bluuebunny/crossref_metadata_2025 huggingface dataset:
Fertilisation of agricultural soils with municipal biosolids: Part 1- Glyphosate and aminomethylphosphonic acid inputs to Québec field crop soils
Authors: Charbonneau Ariane , Lucotte Marc , Moingt Matthieu , Blakney J. C. Andrew , Morvan Simon , Bipfubusa Marie , Pitre Frédéric E.
Published: December 2023

Municipal biosolids (MBS) are suggested to be abundant, sustainable, inexpensive fertilisers, rich in phosphorus and nitrogen. However, MBS can also contain glyphosate and phosphonates that can degrade to AMPA. Glyphosate-based herbicides (HBG) are used in field crops all over the world. Most glyphosate generally degrades within a few weeks, mainly as aminomethylphosphonic acid (AMPA). AMPA is more persistent than glyphosate, and can accumulate from one crop year to the next. AMPA is phytotoxic even to glyphosate-resistant crops. The aims of this study were to assess whether applications of MBS significantly contribute to: 1) glyphosate and AMPA contents of agricultural soils, 2) trace metal elements contents, and 3) partial replacement of mineral fertilisation while maintaining similar yields. To this end, four experimental agricultural sites were selected in Québec (Canada). Soil samples (0-20 cm) were collected to estimate the as yet unmeasured contribution of BSM application to glyphosate and AMPA inputs in agricultural soils. MBS applied in 2021 and 2022 had mean concentrations of 0.69 ± 0.53 µg glyphosate/dry g and 6.26 ± 1.93 µg AMPA/dry g. Despite the presence of glyphosate and AMPA in MBS, monitoring of these two compounds in corn and soybean crops over two years showed no significant difference between plots treated with and without MBS applications. For the same site, yields measured at harvest were similar between treatments. MBS application could thus represent a partial alternative to mineral fertilisers for field crops, while limiting the economic and environmental costs associated with their incineration and landfilling. It is also an economic advantage for agricultural producers given the possibility of using fewer mineral fertilisers and therefore reducing the environmental impact of their use.

Highlights

Municipal biosolids (MBS) offer significant potential for fertilising field crops

MBS contain significant amounts of both glyphosate and AMPA

Soil chemistry and crop yields were followed in MBS treated and untreated plots

Glyphosate and AMPA contents in soil do not increase with MBS treatment

MBS are a good substitute for mineral fertilisers leading to similarly crop yields

Graphical abstract
Optimal stimulation sites of the subthalamic nucleus for the treatment of gait symptoms of Parkinson’s disease
Authors: Mei Zhongke , Hofer Anna-Sophie , Baumann Christian , Uhl Mechtild , Singh Navrag , Taylor William R. , Stieglitz Lennart , Ravi Deepak
Published: December 2023

Deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) is a widely adopted therapy for mitigating motor symptoms in Parkinson’s Disease (PD). Although the electrode placement site has been proposed as a significant factor influencing motor outcomes, the specific relationships between electrode location and therapeutic effects on gait performance remain unclear. This study seeks to identify optimal stimulation sites within the STN to effectively address gait symptoms in patients with PD (PwPD). We assessed overground gait performance in 49 PwPD who underwent bilateral STN-DBS surgery, both before treatment initiation and six months post-implantation, comparing the results to 51 asymptomatic individuals. Our evaluation focused on treatment-induced changes in the mean (mean set) and coefficient of variability (variability set) of ten commonly used spatio-temporal gait parameters, such as stride length and walking speed. We also examined their correlation with the location of the active contacts of the DBS electrodes utilized for therapeutic stimulation. Our findings indicate that DBS treatment resulted in a significant reduction in stride time, stance time, swing time, and step time, in addition to an increase in the variability of double limb stance time, stride time, stance time, and step time. Furthermore, we observed that the location of the active contacts resulted in alterations in mean step length, stride length, and walking speed, as well as changes to cadence, stride time, stance time, and step width. We identified the postero-superior region of the STN as the most effective region for improving the mean set, whereas the antero-superior region of the STN emerged as the most effective region for improving the variability set. This study provides empirical evidence on how STN-DBS, in tandem with the location of active lead contacts, impacts both mean and variability of spatio-temporal gait parameters in PwPD. Importantly, our results indicate specific STN spatial targets for DBS implantation to address patient specific gait symptoms.
Impaired incretin homeostasis in non-diabetic moderate-severe CKD
Authors: Ahmadi Armin , Gamboa Jorge , Norman Jennifer E. , Enkhmaa Byambaa , Tucker Madelynn , Bennett Brian J. , Zelnick Leila R. , Fan Sili , Berglund Lars F. , Ikizler Talat Alp , de Boer Ian H. , Cummings Bethany P. , Roshanravan Baback
Published: December 2023

Background

Incretins are regulators of insulin secretion and glucose homeostasis that are metabolized by dipeptidyl peptidase-4 (DPP-4). Moderate-severe CKD may modify incretin release, metabolism, or response.

Methods

We performed 2-hour oral glucose tolerance testing (OGTT) in 59 people with non-diabetic CKD (eGFR<60 ml/min per 1.73 m2) and 39 matched controls. We measured total (tAUC) and incremental (iAUC) area under the curve of plasma total glucagon-like peptide-1 (GLP-1) and total glucose-dependent insulinotropic polypeptide (GIP). Fasting DPP-4 levels and activity were measured. Linear regression was used to adjust for demographic, body composition, and lifestyle factors.

