bluuebunny/crossref_metadata_2025 huggingface dataset:
The Association of the Lactate-Albumin Ratio With Mortality and Multiple Organ Dysfunction in PICU Patients*
Authors: Ray Christopher C. , Pollack Murray M. , Gai Jiaxiang , Patel Anita K.
Published: May 2023

OBJECTIVES:

To compare the relative associations of lactate, albumin, and the lactate-albumin ratio (LAR) measured early in disease course against mortality and prevalence of multiple organ dysfunction syndrome (MODS) in a general sample of critically ill pediatric patients.

DESIGN:

Retrospective analysis of the Health Facts (Cerner Corporation, Kansas City, MO) national database.

SETTING:

U.S. hospitals with PICUs.

PATIENTS:

Children admitted to the ICU (n = 648) from 2009 to 2018 who had lactate and albumin measured within 6 hours of admission.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

A total of 648 admissions were included, with an overall mortality rate of 10.8% (n = 70) and a MODS prevalence of 29.3% (n = 190). Compared with survivors, deaths had higher initial lactates (7.3 mmol/L [2.6–11.7 mmol/L] vs 1.9 mmol/L [1.2–3.1 mmol/L]; p < 0.01), lower initial albumins (3.3 g/dL [2.7–3.8 g/dL] vs 4.2 g/dL [3.7–4.7 g/dL]; p < 0.01), and higher LARs (2.2 [1.0–4.2] vs 0.5 [0.3–0.8]; p < 0.01), with similar trends in patients with MODS versus those without MODS. LAR demonstrated a higher odds ratio (OR) for death than initial lactate alone (2.34 [1.93–2.85] vs 1.29 [1.22–1.38]) and a higher OR for MODS than initial lactate alone (2.10 [1.73–2.56] vs 1.22 [1.16–1.29]). Area under the receiver operating characteristic (AUROC) curve of LAR for mortality was greater than initial lactate (0.86 vs 0.82; p < 0.01). The LAR AUROC for MODS was greater than the lactate AUROC (0.71 vs 0.66; p < 0.01). Trends of lactate, albumin, and LAR for mortality were consistent across several diagnostic subgroups (trauma, primary respiratory failure, toxicology), but not all.

CONCLUSIONS:

LAR measured early in the course of critical illness is significantly associated with mortality and development of MODS when compared with initial lactate or initial albumin alone in critically ill pediatric patients.
Surgical Outcomes of Autologous Breast Reconstruction in Low BMI Patients; Beyond the Gold Standard DIEP Flap
Authors: Haddock Nicholas T. , Mejia Martinez Valeria , Teotia Sumeet S.
Published: May 2023

Background:

Autologous breast reconstruction provides higher satisfaction than implant-based reconstruction in women with low Body Mass Index (BMI). However, the gold standard of microvascular breast reconstruction, the Deep Inferior Epigastric Perforator (DIEP) flap, can be challenging to achieve due to the paucity of adnominal bulk in these patients. This study compares operative outcomes in women with BMIs less than 23.5 following reconstruction after one of three free flap methods: The DIEP flap, alternative flaps (I.e., lumbar artery perforator flap (LAP) or profounda artery perforator flap (PAP)), and stacked flaps.

Methods:

A retrospective study was conducted on thin patients (BMI < 23.5) who underwent autologous breast reconstruction between 2010 and 2021 by two senior authors (NTH, SST) at a single institution. One hundred and fifteen patients were divided into three reconstructive groups. Flap weights, complication rates, secondary revisions, and fat grafting in each group were then compared.

Results:

The success rate in all three groups was 100%, with only one partial flap loss in the stacked group. There was a significant difference in overall minor complications and donor complications between the three groups, with alternative flaps experiencing the most. All three groups had similar incidences of recipient breast complications, medical complications, need for secondary revisions, and amount of fat grafted.

Conclusions:

Autologous breast reconstruction in low BMI patients yields successful and durable results. This study shows that predictable results in the thin patient population can be obtained via alternate autologous methods beyond the gold standard DIEP flap.
Macrosomia is associated with overweight in childhood: a follow-back of a cohort established in the early years of the obesity epidemic
Authors: Adebile Temitayo , Orji Amarachukwu F. , Twum Felix , Zhang Jian
Published: May 2023

Objective:

Interventions currently recommended to control and prevent obesity have not been successful. Recent research has shifted toward the transgenerational cycle of obesity. We assessed the association between fetal macrosomia and early childhood body weight.

Methods:

We conducted a follow-back study to link birth certificate data to the Third National Health and Nutrition Examination Survey (1988–1994) of 2621 United States-born singletons aged 2–6 years. Birth weight and gestational age data were collected from birth certificates. Fetal macrosomia was defined as ≥90th percentile of gestational age-race-sex-parity specific body weight distribution in 1989 vital statistics.

Results:

With 12.7% (standard error = 0.85%) of participants born macrosomic, the prevalence of obesity and overweight (BMI percentiles ≥85th in the CDC growth chart) among children was 17.8% (1.17%). When the body weight was measured against age-sex-specific height (BMI percentiles), macrosomia was significantly associated with overweight and obesity (odds ratio [OR] = 1.64, 95% confidence interval = 1.07–2.50) adjusted for family income, maternal age and marital status, race, maternal smoking during pregnancy, and breastfeeding. The association became insignificant after adjusting for postnatal lifestyle and parental body mass index (OR = 1.38 [0.84-2.26]]. When body weight was measured against age, children who were too heavy for their age were more likely to be born macrosomically (OR = 2.64 [1.66-4.22]) than their peers with healthy age-specific body weight.

