Hypertension is a major risk factor for cardiovascular diseases such as stroke and heart failure. Recent studies have shown that changes in the composition and function of the gut microbiota are closely related to the onset and development of hypertension. However, the individual differences in gut microbiota species make it difficult for traditional analysis methods to effectively reveal the pathogenic mechanisms of hypertension. In contrast, the inter-individual variability in gut microbial metabolites is much smaller, allowing for better cross-individual comparisons and reducing confounding factors in analysis. The interactions between gut microbiota and metabolites are highly complex, and network analysis can systematically capture this complexity. In this study Flux Balance Analysis (FBA) was utilized to predict the metabolic flux of gut microbiota and constructed cross-feeding networks. Random Forest and XGBoost models were employed to identify metabolites associated with hypertension. A differential microbial correlation network was used to analyze important metabolically related microbial sub-networks, and ultimately, the metabolic abnormalities and metabolite-related pathways were analyzed at the network level using the metabolite correlation network and cross-feeding networks. It was observed that the interaction patterns among 25 species—collectively referred to as the KEPR guild, with the most abundant genera being Eubacterium, Ruminococcus, Klebsiella, and Parabacteroides—changed, leading to alterations in 12 metabolites, such as choline (chol), 1-butanol (btoh), trimethylamine (tma), cytidine (cytd), and betaine (glyb) etc. Choline can be oxidized to form betaine, thereby affecting host blood pressure. Abnormalities in siroheme and methanethiol may result in reduced secretion of hydrogen sulfide by microbes, which in turn impacts blood pressure regulation mechanisms. The changes in these 12 metabolites may also enhance the degradation of mucin-type O-glycans and reduce butyrate metabolic activity, weakening the protective ability of intestinal epithelial cells. This may lead to inflammation and oxidative stress, exacerbating endothelial cell damage and consequently resulting in endothelial dysfunction and increased blood pressure. The findings of this study provide new insights into the pathogenic mechanisms of hypertension and offer potential targets for clinical intervention.
Structural basis of TMPRSS11D specificity and autocleavage activation
Authors: Fraser Bryan J. , Wilson Ryan P. , Ilyassov Olzhas , Lac Jackie , Dong Aiping , Li Yen-Yen , Seitova Alma , Li Yanjun , Hejazi Zahra , Kenney Tristan M.G. , Penn Linda Z. , Edwards Aled , Morin Gregg B. , Bénard François , Arrowsmith Cheryl H.
Published: October 2024

Transmembrane Protease, Serine-2 (TMPRSS2) and TMPRSS11D are human proteases that enable SARS-CoV-2 and Influenza A/B virus infections, but their biochemical mechanisms for facilitating viral cell entry remain unclear. We demonstrate these proteases can spontaneously and efficiently cleave their own zymogen activation motifs, thereby activating their wider protease activity on other cellular substrates. We determined TMPRSS11D co-crystal structures in complexes with a native TMPRSS11D zymogen activation motif and with an engineered activation motif, providing insights into TMPRSS11D autocleavage activation and revealing unique regions of its substrate binding cleft. We further show that a protease inhibitor that underwent clinical trials for TMPRSS2-targeted COVID-19 therapy, nafamostat mesylate, was rapidly cleaved by TMPRSS11D and converted to low activity derivatives. These insights into human protease viral tropism and into liabilities with existing human serine protease inhibition strategies will guide future drug discovery campaigns for these targets.
Late Quaternary climatic impact on the woodland strawberry genome: a perennial herb's tale
Authors: Toivainen Tuomas , Salonen J. Sakari , Kirshner Jonathan , Lembinen Sergei , De Kort Hanne , Lyyski Annina , Edger Patrick P. , Hilmarsson Hrannar Smari , Hallsson Jon Hallsteinn , Sargent Daniel J. , Olbricht Klaus , Sanchez-Sevilla Jose F. , Jaakola Laura , Stenberg Johan A. , Duralija Boris , Labokas Juozas , Vare Henry , Salojarvi Jarkko , Auvinen Petri , Pose David , Albert Victor A , Hytonen Timo
Published: October 2024