Results

Mean eGFR was 38 ±13 and 89 ±17ml/min per 1.73 m2in CKD and controls. GLP-1 iAUC and GIP iAUC were higher in CKD than controls with a mean of 1531 ±1452 versus 1364 ±1484 pMxmin, and 62370 ±33453 versus 42365 ±25061 pgxmin/ml, respectively. After adjustment, CKD was associated with 15271 pMxmin/ml greater GIP iAUC (95% CI 387, 30154) compared to controls. Adjustment for covariates attenuated associations of CKD with higher GLP-1 iAUC (adjusted difference, 122, 95% CI -619, 864). Plasma glucagon levels were higher at 30 minutes (mean difference, 1.6, 95% CI 0.3, 2.8 mg/dl) and 120 minutes (mean difference, 0.84, 95% CI 0.2, 1.5 mg/dl) in CKD compared to controls. There were no differences in insulin levels or plasma DPP-4 activity or levels between groups.

Conclusion

Incretin response to oral glucose is preserved or augmented in moderate-severe CKD, without apparent differences in circulating DPP-4 concentration or activity. However, neither insulin secretion nor glucagon suppression are enhanced.

Significance statement

CKD is associated with metabolic and physiological disturbances including disturbed glucose and insulin homeostasis. Incretin hormones are potent regulators of insulin secretion and glucose metabolism; however, determinants and potential consequence of incretin response in CKD are incompletely understood. This study revealed that total incretin levels and incretin response during oral glucose tolerance testing (OGTT) were significantly higher among patients with moderate-severe non-diabetic CKD compared to healthy. Unlike in healthy individuals, increased incretin response was not correlated with insulin and C-peptide response to OGTT in CKD. These differences coincided with persistently greater glucagon levels in response to physiological stimuli in CKD. Disruption in the incretin system and glucagon dynamics may contribute to metabolic disturbances in moderate-severe CKD.

Visual abstract
LITERATURE REVIEW: DISASTER RISK REDUCTION PROGRAMS TO INCREASE PUBLIC AWARENESS OF NATURAL DISASTERS
Authors: Asih Susi Wahyuning , Pandin Moses Glorino Rumambo , Yusuf Ahmad , Supriyadi
Published: December 2023

Background

The key components of disaster risk reduction typically include risk assessment, early warning systems, public awareness and education, infrastructure and land-use planning, preparedness and response planning, and sustainable development. The third component is the public awareness and education. Educating communities about potential risks and how to prepare for and respond to disasters is crucial for building resilience and ensuring the effective implementation of DRR measures. The fourth component is infrastructure and land-use planning. Regarding the preparedness and response planning, developing comprehensive disaster preparedness and response plans is helpful in ensuring a swift and coordinated response during emergencies, thereby minimizing the impact on life and property. Lastly, regarding sustainable development, integrating DRR into development planning can help create sustainable and resilient communities that are better equipped to withstand and recover from disasters.

Purpose

This study aims to review articles that examine the disaster risk reduction program to increase public awareness of natural disasters

Design

This study was categorized as a literature review

Method

Data were collected by searching articles published on SAGE, Springer link, Proquest, Scopus, and Science Direc in 2020-2023.

Results

263 articles were used in the review. These articles discuss the disaster risk reduction program to increase public awareness of natural disasters. Fifteen articles reviewed were original research.

Conclusion

Local communities play a central role in hazard identification, development of preparedness plans, detection and response to emergencies, and implementation of recovery efforts. Community leaders and local health workers (e.g. family doctors, nurses, midwives, pharmacists, community health workers).
Human cranial bone-derived mesenchymal stem cells cultured under microgravity can improve cerebral infarction in rats
Authors: Kuwabara Masashi , Mitsuhara Takafumi , Teranishi Masataka , Okazaki Takahito , Takeda Masaaki , Ishii Daizo , Kondo Hiroshi , Shimizu Kiyoharu , Hosogai Masahiro , Hara Takeshi , Maeda Yuyo , Kurose Tomoyuki , Kawahara Yumi , Yuge Louis , Horie Nobutaka
Published: December 2023

Background

Transplantation of human cranial bone-derived mesenchymal stem cells (hcMSCs) in patients with central nervous system disorders may improve motor function through high neurotrophic factor expression. However, the effects of hcMSCs cultured under microgravity (MG) conditions on cerebral infarction remain unclear. Thus, this study investigated the transplantation effects of hcMSCs cultured in a simulated MG environment on cerebral infarction model rats.

Methods

For immunohistological analysis and neurological function evaluation, hcMSCs cultured in normal gravity (1G) or MG environment were transplanted in rats 1 day after inducing cerebral infarction. The expression of endogenous neurotrophic; axonal, neuronal, and synaptogenic; angiogenic; and apoptosis-related factors in infarcted rat brain tissue was examined by real-time polymerase chain reaction (PCR) and western blotting analyses 35 days after stroke induction. MicroRNAs (miRNAs) of hcMSCs cultured under 1G or MG environments were sequenced.

Results

Neurological function was significantly improved after transplantation of hcMSCs from the MG group compared with that from the 1G group. Protein expressions of nerve growth factor, fibroblast growth factor 2, and synaptophysin were significantly higher in the MG group than in the 1G group, whereas sortilin 1 expression was significantly lower. MiRNA analysis revealed that genes related to cell proliferation, angiogenesis, neurotrophy, anti-apoptosis, neural and synaptic organization, and cell differentiation inhibition were significantly upregulated in the MG group. In contrast, genes promoting microtubule and extracellular matrix formation and cell adhesion, signaling, and differentiation were downregulated.