Conclusion:

Fetal macrosomia was significantly associated with a doubled risk of heavy body weight in children aged 2–6 years.
Clinical Characteristics and Outcomes of Mexican Patients With Behçet’s Syndrome
Authors: Hinojosa-Azaola Andrea , Ramírez-Mulhern Isabela , Figueroa-Pariente Ana , Martín-Nares Eduardo
Published: May 2023

Objective

The aim of this study was to describe the clinical characteristics and outcomes of Mexican patients with Behçet syndrome (BS) from a single center.

Methods

This medical records review study included patients with established BS diagnosis, followed up in a tertiary care center in Mexico City from 2000 to 2020. Demographics, clinical characteristics, laboratory and imaging studies, disease activity, damage, treatment, and outcomes were assessed and compared according to sex and with other international cohorts. Descriptive statistics were used, and differences between groups were evaluated using the χ
2 or Mann-Whitney U tests.

Results

Thirty-eight patients were included, 23 (60%) women and 15 (40%) men; the median age at BS diagnosis was 33 years (range, 24–39 years). The most frequent manifestations at diagnosis were recurrent oral and genital ulcers in 34 (89%) and 29 (76%), respectively, musculoskeletal in 21 (55%), and cutaneous in 15 (39%). The most frequent phenotype was the joint involvement. Treatment comprised prednisone in all, colchicine (24 [63%]), pentoxifylline (12 [32%]), and thalidomide (10 [26%]). During a median follow-up time of 12.5 years (range, 7–23 years), relapses were frequent (97%), severe infections were present in 5 patients (13%), and 2 patients (5%) died due to sepsis and pneumonia. Men showed a higher frequency of arterial hypertension (47% vs. 13%, p = 0.03) and thrombosis (20% vs. 0, p = 0.05), and a lower frequency of genital ulcers (40% vs. 78%, p = 0.03) than women.

Conclusions

This cohort of Mexican patients with BS showed a predominance of female sex, joint involvement phenotype, frequent relapses, and favorable outcomes. Differences in comorbidities and clinical manifestations were identified according to sex.
Single-Port Robotic Intersphincteric Resection for the Treatment of Rectal Cancer
Authors: Kim Hye Jin , Choi Gyu-Seog , Song Seung Ho , Park Jun Seok , Park Soo Yeun , Lee Sung Min , Na Dong Hee , Jeong Min Hye
Published: May 2023

Background:

The da Vinci Single-port (SP) system is designed to facilitate single-incision robotic surgery in a narrow space. We developed a new procedure of intersphincteric resection (ISR) using the SP platform and evaluated the technical safety and feasibility of this procedure for the treatment of very low rectal cancer.

Materials and Methods:

Eleven rectal cancer patients who underwent SP robotic ISR between August 2020 and July 2021 were included. Patients’ clinical characteristics, operative and pathologic findings of the patients were retrospectively analyzed.

Results:

The median tumor height was 3 cm (range, 2–4 cm). A single docking was performed, and the median docking time was 3 min 10 sec (range, 2 min 50 sec–3 min 30 sec). The median total operation time was 210 min (range, 150–280 min), and the median time of pelvic dissection was 57 min (range, 45–68 min). All patients presented with negative distal resection margins [median 1 cm (range, 0.5–2.0 cm)], and only one patient had less than 1mm of circumferential resection margin (0.9 mm).

Conclusions:

Our initial experience suggests that SP robotic ISR is safe and feasible.
Halomonas dongshanensis sp. nov., isolated from the seawater of Dongshan Island
Authors: Lin Wen-zhen , Gong Lin-feng , Guo Ying , Liu Ru-zhen , Xu Wei , Guan Qi-yang , Guo Chi-ming , Lin Zhi-kai , Meng Hong-yan , Chen Xiao-yao
Published: May 2023

A taxonomic study was carried out on strain yzlin-01T, isolated from Dongshan Island seawater. The bacterium was Gram-stain-negative, catalase-positive, oxidase-negative, rod-shaped, and motile by polar flagella. Growth was observed at temperatures of 10–40 °C, at salinities of 0.5–18 %, and at pH of 6–10. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain yzlin-01T belonged to the genus

Halomonas

, with the highest sequence similarity to

Halomonas malpeensis

YU-PRIM-29T (96.7 %), followed by

Halomonas johnsoniae

T68687T (96.4 %) and

Halomonas gomseomensis

M12T (96.4 %), and other species of the genus

Halomonas

(93.4–96.3 %). The ANI and digital DNA–DNA hybridization estimate values between strain yzlin-01T and the closest type strain

Halomonas malpeensis

YU-PRIM-29T were 77.44 and 21.6 %, respectively. The principal fatty acids were summed feature 8 (consisting of C18 : 1
 ω7c and/or C18 : 1
 ω6c; 55.7 %), C16 : 0 (20.6 %), C12 : 0 3-OH (6.8 %), summed feature 3 (consisting of C16 : 1
 ω7c and/or C16 : 1
 ω6c; 5.1 %). The G+C content of the chromosomal DNA was 60.0 mol %. The respiratory quinone was identified as Q-9 (100 %). Phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, aminophospholipid, and three unidentified phospholipids were present. Combined genotypic and phenotypic data suggest that strain yzlin-01T represents a novel species within the genus