Exploring a species paleohistory is crucial for understanding its responsiveness to climatic events, identifying drivers of adaptation, and developing effective biodiversity conservation strategies in the face of ongoing climate change. We analyzed 200 genomes of the perennial herb woodland strawberry (Fragaria vesca L.) from across Europe and investigated the population structure and demographic history of the species during past geoclimatic events. We found a clear division of populations into western and eastern genetic clusters, indicative of distinct glacial refugia and adaptations to variation in temperature seasonality. The eastern core populations were several times larger (defined as effective population size, NE) than populations in other regions, showed no evidence of inbreeding, and were resilient to several glacial maxima. However, we observed decreasing NE and higher inbreeding in populations toward range edges, particularly in the north, where these individuals went through bottlenecks during glaciations. Population divergence suggested that western and eastern Europe were colonized from separate refugia in multiple waves during the Holocene, while the largest current populations from the northern Mediterranean to southern regions of the Nordic countries formed a connected population chain with gene flow between eastern core populations and western Europe, primarily occurring through Central Europe. Similar patterns of colonization and hybridization may have occurred during past interglacial periods, contributing to the present-day population structure of woodland strawberry. We suggest that the unprecedented resolution of the species climatic history across six glacial-interglacial cycles presented here holds the promise of transforming the general understanding of species paleohistory through geoclimatically tracing ancestral haplotypes.
SOX10 and microRNAs: decoding their interplay in regulating melanoma plasticity
Authors: Lai Xin , Luan Chunyan , Zhang Zhesi , Wessely Anja , Heppt Markus V. , Berking Carola , Vera Julio
Published: October 2024

Recent studies show that the dysregulation of the transcription factor SOX10 is essential for development and progression of melanoma. MicroRNAs (miRNAs) can regulate the expression of transcription factors at the post-transcriptional level. The interactions between SOX10 and its targeting miRNAs form network motifs such as feedforward and feedback loops. Such motifs can result in non-linear dynamics in gene expression levels, therefore playing a crucial role in regulating tumor proliferation and metastasis as well as tumor’s responses to therapies. Here, we reviewed and discussed the intricate interplay between SOX10 and miRNAs in melanoma biology including melanogenesis, phenotype switch, and therapy resistance. Additionally, we investigated the gene regulatory interactions in melanoma, identifying crucial network motifs that involve both SOX10 and miRNAs. We also analyzed the expression levels of the components within these motifs. From a control theory perspective, we explained how these dynamics are linked to the phenotypic plasticity of melanoma cells. In summary, we underscored the importance of employing a data-driven network biology approach to elucidate the complex regulatory mechanisms and identify driver network motifs within the melanoma network. This methodology facilitates a deeper understanding of the regulation of SOX10 by miRNAs in melanoma. The insight gained could potentially contribute to the development of miRNA-based treatments for SOX10, thereby enhancing the clinical management of this malignancy.
Suspended and sinking particle-associated microbiomes exhibit distinct lifestyles in the Elbe estuary
Authors: Tobias-Hünefeldt Sven P. , Woodhouse Jason N. , Ruscheweyh Hans-Joachim , Sunagawa Shinichi , Russnak Vanessa , Streit Wolfgang R. , Grossart Hans-Peter
Published: October 2024

Estuaries are important components of the global carbon cycle; exchanging carbon between aquatic, atmospheric, and terrestrial environments, representing important loci for blue carbon storage and greenhouse gas emissions. Estuarine particles are especially important due to their microbial transformation and vertical/horizontal transport. We used metagenomes and metatranscriptomes to assess changes in microbial community composition and functions across the Elbe estuary over one year, linking changes to dissolved and particulate organic matter. We will be the first to link microbial activity derived from molecular data to particulate and dissolved organic carbon characteristics. There were no microbial species responses to the measured physicochemical and dissolved/particulate organic matter parameters, however Weighted Correlation Network Analyses showed significant spatial microbiome differences linked to the estuarine salinity profile. Meanwhile, suspended and sinking particle fractions did not show any community wide differences, but individual gene analyses revealed clear microbial lifestyle differences. Sinking particle-associated transcripts highly expressed competition and stress-responses genes, while suspended particle-associated transcripts favoured energy acquisition and growth. Transcription patterns further indicate that suspended particles may represent a mitigating influence on methane release via methanotrophy, while both suspended and sinking particles produce methane through the same gene complex. This notion suggests that increased sinking particle abundance, such as under high turbidity conditions, leads to increased methane production. Our findings further imply that urban activities such as dredging may have a high impact on greenhouse gas emissions, and higher suspended-sinking particle ratios may alleviate aquatic-atmospheric methane exchanges. Future studies should explore in detail the underlying mechanisms and controlling variables, in particular when taking predicted global changes into account.
Acute and chronic pesticide exposure trigger fundamentally different molecular responses in bumble bee brains
Authors: Witwicka Alicja , López-Osorio Federico , Arce Andres , Gill Richard J , Wurm Yannick
Published: October 2024