Conclusions

These results indicate that hcMSCs cultured in an MG environment may be a useful source of stem cells for the recovery of neurological function in cerebral infarction patients.
Hofbauer cells and fetal brain microglia share transcriptional profiles and responses to maternal diet-induced obesity
Authors: Batorsky Rebecca , Ceasrine Alexis M. , Shook Lydia L. , Kislal Sezen , Bordt Evan A. , Devlin Benjamin A. , Perlis Roy H. , Slonim Donna K. , Bilbo Staci D. , Edlow Andrea G.
Published: December 2023

Maternal immune activation is associated with adverse offspring neurodevelopmental outcomes, many mediated by in utero microglial programming. As microglia remain inaccessible throughout development, identification of noninvasive biomarkers reflecting fetal brain microglial programming could permit screening and intervention. We used lineage tracing to demonstrate the shared ontogeny between fetal brain macrophages (microglia) and fetal placental macrophages (Hofbauer cells) in a mouse model of maternal diet-induced obesity, and single-cell RNA-seq to demonstrate shared transcriptional programs. Comparison with human datasets demonstrated conservation of placental resident macrophage signatures between mice and humans. Single-cell RNA-seq identified common alterations in fetal microglial and Hofbauer cell gene expression induced by maternal obesity, as well as sex differences in these alterations. We propose that Hofbauer cells, which are easily accessible at birth, provide novel insights into fetal brain microglial programs, and may facilitate the early identification of offspring vulnerable to neurodevelopmental disorders in the setting of maternal exposures.
Expansion of Artemisinin Partial Resistance Mutations and Lack of Histidine Rich Protein-2 and -3 Deletions inPlasmodium falciparum infectionsfrom Rukara, Rwanda
Authors: Schreidah Cecile , Giesbrecht David , Gashema Pierre , Young Neeva , Munyaneza Tharcisse , Muvunyi Claude Mambo , Thwai Kyaw , Mazarati Jean-Baptiste , Bailey Jeffrey , Juliano Jonathan J , Karema Corine
Published: December 2023

Background

Emerging artemisinin resistance and diagnostic resistance are a threat to malaria control in Africa.Plasmodium falciparumkelch13 (K13) propeller-domain mutations that confer artemisinin partial resistance have emerged in Africa. K13-561H was initially described at a frequency of 7.4% from Masaka in 2014-2015 but not present in nearby Rukara. By 2018, 19.6% of isolates in Masaka and 22% of isolates in Rukara contained the mutation. Longitudinal monitoring is essential to inform control efforts. In Rukara, we sought to assess recent K13-561H prevalence changes, as well as for other key mutations. Prevalence ofhrp2/3deletions was also assessed.

Methods

We genotyped samples collected in Rukara in 2021 for key artemisinin and partner drug resistance mutations using molecular inversion probe assays and forhrp2/3deletions using qPCR.

Results

Clinically validated K13 artemisinin partial resistance mutations continue to increase in prevalence with the overall level of artemisinin resistance mutant infections reaching 32% in Rwanda. The increase appears to be due to the rapid emergence of K13-675V (6.4%, 6/94 infections), previously not observed, rather than continued expansion of 561H (23.5% 20/85). Mutations to partner drugs and other antimalarials were variable, with high levels of multidrug resistance 1 (MDR1) N86 (95.5%) associated with lumefantrine resistance and dihydrofolate reductase (DHFR) 164L (24.7%) associated with antifolate resistance, but low levels of amodiaquine resistance polymorphisms with chloroquine resistance transporter (CRT)76T: at 6.1% prevalence. Nohrp2orhrp3gene deletions associated with diagnostic resistance were found.

Conclusions

Increasing prevalence of artemisinin partial resistance due to K13-561H and the rapid expansion of K13-675V is concerning for the longevity of artemisinin effectiveness in the region. False negative mRDT results do not appear to be an issue with nohrp2 or hpr3deletions detected. Continued molecular surveillance in this region and surrounding areas is needed to follow artemisinin resistance and provide early detection of partner drug resistance, which would likely compromise control and increase malaria morbidity and mortality in East Africa.
Knockdown resistance (kdr) Associated organochlorine Resistance in mosquito-borne diseases (Culex pipiens): Systematic study of reviews and meta-analysis
Authors: Abbasi Ebrahim , Daliri Salman , Talbalaghi Asghar , Mehrpouya Fatemeh , Hasanzadeh arab Maryam , Aslvaeli Atena
Published: December 2023

Background

Culex pipiensis the vector of a large number of pathogenic pathogens in humans. Using insecticides to deal with this vector is the most important way to control it. However, in recent decades, resistance to insecticides has been reported in this vector. One of the main insecticides used to fight this vector is organochlorine insecticides. Based on this, this study was conducted to investigate the prevalence of Knockdown resistance (kdr) inCulex pipiensagainst organochlorine insecticides.

Methods

This study was conducted by systematic review and meta-analysis in the field of kdr prevalence inCulex pipiensagainst organochlorine insecticides. Based on this, during the search in the scientific databases PubMed, Web of Science, biooan.org, Embase, ProQuest, Scopus, and Google Scholar without time limit until the end of November 2023, all related articles were extracted and analyzed. The statistical analysis of the data was performed using the random and fixed effects model in the meta-analysis, Cochran’s test,I2index, and meta-regression by STATA software version 17.