Halomonas

, for which the name Halomonas dongshanensis sp. nov. is proposed, with the type strain yzlin-01T (=GDMCC 1.3202T=KCTC 92467T).
Cellulosimicrobium fucosivorans is a later heterotypic synonym of Cellulosimicrobium composti
Authors: Jiang Lingmin , Han Ho Le
Published: May 2023

The taxonomic relationship of

Cellulosimicrobium fucosivorans

SE3T and

Cellulosimicrobium composti

BIT-GX5T was re-evaluated. The type strains of the two species shared 99.9 % 16S rRNA gene sequence similarity, and whole genome sequence comparisons showed that the two species shared a 86.3 % digital DNA‒DNA hybridization (dDDH) value, a 98.5 % average nucleotide identity (ANI) score and a 98.2 % average amino acid identity (AAI) value. These values were higher than the recommend novel species recognition threshold values of 16S rRNA gene similarity of 98.6 %, dDDH cutoff value of 70 %, and ANI and AAI cutoff values of 95–96 %. In addition, the phylogenetic tree based on the 16S rRNA gene sequences as well as the phylogenomics tree based on whole genomes supported these two strains being closely related. Based on the principle of priority, we propose that

Cellulosimicrobium fucosivorans

is a later heterotypic synonym of

Cellulosimicrobium composti

.
17 β-estradiol impedes aortic root dilation and rupture in male Marfan mice
Authors: Saddic Louis , Escopete Sean , Zilberberg Lior , Kalsow Shannon , Gupta Divya , Egbhali Mansoureh , Parker Sarah
Published: May 2023

Marfan syndrome causes a hereditary form of thoracic aortic aneurysms with dilation of the aortic root. Human and animal models suggest a worse phenotype for males compared to females with respect to aneurysm size and risk of dissection. In this study we examine the effects of 17 β-estradiol on aortic dilation and rupture in a Marfan mouse model. Marfan male mice were administered 17 β-estradiol and the growth in aortic root size along with the risk of aortic rupture or dissection with the addition of angiotensin II was measured. Transcriptomic profiling was used to identify enriched pathways from 17 β-estradiol treatment. Aortic smooth muscle cells were then treated with cytokines in order to validate the mechanism of 17 β-estradiol protection. We show that 17 β-estradiol decreased the size and rate of aortic root dilation and improved survival from rupture and dissection after treatment with angiotensin II. The Marfan transcriptome was enriched in inflammatory genes and the addition of 17 β-estradiol modulated a set of genes that function through TNFα mediated NF-κB signaling. These included many proteins known to play a role in the phenotypic shift of aortic smooth muscle cells from a contractile to a more inflammatory-like state such as Vcam-1, Mcp-1, Lgals3, Il-6, Il-1b, and C3. In addition, 17 β-estradiol suppressed the induction of these TNFα induced genes in aortic smooth muscle cells in vitro and this effect appears to be NF-κB dependent. In conclusion, 17 β-estradiol protects against the dilation and rupture of aortic roots in Marfan male mice through the inhibition of TNFα -NF-κB signaling and thus prevents the phenotypic switch of aortic smooth muscle cells from a contractile to an inflammatory state.
E2F1 promotes, JNK and DIAP1 inhibit, and chromosomal position has little effect on radiation-induced Loss of Heterozygosity inDrosophila
Authors: Brown Jeremy , Su Tin Tin
Published: May 2023

Loss of Heterozygosity (LOH) can occur when a heterozygous mutant cell loses the remaining wild type allele to become a homozygous mutant. LOH can have physiological consequences if, for example, the affected gene encodes a tumor suppressor. We used two fluorescent reporters to study mechanisms of LOH induction by X-rays, a type of ionizing radiation (IR), inDrosophilalarval wing discs. IR is used to treat more than half of cancer patients, so understanding its effects is of biomedical relevance. Quantitative analysis of IR-induced LOH at seven different positions between the telomere and the centromere, the first such study that we know of, showed that while a homologous chromosome is required to produce LOH after irradiation, position along the chromosome makes little difference. This suggests that IR-induced LOH occurs via non-recombination-based mechanisms, unlike what was previously reported for spontaneously occurring LOH. Using a focused screen, we identified E2F1 as a key promotor of LOH and further testing suggests a mechanism involving its role in cell cycle regulation rather than apoptosis. We leveraged the loss of a transcriptional repressor through LOH to express transgenes specifically in cells that have already acquired LOH. This approach identified JNK signaling and apoptosis as key determinants of LOH maintenance. These studies reveal previously unknown mechanisms for generation and elimination of cells with chromosome aberrations after exposure to IR.

Loss of Heterozygosity (LOH) can lead to homozygous mutant cells, with potential physiological consequences if it affects tumor suppressor genes. Using fluorescent reporters of LOH inDrosophilawing discs, we found that X-ray-induced LOH requires a homologous chromosome but was unaffected by position along the chromosome. This suggests non-recombination mechanisms for X-ray-induced LOH, unlike spontaneous LOH. We found that E2F1 promotes LOH while JNK signaling and apoptosis eliminates cells with LOH, uncovering new insights into chromosomal aberrations post-exposure to radiation.
Acute resistance exercise-induced changes in IL-6, IL-10, and IL-1ra in healthy adults: a systematic review and meta-analysis
Authors: Ringleb Miriam , Javelle Florian , Haunhorst Simon , Bloch Wilhelm , Fennen Lena , Baumgart Sabine , Drube Sebastian , Reuken Philipp A. , Pletz Mathias W. , Wagner Heiko , Gabriel Holger H. W. , Puta Christian
Published: May 2023

Background

Myokines, released from the contracting muscle, enable communication between the working muscles and other tissue. Their release during physical exercise is assumed to depend on mode, duration, and intensity.

