bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and characterization of aging/senescence-induced genes in osteosarcoma and predicting clinical prognosis
Authors: Lv Yigang , Wu Liyuan , Jian Huan , Zhang Chi , Lou Yongfu , Kang Yi , Hou Mengfan , Li Zhen , Li Xueying , Sun Baofa , Zhou Hengxing
Published: October 2022

Background

Aging is an influential risk factor for progression of both degenerative and oncological diseases of the bone. Osteosarcoma, considered the most common primary mesenchymal tumor of the bone, is a worldwide disease with poor 5-year survival. This study investigated the role of aging-/senescence-induced genes (ASIGs) in contributing to osteosarcoma diagnosis, prognosis, and therapeutic agent prediction.

Methods

Therapeutically Applicable Research to Generate Effective Treatments (TARGET), Gene Expression Omnibus (GEO), and The Cancer Genome Atlas (TCGA) were used to collect relevant gene expression and clinical data of osteosarcoma and paracancerous tissues. Patients were clustered by consensus using prognosis-related ASIGs. ssGSEA, ESTIMATE, and TIMER were used to determine the tumor immune microenvironment (TIME) of subgroups. Functional analysis of differentially expressed genes between subgroups, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set variation analyses (GSVAs), was performed to clarify functional status. Prognostic risk models were constructed by univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression. SCISSOR was used to identify relevant cells in osteosarcoma single-cell data for different risk groups. The effect of immunotherapy was predicted based on TIDE scores and chemotherapy drug sensitivity using CTRP and PRISM.

Results

Three molecular subgroups were identified based on prognostic differentially expressed ASIGs. Immunological infiltration levels of the three groups differed significantly. Based on GO and KEGG analyses, differentially expressed genes between the three subgroups mainly relate to immune and aging regulation pathways; GSVA showed substantial variations in multiple Hallmark pathways among the subgroups. The ASIG risk score built based on differentially expressed genes can predict patient survival and immune status. We also developed a nomogram graph to accurately predict prognosis in combination with clinical characteristics. The correlation between the immune activation profile of patients and the risk score is discussed. Through single-cell analysis of the tumor microenvironment, we identified distinct risk-group-associated cells with significant differences in immune signaling pathways. Immunotherapeutic efficacy and chemotherapeutic agent screening were evaluated based on risk score.

Conclusion

Aging-related prognostic genes can distinguish osteosarcoma molecular subgroups. Our novel aging-associated gene signature risk score can be used to predict the osteosarcoma immune landscape and prognosis. Moreover, the risk score correlates with the TIME and provides a reference for immunotherapy and chemotherapy in terms of osteosarcoma.
Study on mineral composition design and mechanical properties improvement mechanism of high ferrite oil well cement
Authors: Fan Baitao , Huang Kun , Yang Xiangqian , Wu Zhiqiang , Ni Xiucheng , Cheng Xiaowei
Published: October 2022

In shale gas production, secondary fracturing technology is often used to improve shale gas production capacity. However, the toughness of cement stone used in Class G oil wells is poor, and the cement sheath is easily damaged by impact load during fracturing, resulting in cement sheath sealing failure. To solve this problem, this paper proposes to improve the strength and toughness of cement paste by optimizing the mineral composition of Class G oil well cement. The cement clinker is burned in the laboratory, and the microstructure differences of clinker under different mineral composition ratios are observed by reflection microscope. The mechanical properties of cement paste before and after optimization are analyzed, and the best mineral composition ratio is obtained. The petrographic structure, hydration products and microstructure of high ferrite oil well cement were analyzed by petrography, X-ray diffraction analysis (XRD), thermal analysis (TG/DTG) and scanning electron microscopy (SEM), analyzed and explored its enhancement mechanism. The results show that the best mineral composition mass ratios of C3S, C2S, C3A and C4AF in high ferrite oil well cement are 58.34%, 16.39%, 1.51% and 17.94% respectively. Compared with grade G oil well cement, the compressive strength and flexural strength of curing 28 days are increased by 14.11% and 19.51%, respectively. The stress-strain results show that high ferrite oil well cement has better toughness. The petrographic results show that the lithofacies structure of high ferrite oil well cement is evenly distributed and the particle size is moderate; XRD, TG/DTG and microanalysis show that there are more hydration products in high ferrite oil well cement, the hydration products are closely combined, the hydration degree is more thorough, and the structure of cement paste is more compact. High ferrite oil well cement has the advantages of high strength and good toughness, which has potential advantages for shale gas cementing.
Gestational weight gain in the REVAMP pregnancy cohort in Western India: Comparison with international and national references
Authors: Dangat Kamini , Gupte Sanjay , Wagh Girija , Lalwani Sanjay , Randhir Karuna , Madiwale Shweta , Pisal Hemlata , Kadam Vrushali , Gundu Shridevi , Chandhiok Nomita , Kulkarni Bharati , Joshi Sadhana , Fall Caroline , Sachdev Harshpal Singh
Published: October 2022