Results

seven studies with a sample size of 2,029Culex pipienswere included in the meta-analysis process. Based on the findings, the kdr resistance prevalence against Deltamethrin, Malathion, Permethrin, and DDT insecticides was estimated as 30.6%, 42%, 17.9%, and 76.3% respectively. Among them, the highest resistance to DDT and the lowest to Permethrin was observed.

Conclusion

Based on the findings, a large proportion ofCulex pipiensmosquitoes were resistant to DDT insecticide. However, this vector was highly sensitive to Deltamethrin, Malathion, and Permethrin insecticides. Due to the different resistance ratios in different regions of the world, it is recommended to conduct studies on the prevalence of kdr inCulex pipiens.
Analytical and clinical validation of a targeted-enhanced whole genome sequencing-based comprehensive genomic profiling test
Authors: Ferguson Stephanie , Sriram Shruthi , Wallace Jonathan Kyle , Lee Jeonghoon , Kim Jung-Ah , Lee Yoonsuh , Oh Brian Baek-Lok , Lee Won Chul , Lee Sangmoon , Connolly-Strong Erin
Published: December 2023

Evaluation of the test performance of the targeted enhanced whole-genome sequencing (TE-WGS) assay for comprehensive oncology genomic profiling. The analytical validation of the assay included sensitivity and specificity for single nucleotide variants (SNVs), insertions/deletions (indels), and structural variants (SVs), revealing a revealed a sensitivity of 99.8% for SNVs and 99.2% for indels. The PPV was 99.3% for SNVs and 98.7% for indels. Clinical validation was benchmarked against established orthogonal methods and demonstrated high concordance with reference methods in variant characterization. The TE-WGS assay enhances personalized cancer treatment by offering detailed genomic insights and the adaptability to include emerging biomarkers.
Association between Binge Drinking Behaviors and Comorbidities in Brazil: Network Analysis of a National Health Survey
Authors: Zadey Siddhesh , Franca Diego , Coelho Pessoa Santos Pollyana , Pereira Natan David , Tchuisseu Yolande Pokam , Andrade Luciano , Nunes Bruno Pereira , Lara Machado Wagner De , Staton Catherine A. , Vissoci Joao Ricardo Nickenig
Published: December 2023

Alcohol consumption is the sixth leading cause of death globally. Brazil ranks second in alcohol-related mortality within the American regions with a notable increase in binge drinking behavior from 2013 (5.9%) to 2019 (17.1%). Binge drinking, a form of alcohol misuse, is a known risk factor for several diseases. We aimed to understand the differences in binge drinking across various sociodemographic groups and the patterns of comorbidities in a national-level dataset by doing a cross-sectional network analysis of the 2013 Brazilian National Health Survey. Binge drinking was defined as a binary variable based on alcohol consumption of >5 (4) doses in a month for male (female) responders. Weighted undirected network analysis using Ising models was performed to discover the strength of inter-relations between nineteen chronic conditions. In the network, the nodes represented the conditions and the edges were formed by statistical associations derived using logistic regression. Community analyses identified the clusters within networks. A nationally representative sample of 60,202 people revealed the prevalence of binge drinking to be about 13.5%. The study revealed a less connected network among binge drinkers, potentially impacting disease associations. Binge drinking demonstrated unique correlations with comorbidities across age, gender, ethnicity, and education levels, highlighting the complex interplay between binge drinking and health outcomes. Recognizing the specific comorbidities associated with binge drinking, such as hypertension and chronic spinal problems, allows healthcare professionals to tailor preventive measures and early interventions. In this sense, differences in binge drinking and its direct association with comorbidities as well as in comorbidity structures across sociodemographic characteristics point to the utility of network models to identify specific populations at various health risks.
LowIGFBP7expression identifies a subset of breast cancers with favorable prognosis and sensitivity to IGF-1 receptor targeting with ganitumab: Data from I-SPY2 and SCAN-B
Authors: Godina Christopher , Pollak Michael N , Jernström Helena
Published: December 2023

There has been a long-standing interest in targeting the insulin-like growth factor-1 receptor (IGF-1R) signaling system in breast cancer due to its key role in neoplastic proliferation and survival. However, no IGF-1R targeting agent has shown substantial clinical benefit in controlled trials, and no treatment predictive biomarkers for IGF-1R targeting agents exist. IGFBP7 is an atypical insulin-like growth factor binding protein as it has a higher affinity for the IGF-1R than IGF ligands. We report that lowIGFBP7gene expression identifies a subset of breast cancers for which the addition of ganitumab (an anti-IGF-1R monoclonal antibody) to chemotherapy substantially improved the pathological complete response rate compared to neoadjuvant chemotherapy alone. Furthermore, highIGFBP7expression predicted increased distant metastasis risk. If our findings are confirmed, decisions to halt the development of IGF-1 targeting drugs, which were based on disappointing results of prior trials that did not use predictive biomarkers, should be reviewed.
High-throughput structure determination of an intrinsically disordered protein using cell-free protein crystallization
Authors: Kojima Mariko , Abe Satoshi , Furuta Tadaomi , Hirata Kunio , Yao Xinchen , Kobayashi Ayako , Kobayashi Ririko , Ueno Takafumi
Published: December 2023