Objective

The aim of this meta-analysis is to examine the acute changes in circulating levels of the myokines IL-6, IL-10, and IL-1ra induced by a bout of resistance exercise and to consider potential moderators of the results.

Methods

Systematic literature search was conducted for resistance exercise intervention studies measuring IL-6, IL-10, or IL-1ra before and immediately after resistance exercise in healthy individuals. Random effects meta-analysis was performed for each myokine.

Results

A small to moderate positive effect of resistance exercise for IL-6 and a moderate to large positive effect for IL-1ra were detected. For IL-10 no significant effect was observed. No moderators (training status, type of exercise, risk of bias, age, exercise volume, exercise intensity, exercise dose) of the results were detected.

Conclusion

This systematic review and meta-analysis clearly showed the immediate positive effects of an acute resistance exercise session on IL-6 and IL-1ra levels.
Prognostic Value of Myocardial Perfusion Imaging by Cadmium Zinc Telluride Single-photon Emission Computed Tomography in Patients with Suspected or Known Coronary Artery Disease A Systematic Review and Meta-analysis
Authors: Assante Roberta , Zampella Emilia , Cantoni Valeria , Green Roberta , D’Antonio Adriana , Mannarino Teresa , Gaudieri Valeria , Nappi Carmela , Buongiorno Pietro , Panico Mariarosaria , Petretta Mario , Cuocolo Alberto , Acampa Wanda
Published: May 2023

Background

Aim of this study was to define the prognostic value of stress myocardial perfusion imaging by cadmium zinc telluride (CZT) single-photon emission computed tomography (SPECT) for prediction of adverse cardiovascular events in patients with known or suspected coronary artery disease (CAD).

Methods and Results

Studies published until November 2022 were identified by database search. We included studies using stress myocardial perfusion imaging by CZT-SPECT to evaluate subjects with known or suspected CAD and providing primary data of adverse cardiovascular events. Total of 12 studies were finally included recruiting 36,415 patients. Pooled hazard ratio (HR) for the occurrence of adverse events was 2.17 (95% confidence interval, CI, 1.78-2.65) and heterogeneity was 66.1% (P=0.001). Five studies reported data on adjusted HR for the occurrence of adverse events. Pooled HR was 1.69 (95% CI, 1.44-1.98) and heterogeneity was 44.9% (P=0.123). Seven studies reported data on unadjusted HR for the occurrence of adverse events. Pooled HR was 2.72 (95% CI, 2.00-3.70). Nine studies reported data useful to calculate separately the incidence rate of adverse events in patients with abnormal and normal myocardial perfusion. Pooled incidence rate ratio was 2.38 (95% CI, 1.39-4.06) and heterogeneity was 84.6% (P<0.001). The funnel plot showed no evidence of asymmetry (P=0.517). At meta-regression analysis, we found an association between HR for adverse events and presence of angina symptoms and family history of CAD.

Conclusions

Stress myocardial perfusion imaging by CZT-SPECT is a valuable noninvasive prognostic indicator for adverse cardiovascular events in patients with known or suspected CAD.
Detection of new pioneer transcription factors as cell-type specific nucleosome binders
Authors: Peng Yunhui , Song Wei , Teif Vladimir B. , Ovcharenko Ivan , Landsman David , Panchenko Anna R.
Published: May 2023

Wrapping of DNA into nucleosomes restricts accessibility to the DNA and may affect the recognition of binding motifs by transcription factors. A certain class of transcription factors, the pioneer transcription factors, can specifically recognize their DNA binding sites on nucleosomes, may initiate local chromatin opening and facilitate the binding of co-factors in a cell-type-specific manner. For the majority of human pioneer transcription factors, the locations of their binding sites, mechanisms of binding and regulation remain unknown. We have developed a computational method to predict the cell-type-specific ability of transcription factors to bind nucleosomes by integrating ChIP-seq, MNase-seq and DNase-seq data with details of nucleosome structure. We have demonstrated the ability of our approach in discriminating pioneer from canonical transcription factors and predicted new potential pioneer transcription factors in H1, K562, HepG2 and HeLa cell lines. Lastly, we systemically analyzed the interaction modes between various pioneer transcription factors and detected several clusters of distinctive binding sites on nucleosomal DNA.
Exact calculation of the expected SFS in structured populations
Authors: Arredondo Armando , Corujo Josué , Noûs Camille , Boitard Simon , Chikhi Lounès , Mazet Olivier
Published: May 2023

The Site Frequency Spectrum (SFS), summary statistic of the distribution of derived allele frequencies in a sample of DNA sequences, provides information about genetic variation and can be used to make population inferences. The exact calculation of the expected SFS in panmictic population has been derived in the Markovian coalescent theory for decades, but its generalization to the structured coalescent is hampered by the almost exponential growth of the states space. We propose here a complete algorithmic procedure, from how to build a suitable state space and sort it, to how to take advantage of the sparsity of the rate matrix and to solve numerically the linear system by an iterative method. The simplest case of the symmetricaln-island is then processed to arrive at a ready-to-use demographic parameters inference framework.
Genome-wide profiling of DNA repair proteins identifies higher-order coordination in single cells
Authors: de Luca Kim L. , Rullens Pim M. J. , Karpinska Magdalena A. , de Vries Sandra S. , Gacek-Matthews Agnieszka , Pongor Lőrinc S. , Legube Gaëlle , Jachowicz Joanna W. , Marieke Oudelaar A. , Kind Jop
Published: May 2023