Objective

To determine the trimester specific gestational weight gain (GWG) in a population of pregnant women from Western India and compare it with the Intergrowth–21st international and an Indian reference (GARBH–Ini cohort—Group for Advanced Research on BirtH outcomes).

Study design

A prospective longitudinal observational study was undertaken in Pune, West India and data for gestational weight gain was collected [the REVAMP study (Research Exploring Various Aspects and Mechanisms in Preeclampsia)]. Generalized Additive Models for Location, Scale and Shape method (GAMLSS model) were used to create GWG centile curves according to gestational age, stratified by BMI at recruitment (n = 640) and compared with Intergrowth-21st reference and GARBH–Ini cohort. Multivariable regression analysis was used to evaluate the relationship between GWG and antenatal risk factors.

Results

The median GWG was 1.68, 5.80, 7.06, and 11.56 kg at gestational ages 18, 26, 30, and 40 weeks, respectively. In our study, pregnant women gained less weight throughout pregnancy compared to Intergrowth-21st study, but more weight compared to the GARBH–Ini cohort centile curves in all the BMI categories. GWG in overweight/obese women (BMI ≥ 25) was significantly lower (<0.001) as compared to underweight (BMI < 18.5), or normal weight women (BMI ≥ 18.5 and <25). The median GWG at 40 weeks in underweight, normal and overweight/obese women was 13.18, 11.74, and 10.48 kg, respectively. Higher maternal BMI, older maternal age, higher parity and higher hemoglobin concentrations were associated with lower GWG, while taller maternal height was associated with greater GWG.

Conclusion

GWG of Indian women is lower than the prescriptive standards of the Intergrowth charts.
The dual role of CD6 as a therapeutic target in cancer and autoimmune disease
Authors: Gurrea-Rubio Mikel , Fox David A.
Published: October 2022

Autoimmune disease involves loss of tolerance to self-antigen, while progression of cancer reflects insufficient recognition and response of the immune system to malignant cells. Patients with immune compromised conditions tend to be more susceptible to cancer development. On the other hand, cancer treatments, especially checkpoint inhibitor therapies, can induce severe autoimmune syndromes. There is recent evidence that autoimmunity and cancer share molecular targets and pathways that may be dysregulated in both types of diseases. Therefore, there has been an increased focus on understanding these biological pathways that link cancer and its treatment with the appearance of autoimmunity. In this review, we hope to consolidate our understanding of current and emerging molecular targets used to treat both cancer and autoimmunity, with a special focus on Cluster of Differentiation (CD) 6.
Case Report: Use of endobronchial Watanabe spigot and coagulation factor XIII supplementation in the treatment of persistent pneumothorax due to pneumocystis pneumonia with human immunodeficiency virus infection
Authors: Koyama Katsumasa , Minami Daisuke , Isobe Hayato , Shirai Ryo , Okimoto Niro , Tomoda Koichi
Published: October 2022