Intrinsically disordered proteins (IDPs) play a crucial role in various biological phenomena, dynamically changing their conformations in response to external environmental cues. To gain a deeper understanding of these proteins, it is essential to identify the determinants that fix their structures at the atomic level. Here, we developed a pipeline for rapid crystal structure analysis of IDP using a cell-free protein crystallization (CFPC) method. Through this approach, we successfully demonstrated the determination of the structure of an IDP to uncover the key determinants that stabilize its conformation. Specifically, we focused on the 11-residue fragment of c-Myc, which forms an α-helix through dimerization with a binding partner protein. This fragment was strategically fused with an in-cell crystallizing protein and was expressed in a cell-free system. The resulting crystal structures of the c-Myc fragment were successfully determined at a resolution of 1.92 Å and we confirmed that they are identical to the structures of the complex with the native binding partner protein. This indicates that the environment of the scaffold crystal can fix the structure of c-Myc. Significantly, these crystals were obtained directly from a small reaction mixture (30 μL) incubated for only 72 hours. Analysis of 8 crystal structures derived from 22 mutants revealed two hydrophobic residues as the key determinants responsible for stabilizing the α-helical structure. These findings underscore the power of our CFPC screening method as a valuable tool for determining the structures of challenging target proteins and elucidating the essential molecular interactions that govern their stability.
A hyperparameter-randomized ensemble approach for robust clustering across diverse datasets
Authors: Goggin Sarah M. , Zunder Eli R.
Published: December 2023

Clustering analysis is widely used to group objects by similarity, but for complex datasets such as those produced by single-cell analysis, the currently available clustering methods are limited by accuracy, robustness, ease of use, and interpretability. To address these limitations, we developed an ensemble clustering method with hyperparameter randomization that outperforms other methods across a broad range of single-cell and synthetic datasets, without the need for manual hyperparameter selection. In addition to hard cluster labels, it also outputs soft cluster memberships to characterize continuum-like regions and per cell overlap scores to quantify the uncertainty in cluster assignment. We demonstrate the improved clustering interpretability from these features by tracing the intermediate stages between handwritten digits in the MNIST dataset, and between tanycyte subpopulations in the hypothalamus. This approach improves the quality of clustering and subsequent downstream analyses for single-cell datasets, and may also prove useful in other fields of data analysis.
Vole genomics links determinate and indeterminate growth of teeth
Authors: Calamari Zachary T. , Song Andrew , Cohen Emily , Akter Muspika , Roy Rishi Das , Hallikas Outi , Christensen Mona M. , Li Pengyang , Marangoni Pauline , Jernvall Jukka , Klein Ophir D.
Published: December 2023

Continuously growing teeth are an important innovation in mammalian evolution, yet genetic regulation of continuous growth by stem cells remains incompletely understood. Dental stem cells responsible for tooth crown growth are lost at the onset of tooth root formation. Genetic signaling that initiates this loss is difficult to study with the ever-growing incisor and rooted molars of mice, the most common mammalian dental model species, because signals for root formation overlap with signals that pattern tooth size and shape (i.e., cusp patterns). Different species of voles (Cricetidae, Rodentia, Glires) have evolved rooted and unrooted molars that have similar size and shape, providing alternative models for studying roots. We assembled a de novo genome of Myodes glareolus, a vole with high-crowned, rooted molars, and performed genomic and transcriptomic analyses in a broad phylogenetic context of Glires (rodents and lagomorphs) to assess differential selection and evolution in tooth forming genes. We identified 15 dental genes with changing synteny relationships and six dental genes undergoing positive selection across Glires, two of which were undergoing positive selection in species with unrooted molars, Dspp and Aqp1. Decreased expression of both genes in prairie voles with unrooted molars compared to bank voles supports the presence of positive selection and may underlie differences in root formation. Bulk transcriptomics analyses of embryonic molar development in bank voles also demonstrated conserved patterns of dental gene expression compared to mice, with species-specific variation likely related to developmental timing and morphological differences between mouse and vole molars. Our results support ongoing evolution of dental genes across Glires, revealing the complex evolutionary background of convergent evolution for ever-growing molars.
Novelin vivoTDP-43 stress reporter models to accelerate drug development in ALS
Authors: Ferro Febe , Wolf C. Roland , Henstridge Chris , Inesta-Vaquera Francisco
Published: December 2023

The development of therapies to combat neurodegenerative diseases is widely recognised as a research priority, with conditions like Alzheimer’s, Amyotrophic lateral sclerosis (ALS) and Parkinson’s set to place an ever-heavier burden on healthcare systems in the near future. Despite recent advances in understanding their molecular basis, there is a lack of suitable early biomarkers to test selected compounds and accelerate their translation to clinical trials. We have investigated the utility ofin vivoreporters of cytoprotective pathways (e.g. NRF2, p53) as surrogate early biomarkers of the ALS degenerative disease progression. We hypothesized that cellular stress observed in a model of ALS may precede overt cellular damage and could activate our cytoprotective pathway reporters. To test this hypothesis, we generated novel ALS-reporter mice by crossing the hTDP-43tg model into our oxidative stress/inflammation (Hmox1; NRF2 pathway) and DNA damage (p21; p53 pathway) stress reporter models. Histological analysis of reporter expression in a homozygous hTDP-43tg background demonstrated a time-dependent and tissue-specific activation of the reporters in tissues directly associated with ALS. The activation occurs in Purkinje neurons and other parvalbumin-positive (PV+) cells within the cerebellum of mice, before moderate clinical signs are observed. In addition, reporter expression in hTDP-43tg hom peripheral tissues was not observed at the tested mouse ages (15 and 17 days postnatally). Further work is warranted to determine the specific mechanisms by which TDP-43 accumulation leads to reporter activation and whether therapeutic intervention modulates reporters’ expression. Our current studies suggest that these reporters may represent a powerful approach to accelerate preclinical studies targeting TDP-43 pathologies. We anticipate the reporter strategy could be of great value in developing treatments for a range of degenerative disorders.
Gut microbiota DPP4-like enzymes are increased in type-2 diabetes and contribute to incretin inactivation
Authors: Olivares Marta , Hernandez-Calderon Paula , Cardenas-Brito Sonia , Liebana-Garcia Rebeca , Sanz Yolanda , Benitez-Paez Alfonso
Published: December 2023