Accurate repair of DNA damage is critical for maintenance of genomic integrity and cellular viability. Because damage occurs non-uniformly across the genome, single-cell resolution is required for proper interrogation, but sensitive detection has remained challenging. Here, we present a comprehensive analysis of repair protein localization in single cells using DamID and ChIC sequencing techniques. This study reports genome-wide binding profiles in response to DNA double-strand breaks induced by AsiSI, and explores variability in genomic damage locations and associated repair features in the context of spatial genome organization. By unbiasedly detecting repair factor localization, we find that repair proteins often occupy entire topologically associating domains, mimicking variability in chromatin loop anchoring. Moreover, we demonstrate the formation of multi-way chromatin hubs in response to DNA damage. Notably, larger hubs show increased coordination of repair protein binding, suggesting a preference for cooperative repair mechanisms. Together, our work offers new insights into the heterogeneous processes underlying genome stability in single cells.
In silicomechanics of stem cells intramyocardially transplanted with a biomaterial injectate for treatment of myocardial infarction
Authors: Motchon YD , Sack KL , Sirry MS , Nchejane NJ , Abdalrahman T , Nagawa J , Kruger M , Pauwels E , Van Loo D , De Muynck A , Van Hoorebeke L , Davies NH , Franz T
Published: May 2023

Purpose

Biomaterial and stem cell delivery are promising approaches to treating myocardial infarction. However, the mechanical and biochemical mechanisms underlying the therapeutic benefits require further clarification. This study aimed to assess the deformation of stem cells injected with the biomaterial into the infarcted heart.

Methods

A microstructural finite element model of a mid-wall infarcted myocardial region was developed fromex vivomicrocomputed tomography data of a rat heart with left ventricular infarct and intramyocardial biomaterial injectate. Nine cells were numerically seeded in the injectate of the microstructural model. The microstructural and a previously developed biventricular finite element model of the same rat heart were used to quantify the deformation of the cells during a cardiac cycle for a biomaterial elastic modulus (Einj) ranging between 4.1 and 405,900 kPa.

Results

The transplanted cells’ deformation was largest for Einj= 7.4 kPa, matching that of the cells, and decreased for an increase and decrease in Einj. The cell deformation was more sensitive to Einjchanges for softer (Einj≤ 738 kPa) than stiffer biomaterials.

Conclusions

Combining the microstructural and biventricular finite element models enables quantifying micromechanics and signalling of transplanted cells in the heart. The approach offers a broader scope forin silicoinvestigations of biomaterial and cell therapies for myocardial infarction and other cardiac pathologies.
Upregulated pexophagy limits the capacity of selective autophagy
Authors: Germain Kyla , So Raphaella W. L. , Watts Joel C. , Bandsma Robert , Kim Peter K.
Published: May 2023

Selective autophagy is an essential mechanism to maintain organelle integrity and cellular homeostasis through the constant recycling of damaged or superfluous components. While distinct selective autophagy pathways mediate the degradation of diverse cellular substrates including organelles and pathogens, whether these distinct pathways can influence one another remains unknown. We address this question here using pexophagy, the autophagic degradation of peroxisomes, as a model. We demonstrate in cells that upregulated pexophagy exhausts selective autophagy and limits the degradation of both mitochondria and protein aggregates. We confirmed this finding in the pexophagy-mediated form of Zellweger Spectrum Disorder, a rare disease characterized by peroxisome dysfunction. Further, we extend the generalizability of limited selective autophagy by determining that increased aggrephagy reduces pexophagy using a model of Huntington’s Disease. Our findings suggest that the degradative capacity of selective autophagy can become limited by an increased substrate load.
Sex differences in plasma, adipose tissue, and central accumulation of cannabinoids, and behavioural effects of oral cannabis consumption in male and female C57BL/6 mice
Authors: Sallam Nada , Peterson Colleen , Baglot Samantha L. , Kohro Yuta , Trang Tuan , Hill Matthew N. , Borgland Stephanie L.
Published: May 2023

Background

Cannabis edibles are an increasingly popular form of cannabis consumption. Oral consumption of cannabis has distinct physiological and behavioural effects than injection or inhalation. An animal model is needed to understand the pharmacokinetics and physiological effects of oral cannabis consumption in rodents as a model for human cannabis edible use.

Methods

Adult male and female C57BL/6 mice received a single dose of commercially available cannabis oil (5 mg/kg THC) by oral gavage. At 0.5-, 1-, 2-, 3-, and 6-hours post-exposure, plasma, hippocampus, and adipose tissue was collected for THC, 11-OH-THC, and THC-COOH measures.

Results

We report delayed time to peak THC and 11-OH-THC concentrations in plasma, brain and adipose tissue, which is consistent with human pharmacokinetics studies. We also found sex differences in the cannabis tetrad: (1) female mice had a delayed hypothermic effect 6 hours post-consumption, which was not present in males; (2) females had stronger catalepsy than males; (3) males were less mobile following cannabis exposure, whereas female mice showed no difference in locomotion but an anxiogenic effect at 3h post exposure; and (4) male mice displayed a longer lasting antinociceptive effect of oral cannabis.