Beneficial wild insects including pollinators encounter various pesticide exposure conditions, from brief high concentrations to continuous low-level exposure. To effectively assess the environmental risks of pesticides, it is critical to understand how different exposure patterns influence their effects. Unfortunately, this knowledge remains limited. To clarify whether different exposure schemes disrupt the physiology of pollinators in similar manners, we exposed bumble bees to acute and chronic treatments of three different pesticides: Acetamiprid, clothianidin, and sulfoxaflor. Gene expression profiling enabled us to compare the effects of these treatments on the brain in a high-resolution manner. There were two main surprises: First, acute and chronic exposure schemes affected largely non-overlapping sets of genes. Second, different pesticides under the same exposure scheme showed more comparable effects than the same pesticide under different exposure schemes. Acute exposure caused up-regulation of stress response mechanisms causing distinct regulatory changes, rather than amplifying the effects of prolonged low-dose exposure that affected predominantly immunity and energy metabolism. These findings show that the mode of exposure critically determines the effects of pesticides. Our results signal the need for safety testing practices to better consider mode-of-exposure dependent effects and suggest that transcriptomics can support such improvements.
Identification of potential sepsis therapeutic drugs using a zebrafish rapid screening approach
Authors: Widder Mark , Carbaugh Chance , van der Schalie William , Miller Ronald , Brennan Linda , Moore Ashley , Campbell Robert , Akers Kevin , Ressner Roseanne , Martin Monica , Madejczyk Michael , Dancy Blair , Lee Patricia , Lanteri Charlotte
Published: October 2024

In the military, combat wound infections can progress rapidly to life-threatening sepsis. Discovery of effective small molecule drugs to prevent and/or treat sepsis is a priority. To identify potential sepsis drug candidates, we used an optimized larval zebrafish model of endotoxicity/sepsis (Philip et al., 2017) to screen commercial libraries of U.S. Food and Drug Administration (FDA)- approved drugs and other active pharmaceutical ingredients (API) known to affect pathways implicated in the initiation and progression of sepsis in humans (i.e., inflammation, mitochondrial dysfunction, coagulation, and apoptosis). We induced endotoxicity in 3- and 5-day post fertilization larval zebrafish (characterized by mortality and tail fin edema (vascular leakage)) by immersion exposure toPseudomonas aeruginosa60 μg/mL lipopolysaccharide (LPS) for 24 hours, then screened for the rescue potential of 644 selected drugs simultaneously with LPS at 10 μM. After LPS exposure, we used a neurobehavioral assay (light-dark test) to further evaluate rescue from endotoxicity and to determine possible off-target drug side effects. We identified 29 drugs with > 60% rescue of tail edema and mortality. Three drugs (Ketanserin, Tegaserod, and Brexpiprazole) produced 100% rescue and did not differ from the controls in the light-dark test, suggesting a lack of off-target neurobehavioral effects. Further testing of these three drugs at a nearly 100% lethal concentration ofKlebsiella pneumoniaeLPS (45 μg/mL) showed 100% rescue from mortality and 88%-100% mitigation against tail edema. The success of the three identified drugs in a zebrafish endotoxicity/sepsis model warrants further evaluation in mammalian sepsis models.
Four cell wall-degrading enzymes ofXanthomonas campestrispv.campestrisdetermine bacterial escape from hydathodes to the leaf vasculature
Authors: Paauw Misha , Giesbers Marcel , Pfeilmeier Sebastian , van den Burg Harrold A.
Published: October 2024