Pneumocystis jiroveceii pneumonia is one of the most common opportunistic infections associated with human immunodeficiency virus. Endobronchial Watanabe spigot has been recommended for refractory pneumothorax, even with persistant air leak despite continuous negative pressure control via thoracic drainage. Moreover, coagulation factor XIII is considered effective in wound healing.
Prognostic effect of pulmonary hypertension in patients with chronic kidney disease: Univariate and multivariate analyses of factors associated with survival
Authors: Wang Lei , Zhang Wei , Zhang Cailian , Yan Zhe , Li Shaomei , Zhang Chunxia , Chen Yakun , Pan Qing , Liang Xuzhi , Chen Xian
Published: October 2022

Background

Prognostic effect of pulmonary hypertension (PH) in patients with chronic kidney disease (CKD) is not fully clear yet, this study was designed to elucidate baseline characteristics of CKD patients with different severities of PH, the association between kidney indicators and PH severity, and survival factors in CKD patients with PH.

Methods

We extracted clinical data from electronic medical records of all patients diagnosed with PH in CKD from Jan 2016 to Dec 2020, and those with comorbid conditions causing PH were excluded. CKD stages were defined by estimated glomerular filtration rate thresholds. PH was defined as a systolic pulmonary artery pressure (sPAP) >35 mmHg estimated using echocardiograms. Demographics, clinical data, and test results were analyzed, and all-cause mortality data were obtained.

Results

A total of 137 patients were included in the study. The mean age of the participants was 60 (42.5, 67) years, the mean sPAP was 58 (51, 69.5) mmHg, and 40.9% of the patients were women. Moderate PH group had more patients undergoing dialysis and higher frequency of coronary heart disease. Moderate-severe PH group had higher parathyroid hormone levels and lower low-density lipoprotein levels. Severe PH group had better kidney function parameters and lower serum phosphorus levels. PH severity had no direct relationship with CKD stages. In the univariate analysis, age and PH severity influenced survival. Multivariate analysis also showed independent prognostic effects for age and sPAP. Kaplan-Meyer curve intuitively displayed the survival differences among CKD patients with different PH severity. Predictor values of nomogram identified from survival analyses enabled calculation of death probabilities for CKD with PH patients. Nomogram was validated by ROC analysis.

Conclusions

PH begins with early-stage CKD, and PH severity is not related to CKD progression. A higher pulmonary artery pressure and an older age are associated with an increased risk of death.
Multilocus sequence typing of Giardia duodenalis genotypes circulating in humans in a major metropolitan area
Authors: Hashemi-Hafshejani Saeideh , Meamar Ahmad Reza , Moradi Maryam , Hemmati Nasrin , Solaymani-Mohammadi Shahram , Razmjou Elham
Published: October 2022

Giardia duodenalis is an intestinal protozoan parasite of humans and animal hosts and comprises eight microscopically indistinguishable molecularly-diverse lineages designated as assemblages A–H. Assemblages A and B are the primary sources of infections in humans and a wide range of mammals. Here, we identified assemblages, and inter-/intra-assemblage genetic diversity of human G. duodenalis isolates based on the multilocus sequence typing of the triosephosphate isomerase (tpi), β -giardin (bg), and glutamate dehydrogenase (gdh) loci. Multilocus sequence analysis of 62 microscopically-positive G. duodenalis fecal samples identified 26 (41.9%), 27 (43.5%), and nine (14.5%) isolates belonging to assemblages A, B, and discordant assemblages, respectively. The tpi locus assemblage-specific primers identified dual infections with A and B assemblages (45.2%). The sequence analysis of multiple alignments and phylogenetic analysis showed low genetic polymorphism in assemblage A isolates, classified as sub-assemblage AII at three loci, subtype A2 at tpi and gdh loci, and subtype A2 or A3 at bg locus. High genetic variations were found in assemblage B isolates with 14, 15, and 23 nucleotide patterns at tpi, bg, and gdh loci, respectively. Further concatenated sequence analysis revealed four multilocus genotypes (MLG) in 24 assemblages A isolates, two previously-identified (AII-1 and AII-5), with one novel multilocus genotype. However, the high genetic variations observed in assemblage B isolates among and within the three genetic loci prevented the definitive designation of specific MLGs for these isolates. Multilocus sequence typing may provide new insight into the genetic diversity of G. duodenalis isolates in Tehran, suggesting that humans are likely a potential source of G. duodenalis infection. Further host-specific experimental transmission studies are warranted to elucidate the modes of transmission within multiple host populations.
Development and validation of a sensitive LC-MS/MS method for determination of intracellular concentration of fluconazole in Candida albicans
Authors: Wang Xiaofei , Wang Xiaojuan , Cai Tongkai , Qin Yulin , Li Ling , Jiang Yuanying , Han Bing , Cao Yongbing
Published: October 2022