Conclusions

Oral cannabis consumption is a translationally relevant form of administration that produces similar physiological effects as injection or vaping administration and thus should be considered as a viable approach for examining the physiological effects of cannabis moving forward. Furthermore, given the strong sex differences in metabolism of oral cannabis, these factors should be carefully considered when designing animal studies on the effects of cannabis.

Significance statement

Oral delivery of cannabis oil in mice is a translational model that increases plasma, hippocampal, and adipose cannabinoids. Furthermore, oral cannabis and produces lasting psychoactive effects including sex dependent effects on hypothermia, cataplexy, locomotor activity and nociception.
Synergistic effects of dietary taurine and carbohydrates supplementation on skeleton muscle of juvenile turbotScophthalmus maximus
Authors: Hays Hasi , Zhang Wenbing , Mai Kangsen
Published: May 2023

The present study aims to investigate the effects of dietary taurine and carbohydrate levels on the skeleton muscle growth of turbot. Muscle samples of turbot were collected after 70 days of feeding trial by treatment groups of 0% (C), 0.4% (L1), 1.2% (L2) taurine with 15% dietary carbohydrate level, and 0.4% (H1), 1.2% (H2) taurine with 21% dietary carbohydrate level. Results showed that L2 and H2 treatment has given significantly higher hyperplasia with significantly high muscle fiber frequencies and muscle fiber density than that in the other groups. Hyperplastic muscle fiber generation was significantly stimulated by the high carbohydrate level (21%). Muscle density was not dependent on the level of carbohydrates. Aspartate, Threonine, Serine, Glutamine, Leucine, Phenylalanine, Isoleucine, Lysine, Histidine, and Arginine were significantly high in the H1 group than that in other all groups. H2 treatment was given a significantly higher amount of total collagen content than the other groups by increasing alkaline-soluble, alkaline-insoluble hydroxyproline, and total hydroxyproline levels. Hardness has significantly increased in all the treatment groups than that in the control group. And also, muscle hardness was significantly increased by the dietary carbohydrate levels. Intestine amylase, lipase, and trypsin enzyme activities were significantly increased in all the treatment groups than that in the control. Amylase and lipase activities were significantly highest in the H2 group. Taurine 1.2% with carbohydrates 21% treatment group (H2) was given significantly higher levels of cellular level muscle growth with more collagen in the skeletal muscle of Turbot.
Loss of Skeletal Muscle Pyruvate Dehydrogenase Induces Lactic Acidosis and Adaptive Anaplerotic Compensation via Pyruvate-Alanine Cycling and Glutaminolysis
Authors: Gopal Keshav , Abdualkader Abdualrahman Mohammed , Li Xiaobei , Greenwell Amanda A. , Karwi Qutuba G. , Saed Christina , Uddin Golam M. , Darwesh Ahmed M. , Jamieson K Lockhart , Altamimi Tariq R. , Kim Ryekjang , Eaton Farah , Seubert John M. , Lopaschuk Gary D. , Ussher John R. , Al Batran Rami
Published: May 2023

Pyruvate dehydrogenase (PDH) is the rate-limiting enzyme for glucose oxidation that links glycolysis-derived pyruvate with the TCA cycle. Although skeletal muscle is a significant site for glucose oxidation and is closely linked with metabolic flexibility, the importance of muscle PDH during rest and exercise has yet to be fully elucidated. Here, we demonstrate that mice with muscle-specific deletion of PDH exhibit rapid weight loss and suffer from severe lactic acidosis, ultimately leading to early mortality under low-fat diet provision. Furthermore, loss of muscle PDH induces adaptive anaplerotic compensation by increasing pyruvate-alanine cycling and glutaminolysis. Interestingly, high-fat diet supplementation effectively abolishes the early mortality and rescues the overt metabolic phenotype induced by muscle PDH deficiency. Despite increased reliance on fatty acid oxidation during high-fat diet provision, loss of muscle PDH worsens exercise performance and induces lactic acidosis. These observations illustrate the importance of muscle PDH in maintaining metabolic flexibility and preventing the development of metabolic disorders.

Highlights

Skeletal Muscle PDH is essential for survival

Loss of muscle PDH induces lactic acidosis and premature death

Loss of muscle PDH enhances pyruvate transformations and glutaminolysis

High-fat diet supplementation abolishes early mortality and overt phenotype induced by muscle PDH loss
A pair of RNA binding proteins inhibit ion transporter expression to maintain lifespan
Authors: Napier-Jameson Rebekah , Marx Olivia , Norris Adam
Published: May 2023

Regulation of lifespan by transcription factors has been well established. More recently a role for RNA binding proteins (RBPs) in regulating lifespan has also emerged. In both cases, a major challenge is to determine which regulatory targets are functionally responsible for the observed lifespan phenotype. We recently identified a pair of RBPs,exc-7/ELAVLandmbl-1/Muscleblind, which display synthetic (non-additive) lifespan defects: single mutants do not affect lifespan, butexc-7; mbl-1double mutants have strongly reduced lifespan. Such a strong synthetic phenotype represented an opportunity to use transcriptomics to search for potential causative targets that are synthetically regulated. Focus on such genes would allow us to narrow our target search by ignoring the hundreds of genes altered only in single mutants, and provide a shortlist of synthetically-regulated candidate targets that might be responsible for the double mutant phenotype. We identified a small handful of genes synthetically dysregulated in double mutants and systematically tested each candidate gene for functional contribution to theexc-7; mbl-1lifespan phenotype. We identified one such gene, the ion transporternhx-6, which is highly upregulated in double mutants. Overexpression ofnhx-6causes reduced lifespan, and deletion ofnhx-6in anexc-7; mbl-1background partially restores both lifespan and healthspan. Together, these results reveal that a pair of RBPs mediate lifespan in part by inhibiting expression of an ion transporter, and provide a template for how synthetic phenotypes (including lifespan) can be dissected at the transcriptomic level to reveal potential causative genes.
Spindle checkpoint signalling in anaphase is prevented by KNL1 release from kinetochores
Authors: Lim-Manley Iona , Gruneberg Ulrike
Published: May 2023