To colonize plants, pathogenic bacteria modulate the biology of the host employing different bacterial secretion systems. For example, the type II secretion system (T2SS) releases toxins, proteases, lipases and carbohydrate-degrading enzymes into the extracellular environment to promote tissue softening and soft rot. In this way, the T2SS promotes virulence of phytopathogenic Gram-negative bacteria. However, the role of the T2SS and its substrates for vascular disease remains enigmatic. Here, we show that the Xps-T2SS allowsXanthomonas campestrispv.campestris(Xcc) to breach the tissue barrier between hydathodes– the initial bacterial entry point – and xylem thereby gaining access to the leaf vasculature. Yet, Xps-T2SS was dispensable for bacterial multiplication in the leaf apoplast or inside the hydathode cavity suggesting a role beyond plant defense suppression or nutrient acquisition. Using comparative genomics, four plant cell wall-degrading enzymes (CWDEs) were found to be associated with vascular pathogenesis. Testing gene knockout combinations of those enzymes revealed that virulence of only the quadruple CWDE mutant was down to the level of thexps-T2SS mutant. Our results thus demonstrate that the Xps-T2SS and a set of CWDEs that is likely secreted by this system allow Xcc to break this tissue barrier enabling long-distance mobility of Xcc inside the host plant. We thus expand our understanding on how certain bacterial pathogens have specialized towards vascular pathogens.
UniScore, a unified and universal measure for peptide identification by multiple search engines
Authors: Tabata Tsuyoshi , Yoshizawa Akiyasu C. , Ogata Kosuke , Chang Chih-Hsiang , Araki Norie , Sugiyama Naoyuki , Ishihama Yasushi
Published: October 2024

We propose UniScore as a metric for integrating and standardizing the outputs of multiple search engines in the analysis of data-dependent acquisition (DDA) data from LC/MS/MS-based bottom-up proteomics. UniScore is calculated from the annotation information attached to the product ions alone by matching the amino acid sequences of candidate peptides suggested by the search engine with the product ion spectrum. The acceptance criteria are controlled independently of the score values by using the false discovery rate based on the target-decoy approach. Compared to other rescoring methods that use deep learning-based spectral prediction, larger amounts of data can be processed using minimal computing resources. When applied to large-scale global proteome data and phosphoproteome data, the UniScore approach outperformed each of the conventional single search engines examined (Comet, X! Tandem, Mascot and MaxQuant). Furthermore, UniScore could also be directly applied to peptide matching in chimeric spectra without any additional filters.
Shaping tiny worlds: Paternal microbiota manipulation influences offspring microbial colonization and development in a sex role-reversed pipefish
Authors: Wagner Kim-Sara , Salasc Frédéric , Marten Silke-Mareike , Roth Olivia
Published: October 2024

Microbes are acquired through vertical and environmental horizontal transmission. Vertical transmission is directly linked to reproductive success and entails early transmission, facilitating coexistence of host and microbes over generations. The multiple potentially interacting routes of vertical transmission are challenging to be disentangled in conventional sex-role species, as they are mostly intermingled on the maternal side, i.e., through egg production, pregnancy, birth and postnatal care. The evolution of male pregnancy in syngnathids (pipefishes and seahorses) offers an opportunity to separate vertical microbial provisioning through the egg (maternal) from provisioning through pregnancy (paternal). We experimentally evaluated the existence and role of paternal microbiota provisioning through male pregnancy on offspring development and microbial colonization. Male pipefish were exposed to antibiotics, and subsequently recolonized with bacteria of paternal, maternal, and environmental origin (spike treatment). After pregnancy, the microbiome (16s rRNA) of developing offspring was repeatedly ribotyped. Paternal antibiotic and spike treatments influenced the microbial composition of the brood pouch and offspring microbiome development. Paternal spike treatment gave offspring a kickstart in life by reducing pregnancy duration and inducing offspring survival. Expanding on how distinct vertical microbial transmission routes shape offspring microbiome will foster our understanding of the holobiont function in health and disease.
Genome diversification of symbiotic fungi in beetle-fungus mutualistic symbiosis
Authors: Huang Yin-Tse , Abdrabo Khaled Abdrabo El-Sayid , Phang Guan Jie , Fan Yu-Hsuan , Wu Yu-Ting , Ou Jie-Hao , Hulcr Jiri
Published: October 2024