Systemic candidiasis is the fourth leading cause of healthcare-associated infections worldwide. The combination therapy based on existing antifungal agents is well-established to overcome drug resistance and restore antifungal efficacy against drug-resistant strains. In this study, a simple and sensitive liquid chromatography with tandem mass spectrometry (LC-MS/MS) method was developed to quantify the intracellular fluconazole (FLC) content in the opportunistic human fungal pathogen Candida albicans. The cell lysates were prepared by lysing C. albicans cells with Precellys homogenizers and FLC was extracted with methylene chloride. The entire extraction approach was simple, precise and reliable. The extracts were separated on a Zorbax SB-C18 column using a mobile phase of acetonitrile (solvent A) and deionized water plus 0.1% formic acid. FLC and ketoconazole (KCZ, internal standard) were monitored in positive mode using electrospray ionization source. The multiple reaction monitoring transitions (precursor to product) were monitored for FLC m/z 307.1 → 238.2 and for the internal standard KCZ m/z 531.2 → 489.1. The linear for this method were in the range from 5.0 to 1000.0 ng/mL. The precision and accuracy of the samples were relative standard deviations (RSD) < 1.0% for intra-day and RSD < 0.51% for inter-day. The overall recovery of FLC from samples was higher than 77.61%. Furthermore, this method was successfully applied and validated in 36 clinical isolated strains. Taken together, we established a highly accurate, efficient, and reproducible method for quantifying the intracellular content of FLC in C. albicans.
Effect of cellulase and lactic acid bacteria on the fermentation quality, carbohydrate conversion, and microbial community of ensiling oat with different moisture contents
Authors: Xu Jinyi , Zhang Keyi , Lin Yufan , Li Mengxin , Wang Xuekai , Yu Qiang , Sun Hong , Cheng Qiming , Xie Yixiao , Wang Chunmei , Li Ping , Chen Chao , Yang Fuyu , Zheng Yulong
Published: October 2022

Oat (Avena sativa L.) is one of the most widely cultivated crops used as forage. The aim of this study was to evaluate the effects of cellulase and Lactobacillus plantarum interactions with different moisture contents on oat ensiling. Oats with three moisture contents were treated with nothing (C), cellulase (CE), lactic acid bacteria (LP), or CE+LP and ensiled for 30 and 60 days. Compared with the control, LP and CE treatments increased crude protein and lactic acid concentrations and reduced the pH and ammonia nitrogen/total nitrogen (NH3-N/TN) ratios of silages. The addition of CE improved lignocellulosic degradation, compared with approximately 67% (LD) and 81% moisture content (HD) ensiling, CE (CE, CE+LP) ensiling in the approximately 75% moisture content (MD) group retained higher water-soluble carbohydrate, glucose, sucrose and fructose concents. The LP and CE inoculations significantly reduced the microbial community diversity, and lower values for the observed species, ACE, Chao1, and Shannon indices compared with CK-treated samples. Additives inhibited the growth of unfavorable bacteria (such as Clostridium) and increased the abundances of lactic acid bacteria (LAB); the maximum increases in the Lactiplantibacillus abundance were obtained in the LP- and CE+LP-treated samples, improving the microbial community structure in silage. In summary, adding LP and CE effectively improved the oat fermentation quality, and better performances in ensiling oat and lignocellulose degradation were obtained with LP and CE combinations, especially for the MD group of silages that were ensiled for 60 days. The addition of CE and LP at the appropriate moisture content might be helpful for producing high-quality oat silage, and also provide a simple and feasible method to enhance the effects of bacteria and enzymes.
Long-term mercury contamination does not affect the microbial gene potential for C and N cycling in soils but enhances detoxification gene abundance
Authors: Frey Beat , Rast Basil M. , Qi Weihong , Stierli Beat , Brunner Ivano
Published: October 2022