CDK1-cyclin B1 kinase is the main driver of mitosis and initiates the morphological changes that characterise mitosis, including mitotic spindle assembly and formation of the outer kinetochore. CDK1-cyclin B1 activity is also critically required for spindle assembly checkpoint (SAC) signalling during mitosis. In particular, CDK1-cyclin B1 promotes the targeting of the principal spindle checkpoint kinase MPS1 to kinetochores, leading to the recruitment of SAC proteins to the outer kinetochore scaffold protein KNL1 and initiation of checkpoint signalling. However, cells expressing kinetochore-tethered MPS1 still require CDK1 activity for SAC signalling, suggesting that CDK1 plays both MPS1-dependent and -independent roles in regulating the SAC. Here we show that the latter is due to CDK1-mediated kinetochore recruitment of KNL1, which is reversed by the PP1 phosphatase at the metaphase-to-anaphase transition. Our findings explain the abrupt and irreversible termination of spindle checkpoint signalling in anaphase, since the drop of CDK1 activity means both MPS1 and the spindle checkpoint scaffold KNL1 are lost from kinetochores.

Lim-Manley and Gruneberg investigate MPS1-independent roles of CDK1 in spindle checkpoint signalling. They reveal how PP1 activity following CDK1 inactivation results in the rapid removal of KNL1 from kinetochores at anaphase onset, contributing to prompt spindle checkpoint silencing.
Visualizing and identifying selfish bacteria: a hunting guide
Authors: Reintjes G. , Giljan G. , Fuchs B. M. , Arnosti C. , Amann R.
Published: May 2023

Polysaccharides are dominant components of plant biomass, whose degradation is typically mediated by heterotrophic bacteria. These bacteria use extracellular enzymes to hydrolyze polysaccharides to oligosaccharides that are then also available to other bacteria. Recently, a new mechanism of polysaccharide processing – ‘selfish’ uptake – has been recognized, initially among gut-derived bacteria. In ‘selfish’ uptake, polysaccharides are bound at the outer membrane, partially hydrolyzed, and transported into the periplasmic space without loss of hydrolysis products, thus limiting the availability of smaller sugars to the surrounding environment. Selfish uptake is widespread in environments ranging from the ocean’s cool, oxygen-rich, organic carbon-poor waters to the warm, carbon-rich, anoxic environment of the human gut. We provide a detailed guide of how to hunt for selfish bacteria, including how to rapidly visualize selfish uptake in complex bacterial communities, identify selfish organisms, and distinguish the activity of selfish organisms from other members of the community.
Clustering Protein Binding Pockets and Identifying Potential Drug Interactions: A Novel Ligand-based Featurization Method
Authors: Stevenson Garrett A. , Kirshner Dan , Bennion Brian J. , Yang Yue , Zhang Xiaohua , Zemla Adam , Torres Marisa W. , Epstein Aidan , Jones Derek , Kim Hyojin , Bennett W. F. D. , Wong Sergio E. , Allen Jonathan E. , Lightstone Felice C.
Published: May 2023

Protein-ligand interactions are essential to drug discovery and drug development efforts. Desirable on-target or multi-target interactions are a first step in finding an effective therapeutic; undesirable off-target interactions are a first step in assessing safety. In this work, we introduce a novel ligand-based featurization and mapping of human protein pockets to identify closely related protein targets, and to project novel drugs into a hybrid protein-ligand feature space to identify their likely protein interactions. Using structure-based template matches from PDB, protein pockets are featurized by the ligands which bind to their best co-complex template matches. The simplicity and interpretability of this approach provides a granular characterization of the human proteome at the protein pocket level instead of the traditional protein-level characterization by family, function, or pathway. We demonstrate the power of this featurization method by clustering a subset of the human proteome and evaluating the predicted cluster associations of over 7,000 compounds.
Evolutionary spread of protein L-(iso)aspartylO-methyltransferases guides the discovery of distinct isoaspartate-containing peptides, pimtides
Authors: Lee Hyunbin , Park Sho Hee , Kim Jiyoon , Lee Jaehak , Koh Min Sun , Lee Jung Ho , Kim Seokhee
Published: May 2023

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a structurally diverse class of natural products with a distinct biosynthetic logic, the enzymatic modification of genetically encoded precursor peptides. Although their structural and biosynthetic diversity remains largely underexplored, the identification of novel subclasses with unique structural motifs and biosynthetic pathways has been challenging. Here, we report that protein L-(iso)aspartylO-methyltransferases (PIMTs) present in several RiPP subclasses are highly homologous. Importantly, we discovered that the apparent evolutionary transmission of the PIMT gene could serve as a basis to identify a novel RiPP subclass. Biochemical and structural analyses suggest that these homologous PIMTs commonly convert aspartate to isoaspartate via aspartyl-O-methyl ester and aspartimide intermediates, and often require cyclic or hairpin-like structures for modification. By conducting homology-based bioinformatic analysis of PIMTs, we identified over 2,800 biosynthetic gene clusters (BGCs) for known RiPP subclasses in which PIMTs install a secondary modification, and over 1,500 BGCs in which PIMTs function as a primary modification enzyme, thereby defining a new RiPP subclass, named pimtides. Our results suggest that the genome mining of proteins with secondary biosynthetic roles could be an effective strategy for discovering novel biosynthetic pathways of RiPPs.