Background: The gut microbiota controls broad aspects of human metabolism and feeding behavior, but the basis for this control remains largely unclear. Given the key role of human dipeptidyl peptidase 4 (DPP4) in host metabolism, we investigate whether microbiota DPP4-like counterparts perform the same function. Results: We identify novel functional homologs of human DPP4 in several bacterial species inhabiting the human gut, and specific associations between Parabacteroides and Porphyromonas DPP4-like genes and type 2 diabetes (T2D). We also find that the DPP4-like enzyme from the gut symbiont Parabacteroides merdae mimics the proteolytic activity of the human enzyme on peptide YY, neuropeptide Y, gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) hormones in vitro. Importantly, administration of E. coli overexpressing the P. merdae DPP4-like enzyme to lipopolysaccharide-treated mice with impaired gut barrier function reduces active GIP and GLP-1 levels, which is attributed to increased DPP4 activity in the portal circulation and the cecal content. Finally, we observe that linagliptin, saxagliptin, sitagliptin and vildagliptin, antidiabetic drugs with DPP4 inhibitory activity, differentially inhibit the activity of the DPP4-like enzyme from P. merdae. Conclusions: Our findings confirm that proteolytic enzymes produced by the gut microbiota are likely to contribute to the glucose metabolic dysfunction that underlies T2D by inactivating incretins, which might inspire the development of improved antidiabetic therapies.
A cascade of sulfur transferases delivers sulfur to the sulfur-oxidizing heterodisulfide reductase-like complex
Authors: Tanabe Tomohisa Sebastian , Bach Elena , D’Ermo Giulia , Mohr Marc Gregor , Hager Natalie , Pfeiffer Niklas , Guiral Marianne , Dahl Christiane
Published: December 2023

A heterodisulfide reductase-like complex (sHdr) and novel lipoate-binding proteins (LbpAs) are central players of a wide-spread pathway of dissimilatory sulfur oxidation. Bioinformatic analysis demonstrate that the cytoplasmic sHdr-LbpA systems are always accompanied by sets of sulfur transferases (DsrE proteins, TusA, rhodaneses). The exact composition of these sets may vary depending on the organism and sHdr system type. To enable generalizations, we studied model sulfur oxidizers from distant bacterial phyla, i.e. Aquificota and Pseudomonadota. DsrE3C of the chemoorganotrophic AlphaproteobacteriumHyphomicrobium denitrificansand DsrE3B from the GammaproteobacteriaThioalkalivibriosp. K90mix, an obligate chemolithotroph, andThiorhodospira sibirica, an obligate photolithotroph, are homotrimers that donate sulfur to TusA. Additionally, the hyphomicrobial rhodanese-like protein Rhd442 exchanges sulfur with both TusA and DsrE3C. The latter is essential for sulfur oxidation inHm. denitrificans. TusA fromAquifex aeolicus(AqTusA) interacts physiologically with AqDsrE, AqLbpA and AqsHdr proteins. This is particularly significant as it establishes a direct link between sulfur transferases and the sHdr-LbpA complex that oxidizes sulfane sulfur to sulfite.In vivo,it is unlikely that there is a strict unidirectional transfer between the sulfur-binding enzymes studied. Rather, the sulfur transferases form a network, each with a pool of bound sulfur. Sulfur flux can then be shifted in one direction or the other depending on metabolic requirements. A single pair of sulfur-binding proteins with a preferred transfer direction, such as a DsrE3-type protein towards TusA, may be sufficient to push sulfur into the sink where it is further metabolized or needed.

SIGNIFICANCE STATEMENT

A network of bacterial sulfur transferases is uncovered and characterized that ultimately delivers sulfur to a complex cytoplasmic sulfur-oxidizing metalloenzyme, sHdr, that resembles heterodisulfide reductase from methanogenic archaea and interacts with lipoate-binding proteins. Similar sets of sulfur transferases occur in phylogenetically distant bacteria, underscoring the fundamental importance of the work.
J chain dictates the recognition of IgA by FcRL4
Authors: Su Chen , Wang Yuxin , Yang Xiaoke , Xiao Junyu
Published: December 2023

Fc-receptor-like 4 (FcRL4) selectively recognizes systemic IgA. The cryo-electron microscopy structure of the FcRL4–Fcα (IgA-Fc)–Joining (J) chain complex reveals that FcRL4 interacts with Fcα–J in a 1:1 stoichiometry, with FcRL4 primarily interacting with the J chain. The binding of Fcα–J to FcRL4 would hinder the binding of pIgR, but not FcαRI. These findings provide new insights into IgA and emphasize significant differences between various IgA receptors.
Understanding Genome Structure Facilitates the Use of Wild Lentil Germplasm for Breeding: A Case Study with Shattering Loci
Authors: Cao Zhe , Socquet-Juglard Didier , Daba Ketema , Vandenberg Albert , Bett Kirstin E
Published: December 2023