Soil microorganisms are key transformers of mercury (Hg), a toxic and widespread pollutant. It remains uncertain, however, how long-term exposure to Hg affects crucial microbial functions, such as litter decomposition and nitrogen cycling. Here, we used a metagenomic approach to investigate the state of soil functions in an agricultural floodplain contaminated with Hg for more than 80 years. We sampled soils along a gradient of Hg contamination (high, moderate, low). Hg concentrations at the highly contaminated site (36 mg kg–1 dry soil on average) were approximately 10 times higher than at the moderately contaminated site (3 mg kg–1 dry soil) and more than 100 times higher than at the site with low contamination (0.25 mg kg–1 dry soil; corresponding to the natural background concentration in Switzerland). The analysis of the CAZy and NCyc databases showed that carbon and nitrogen cycling was not strongly affected with high Hg concentrations, although a significant change in the beta-diversity of the predicted genes was observed. The only functional classes from the CAZy database that were significantly positively overrepresented under higher Hg concentrations were genes involved in pectin degradation, and from the NCyc database dissimilatory nitrate reduction and N-fixation. When comparing between low and high Hg concentrations the genes of the EggNOG functional category of inorganic ion transport and metabolism, two genes encoding Hg transport proteins and one gene involved in heavy metal transport detoxification were among those that were highly significantly overrepresented. A look at genes specifically involved in detoxification of Hg species, such as the mer and hgc genes, showed a significant overrepresentation when Hg contamination was increased. Normalized counts of these genes revealed a dominant role for the phylum Proteobacteria. In particular, most counts for almost all mer genes were found in Betaproteobacteria. In contrast, hgc genes were most abundant in Desulfuromonadales. Overall, we conclude from this metagenomic analysis that long-term exposure to high Hg triggers shifts in the functional beta-diversity of the predicted microbial genes, but we do not see a dramatic change or breakdown in functional capabilities, but rather functional redundancy.
Alleviation effects of niacin supplementation on beef cattle subjected to heat stress: A metagenomic insight
Authors: Zou Bicheng , Long Fan , Xue Fuguang , Qu Mingren , Chen Chuanbin , Zhang Xian , Xu Lanjiao
Published: October 2022

The objective of this study was to investigate the alleviation effects of niacin supplementation on beef cattle subjected to heat stress and to provide a theoretical basis for exploring the alleviation methods of heat stress environmental factors on the rumen of beef cattle. In the experiment, 36 Jinjiang bull cattle with a body weight of about 400 ± 20.0 kg were randomly divided into three treatments, each treatment contains four replicates, with three cattle in each replicate. Treatments included thermoneutral treatment (TN; temperature: 24–25°C, humidity: 45–55%), heat stress treatment, exposure to environmental temperature (HS; average THI: 82.74), and heat stress supplemented with niacin treatment (HN; high temperature + 800 mg/kg NA). Measured indicators were body temperature, respiratory rate, production performances, rumen fermentations, and microbial diversity. Results showed that adding niacin reduced the body temperature and respiratory rate (P < 0.05) but had no significant effect on the production performances compared with heat-stressed beef cattle. HS treatment significantly increased body temperature and respiratory rate (P < 0.01), while decreasing the content of acetic acid, butyric acid, and total volatile fatty acids (P < 0.05) compared with the TN treatment. Supplement of niacin did not affect ruminal fermentation parameters (P > 0.05) but had a decreased tendency on A/P (P < 0.1). Microbial diversity results showed that, at the phylum level, the relative abundance of Desulfobacterota in the HS treatment was increased compared with TN and HN treatment (P < 0.05). At the genus level, the relative abundance of Succiniclasticum and Family_XIII_AD3011 group in the HN treatment significantly proliferated compared with the HS treatment (P < 0.05). In conclusion, niacin supplementation may alleviate heat stress by proliferating those bacteria belonging to the phylum Succiniclasticum, which may further contribute to the digestion of cellulose and the improvement of the metabolic function of Jinjiang cattle under heat-stress conditions.
Characterizing viral within-host diversity in fast and non-equilibrium demo-genetic dynamics
Authors: Alamil Maryam , Thébaud Gaël , Berthier Karine , Soubeyrand Samuel
Published: October 2022