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Genomic variation of a keystone forest tree species reveals signals of local adaptation despite high levels of phenotypic plasticity
Authors: Lazic Desanka , Gessner Cornelia , Liepe Katharina J , Lesur-Kupin Isabelle , Mader Malte , Blanc-Jolivet Celine , Gomory Dusan , Liesebach Mirko , Gonzalez-Martinez Santiago C , Fladung Matthias , Degen Bernd , Mueller Niels A.
Published: May 2023

Local adaptation is key for ecotypic differentiation and species evolution. Understanding the underlying genomic patterns can allow the prediction of future maladaptation and ecosystem stability. Here, we report the whole-genome resequencing of 874 individuals from 100 range-wide populations of European beech (Fagus sylvatica L.), one of the most important forest tree species in Europe. We show that genetic variation closely mirrors geography with a clear pattern of isolation-by-distance. Genome-wide analyses for genotype-environment associations (GEAs) identified relatively few potentially adaptive variants after correcting for an overwhelming signal of statistically significant but non-causal GEAs. We characterized the single high confidence genomic region and pinpoint a candidate gene possibly involved in winter temperature adaptation acting by modulating spring phenology. Surprisingly, however, allelic variation at this locus did not result in any apparent fitness differences in a common garden. More generally, reciprocal transplant experiments across large climate distances demonstrated extensive phenotypic plasticity. Nevertheless, we find indications of polygenic adaptation which may be essential in natural ecosystems. This polygenic signal exhibits broad- and fine-scale variation across the landscape highlighting the relevance of spatial resolution. In summary, our results emphasize the importance but also exemplify the complexity of employing natural genetic variation for forest conservation under climate change.
De novodistillation of thermodynamic affinity from deep learning regulatory sequence models ofin vivoprotein-DNA binding
Authors: Alexandari Amr M. , Horton Connor A. , Shrikumar Avanti , Shah Nilay , Li Eileen , Weilert Melanie , Pufall Miles A. , Zeitlinger Julia , Fordyce Polly M. , Kundaje Anshul
Published: May 2023

Transcription factors (TF) are proteins that bind DNA in a sequence-specific manner to regulate gene transcription. Despite their unique intrinsic sequence preferences,in vivogenomic occupancy profiles of TFs differ across cellular contexts. Hence, deciphering the sequence determinants of TF binding, both intrinsic and context-specific, is essential to understand gene regulation and the impact of regulatory, non-coding genetic variation. Biophysical models trained onin vitroTF binding assays can estimate intrinsic affinity landscapes and predict occupancy based on TF concentration and affinity. However, these models cannot adequately explain context-specific,in vivobinding profiles. Conversely, deep learning models, trained onin vivoTF binding assays, effectively predict and explain genomic occupancy profiles as a function of complex regulatory sequence syntax, albeit without a clear biophysical interpretation. To reconcile these complementary models ofin vitroandin vivoTF binding, we developed Affinity Distillation (AD), a method that extracts thermodynamic affinitiesde-novofrom deep learning models of TF chromatin immunoprecipitation (ChIP) experiments by marginalizing away the influence of genomic sequence context. Applied to neural networks modeling diverse classes of yeast and mammalian TFs, AD predicts energetic impacts of sequence variation within and surrounding motifs on TF binding as measured by diversein vitroassays with superior dynamic range and accuracy compared to motif-based methods. Furthermore, AD can accurately discern affinities of TF paralogs. Our results highlight thermodynamic affinity as a key determinant ofin vivobinding, suggest that deep learning models ofin vivobinding implicitly learn high-resolution affinity landscapes, and show that these affinities can be successfully distilled using AD. This new biophysical interpretation of deep learning models enables high-throughputin silicoexperiments to explore the influence of sequence context and variation on both intrinsic affinity andin vivooccupancy.
Social experiences shape song preference learning independent of developmental exposure to song
Authors: Wall Erin , Woolley Sarah
Published: May 2023

Communication governs the formation and maintenance of social relationships. The interpretation of communication signals depends not only on the signal’s content, but also on a receiver’s individual experience. Experiences throughout life may interact to affect behavioral plasticity, such that a lack of developmental sensory exposure could constrain adult learning, while salient adult social experiences could remedy developmental deficits. We investigated how experiences impact the formation and direction of female auditory preferences in the zebra finch. Zebra finches form long-lasting pair bonds and females learn preferences for their mate’s vocalizations. We found that after two weeks of cohabitation with a male, females formed pair-bonds and learned to prefer their mate’s song regardless of whether they were reared with (“normally-reared”) or without (“song-naïve”) developmental exposure to song. In contrast, females that heard but did not physically interact with a male did not prefer his song. Moreover, even following mating, song-naive females failed to show species-typical preferences for courtship song, hinting that mating is insufficient to ameliorate broader deficits in sensory processing that arise during development. Thus, courtship and mating interactions, but not acoustic-only interactions, strongly influence preference learning regardless of rearing experience, and may dynamically drive auditory plasticity for recognition and preference.