Plant breeders are generally reluctant to cross elite crop cultivars with their wild relatives to introgress novel desirable traits due to associated negative traits such as pod shattering. This results in a genetic bottleneck that could be reduced through better understanding of the genomic locations of the gene(s) controlling this trait. We integrated information on parental genomes, pod shattering data from multiple environments, and high-density genetic linkage maps to identify pod shattering QTLs in three lentil interspecific recombinant inbred line (RIL) populations. The broad-sense heritability on a multi-environment basis varied from 0.46 (in LR-70,Lens culinaris x L. odemensis) to 0.77 (in LR-68,L. orientalis x L. culinaris). Genetic linkage maps of the interspecific populations revealed reciprocal translocations of chromosomal segments that differed among the populations, and which were associated with reduced recombination. Segregation distortion was also observed for clusters of SNPs on multiple chromosomes per population, further affecting introgression. Two major QTL, on chromosomes 4 and 7, were repeatedly detected in the three populations and contain several candidate genes. These findings will be of significant value for lentil breeders to strategically access novel superior alleles while minimizing the genetic impact of pod shattering from wild parents.
Bile is a route of excretion for homogentisic acid in alkaptonuria
Authors: Norman BP , Sutherland H , Wilson PJM , Rutland DA , Milan AM , Hughes AT , Davison AS , Khedr M , Jarvis JC , Gallagher JA , Bou-Gharios G , Ranganath LR
Published: December 2023

Altered activity of specific enzymes in phenylalanine-tyrosine (phe-tyr) metabolism results in incomplete breakdown of various metabolite substrates in this pathway. Increased biofluid concentration and tissue accumulation of the phe-tyr pathway metabolite homogentisic acid (HGA) is central to pathophysiology in the inherited disorder alkaptonuria (AKU). Accumulation of the metabolites upstream of HGA, including tyrosine, occurs in patients on nitisinone, a licenced drug for AKU and hereditary tyrosinaemia type-1, which inhibits the enzyme responsible for HGA production. The aim of this study was to investigate the phe-tyr metabolite content of key biofluids and tissues in AKU mice on and off nitisinone to gain new insights into the biodistribution of metabolites in these altered metabolic states. The data show for the first time that HGA is present in the bile in AKU (mean [±SD] = 1003[±410] μmol/L; nitisinone-treated AKU mean [±SD] = 45[±23] μmol/L). Biliary tyrosine, HPPA and HPLA are also increased on nitisinone. Urine was confirmed as the dominant elimination route of HGA in untreated AKU, but with indication of biliary excretion and possible metabolism of HGA by the gut microbiome. These data provide new insights into the pathways of phe-tyr metabolite biodistribution and metabolism, showing for the first time that hepatobiliary excretion contributes to the total pool of metabolites in this pathway. Our data suggest that biliary elimination of organic acids and other metabolites may play an underappreciated role in disorders of metabolism.

Take-home message

This paper presents the first observation of elevated hepatobiliary circulation of metabolites associated with disease in alkaptonuria, including homogentisic acid in addition to tyrosine and the tyrosine metabolites 4-hydroxyphenylpyruvic acid and 4-hydroxyphenyllactic acid on nitisinone treatment.
GTalign: Spatial index-driven protein structure alignment, superposition, and search
Authors: Margelevičius Mindaugas
Published: December 2023

In response to the challenge posed by vast protein structure repositories, GTalign offers an innovative solution to protein structure alignment and search—an algorithm that achieves optimal superposition at high speeds. Through the design and implementation of spatial structure indexing, GTalign parallelizes all stages of superposition search across residues and protein structure pairs, yielding rapid identification of optimal superpositions. Rigorous evaluation across diverse datasets reveals GTalign as the most accurate among structure aligners while presenting orders of magnitude in speedup at state-of-the-art accuracy. GTalign’s high speed and accuracy make it useful for numerous applications, including functional inference, evolutionary analyses, protein design, and drug discovery, contributing to advancing understanding of protein structure and function.
Unveiling Vaginal Fibrosis: A Novel Murine Model Using Bleomycin and Epithelial Disruption
Authors: McCracken Jennifer M , Calderon Gisele A , Kumar Lishore A , Balaji Swathi , Rivas Felipe , Erxleben Dorothea , Hall Adam , Hakim Julie CE
Published: December 2023

Objective

Develop, validate, and characterize a fibrotic murine vaginal wound healing model using bleomycin instillations and epithelial disruption.

Approach

We tested the effect of repeated bleomycin instillations with mucosal layer disruption on induction of vaginal fibrosis. Tissue samples collected at various time points were analyzed for fibrosis-related gene expression changes and collagen content.

Results

Low (1.5U/kg) and high-dose (2.5U/kg) bleomycin instillations alone did not induce fibrosis, but when high-dose bleomycin was combined with epithelial disruption, increased pro-fibrotic gene expression and trichrome staining were observed. To evaluate spatial and temporal changes in the ECM structure and gene expression, tissue samples were collected at 1 day, 3 weeks, and 6 weeks after bleomycin and epithelial disruption. Data analyses revealed a significant decrease in matrix metabolizing genes and an increase in pro-fibrotic genes and inhibitors of matrix metabolizing genes in the bleomycin plus epithelial disruption group at 3 weeks. Elevated levels of the profibrotic genesActa2,Col1a1, andCol3awere exclusively detected in this group at 3 weeks, and trichrome staining confirmed increased collagen content after 3 weeks. Hydroxyproline levels showed a tendency towards elevation at 3 weeks (p=0.12) and 6 weeks (p=0.14), indicating fibrosis manifestation at 3 weeks and resolution by 6 weeks post-instillation and epithelial disruption.