Ambrosia beetles and their fungal symbionts represent a widespread and diverse insect-fungus mutualism. This study investigates the genomic adaptations associated with the evolution of the ambrosia lifestyle across multiple fungal lineages. We performed comparative genomic analyses on 70 fungal genomes from four families (Irpicaceae, Ceratocystidaceae, Nectriaceae, and Ophiostomataceae), including 24 ambrosia and 34 non-ambrosia lineages. Our phylogenomic analyses reveal multiple independent colonization of insect vectors by the fungi, spanning from the mid-Cretaceous (114.6 Ma) to the early Quaternary (1.9 Ma). Contrary to expectations for obligate symbionts, ambrosia fungi showed no significant genome-wide reductions in size, gene count, or secreted protein repertoire compared to their non-symbiotic relatives. Instead, we observed complex, lineage-specific patterns of genomic adaptation. Key findings include lineage-specific expansions in carbohydrate-active enzyme families (AA4 in Nectriaceae, CE4 in Ophiostomataceae, and GH3 in Ophiostomataceae and Ceratocystidaceae), suggesting potential enhancement or loss of lignin modification, hemicellulose deacetylation, and cellulose degradation in different ambrosia lineages. Repeat-Induced Point mutation analysis revealed family-specific patterns rather than lifestyle-associated differences. These results highlight the diverse genomic strategies employed by ambrosia fungi, demonstrating that symbiont evolution can proceed through refined, lineage-specific changes rather than genome-wide, or convergent alterations. Our study suggests that unlike other insect-farmed fungi, ambrosia fungi are not domesticated crops, but rather free-living fungi which co-opted wood boring beetles as vectors via subtle, lineage-specific adaptations.
Decoding sequence determinants of gene expression in diverse cellular and disease states
Authors: Lal Avantika , Karollus Alexander , Gunsalus Laura , Garfield David , Nair Surag , Tseng Alex M , Gordon M Grace , Blischak John D , Van de Geijn Bryce , Bhangale Tushar , Collier Jenna L , Diamant Nathaniel , Biancalani Tommaso , Corrada Bravo Hector , Scalia Gabriele , Eraslan Gokcen
Published: October 2024

Sequence-to-function models that predict gene expression from genomic DNA sequence have proven valuable for many biological tasks, including understanding cis-regulatory syntax and interpreting non-coding genetic variants. However, current state-of-the-art models have been trained largely on bulk expression profiles from healthy tissues or cell lines, and have not learned the properties of precise cell types and states that are captured in large-scale single-cell transcriptomic datasets. Thus, they lack the ability to perform these tasks at the resolution of specific cell types or states across diverse tissue and disease contexts. To address this gap, we present Decima, a model that predicts the cell type- and condition- specific expression of a gene from its surrounding DNA sequence. Decima is trained on single-cell or single-nucleus RNA sequencing data from over 22 million cells, and successfully predicts the cell type-specific expression of unseen genes based on their sequence alone. Here, we demonstrate Decima's ability to reveal the cis-regulatory mechanisms driving cell type-specific gene expression and its changes in disease, to predict non-coding variant effects at cell type resolution, and to design regulatory DNA elements with precisely tuned, context-specific functions.
DNA methylation clocks struggle to distinguish inflammaging from healthy aging, but feature rectification improves coherence and enhances detection of inflammaging
Authors: Skinner Colin M. , Conboy Michael J. , Conboy Irina M.
Published: October 2024

Biological age estimation from DNA methylation and determination of relevant biomarkers is an active research problem which has predominantly been tackled with black-box penalized regression. Machine learning is used to select a small subset of features from hundreds of thousands CpG probes and to increase generalizability typically lacking with ordinary least-squares regression. Here, we show that such feature selection lacks biological interpretability and relevance in the clocks of the first- and next-generations, and clarify the logic by which these clocks systematically exclude biomarkers of aging and disease. Moreover, in contrast to the assumption that regularized linear regression is needed to prevent overfitting, we demonstrate that hypothesis-driven selection of biologically relevant features in conjunction with ordinary least squares regression yields accurate, well-calibrated, generalizable clocks with high interpretability. We further demonstrate that the interplay of disease-related shifts of predictor values and their corresponding weights, which we term feature shifts, contributes to the lack of resolution between health and disease in conventional linear models. Lastly, we introduce a method of feature rectification, which aligns these shifts to improve the distinction of age predictions for healthy people vs. patients with various diseases.

Key Findings

There is no apparent biological significance of the CpGs selected by first- and next-generation clocks

The range of residuals for first- and next-generation clock predications on healthy samples is very large; for all models tested, a prediction error of +/-10-20 years is within the 95% range of variation for healthy controls and does not signify age acceleration

There is no significant shift in the mean of residuals for patient populations relative to healthy populations for most studied first- and next-generation clocks. For those with significance, the effect size is very small.

Hypothesis-driven feature pre-selection, coupled with modified forward step-wise selection yields age predictors on par with first and next-generation clocks. EN/ML is not needed.

Disease-related shifts at different CpG probes, along with learned model weights, can be either positive or negative; their combination leads to de-coherence effect in linear models.

Model coherence can be induced by rectifying features to have only positive shifts in patient samples; this provides a better resolution between health and disease in DNAm age models, and expectedly, introduces more non-linearity to the input data.