Innovation

We combined bleomycin instillations with epithelial disruption to induce fibrosis and understand the mechanisms of the vaginal repair process.

Conclusions

Epithelial disruption combined with bleomycin induces murine vaginal fibrosis within three weeks, characterized by increased collagen synthesis. Remarkably, the vaginal tissue fully recovers within six weeks, elucidating the regenerative capacity of the vagina.
Closed-loop microstimulations of the orbitofrontal cortex during real-life gaze interaction enhance dynamic social attention
Authors: Fan Siqi , Dal Monte Olga , Nair Amrita R. , Fagan Nicholas A. , Chang Steve W. C.
Published: December 2023

The prefrontal cortex is extensively involved in social exchange. During dyadic gaze interaction, multiple prefrontal areas exhibit neuronal encoding of social gaze events and context-specific mutual eye contact, supported by a widespread neural mechanism of social gaze monitoring. To explore causal manipulation of real-life gaze interaction, we applied weak closed-loop microstimulations that were precisely triggered by specific social gaze events to three prefrontal areas in monkeys. Microstimulations of orbitofrontal cortex (OFC), but not dorsomedial prefrontal or anterior cingulate cortex, enhanced momentary dynamic social attention in the spatial dimension by decreasing distance of one’s gaze fixations relative to partner monkey’s eyes. In the temporal dimension, microstimulations of OFC reduced the inter-looking interval for attending to another agent and the latency to reciprocate other’s directed gaze. These findings demonstrate that primate OFC serves as a functionally accessible node in controlling dynamic social attention and suggest its potential for a therapeutic brain interface.
Optimized mucin-selective enrichment strategy to probe the mucinome
Authors: Mahoney Keira E. , Chang Vincent , Lucas Taryn M. , Maruszko Krystyna , Malaker Stacy A.
Published: December 2023

Mucin-domain glycoproteins are densely O-glycosylated and play critical roles in a host of healthy and diseasedriven biological functions. Previously, we developed a mucin-selective enrichment strategy by employing a catalytically inactive mucinase (StcE) conjugated to solid support. While this method was effective, it suffered from low throughput and high sample requirements. Further, the elution step required boiling in SDS, thus necessitating an in-gel digest with trypsin. Here, we optimized our previous enrichment method to include elution conditions amenable to mucinase digestion and downstream analysis with mass spectrometry. This increased throughput and lowered sample input while maintaining mucin selectivity and enhancing glycopeptide signal. We then benchmarked this technique against different O-glycan binding moieties for their ability to enrich mucins from various cell lines and human serum. Overall, the new method outperformed our previous procedure and all other enrichment techniques tested. This allowed for effective isolation of more mucin-domain glycoproteins, resulting in a high number of O-glycopeptides, thus enhancing our ability to analyze the mucinome.
Delayed Center of Mass Feedback in Elderly Humans Leads to Greater Muscle Co-Contraction and Altered Balance Strategy under Perturbed Balance: a Predictive Musculoskeletal Simulation Study
Authors: Jones Rachel , Ratnakumar Neethan , Akbaş Kübra , Zhou Xianlian
Published: December 2023

Falls are one of the leading causes of non-disease death and injury in the elderly, often due to delayed sensory neural feedback essential for balance. This delay, challenging to measure or manipulate in human studies, necessitates exploration through neuromusculoskeletal modeling to reveal its intricate effects on balance. In this study, we developed a novel three-way muscle feedback control approach, including muscle length feedback, muscle force feedback, and enter of mass feedback, for balancing and investigated specifically the effects of center of mass feedback delay on elderly people’s balance strategies. We conducted simulations of cyclic perturbed balance at different magnitudes ranging from 0 to 80 mm and with three center of mass feedback delays (100, 150 & 200 ms). The results reveal two key points: 1) Longer center of mass feedback delays resulted in increased muscle activations and co-contraction, 2) Prolonged center of mass feedback delays led to noticeable shifts in balance strategies during perturbed standing. Under low-amplitude perturbations, the ankle strategy was predominantly used, while higher amplitude disturbances saw more frequent employment of hip and knee strategies. Additionally, prolonged center of mass delays altered balance strategies across different phases of perturbation, with a noticeable increase in overall ankle strategy usage. These findings underline the adverse effects of prolonged feedback delays on an individual’s stability, necessitating greater muscle co-contraction and balance strategy adjustment to maintain balance under perturbation. Our findings advocate for the development of training programs tailored to enhance balance reactions and mitigate muscle feedback delays within clinical or rehabilitation settings for fall prevention in elderly people.
A long-context language model for deciphering and generating bacteriophage genomes
Authors: Shao Bin
Published: December 2023

Abstract

Inspired by the success of large language models, we develop a long-context generative model for genomes. Our multiscale transformer model was pre-trained on unannotated bacteriophage genomes with byte-level tokenization. We demonstrate the foundational capabilities of our model including the prediction of essential genes, genetic variant effects, regulatory element activity and taxonomy of unannotated sequences. Furthermore, it generatesde novosequences up to 96K base pairs, which contain functional regulatory elements and novel proteins with phage-related functions.