High-throughput sequencing has opened the route for a deep assessment of within-host genetic diversity that can be used, e.g., to characterize microbial communities and to infer transmission links in infectious disease outbreaks. The performance of such characterizations and inferences cannot be analytically assessed in general and are often grounded on computer-intensive evaluations. Then, being able to simulate within-host genetic diversity across time under various demo-genetic assumptions is paramount to assess the performance of the approaches of interest. In this context, we built an original model that can be simulated to investigate the temporal evolution of genotypes and their frequencies under various demo-genetic assumptions. The model describes the growth and the mutation of genotypes at the nucleotide resolution conditional on an overall within-host viral kinetics, and can be tuned to generate fast non-equilibrium demo-genetic dynamics. We ran simulations of this model and computed classic diversity indices to characterize the temporal variation of within-host genetic diversity (from high-throughput amplicon sequences) of virus populations under three demographic kinetic models of viral infection. Our results highlight how demographic (viral load) and genetic (mutation, selection, or drift) factors drive variations in within-host diversity during the course of an infection. In particular, we observed a non-monotonic relationship between pathogen population size and genetic diversity, and a reduction of the impact of mutation on diversity when a non-specific host immune response is activated. The large variation in the diversity patterns generated in our simulations suggests that the underlying model provides a flexible basis to produce very diverse demo-genetic scenarios and test, for instance, methods for the inference of transmission links during outbreaks.
Modulation of the H+/ATP coupling ratio by ADP and ATP as a possible regulatory feature in the F-type ATP synthases
Authors: Turina Paola
Published: October 2022

F-type ATP synthases are transmembrane enzymes, which play a central role in the metabolism of all aerobic and photosynthetic cells and organisms, being the major source of their ATP synthesis. Catalysis occurs via a rotary mechanism, in which the free energy of a transmembrane electrochemical ion gradient is converted into the free energy of ATP phosphorylation from ADP and Pi, and vice versa. An ADP, tightly bound to one of the three catalytic sites on the stator head, is associated with catalysis inhibition, which is relieved by the transmembrane proton gradient and by ATP. By preventing wasteful ATP hydrolysis in times of low osmotic energy and low ATP/ADP ratio, such inhibition constitutes a classical regulatory feedback effect, likely to be an integral component of in vivo regulation. The present miniview focuses on an additional putative regulatory phenomenon, which has drawn so far little attention, consisting in a substrate-induced tuning of the H+/ATP coupling ratio during catalysis, which might represent an additional key to energy homeostasis in the cell. Experimental pieces of evidence in support of such a phenomenon are reviewed.
Noncovalent hyaluronan crosslinking by TSG-6: Modulation by heparin, heparan sulfate, and PRG4
Authors: Sin Yun Jin Ashley , MacLeod Rebecca , Tanguay Adam P. , Wang Andrew , Braender-Carr Olivia , Vitelli Teraesa M. , Jay Gregory D. , Schmidt Tannin A. , Cowman Mary K.
Published: October 2022

The size, conformation, and organization of the glycosaminoglycan hyaluronan (HA) affect its interactions with soluble and cell surface-bound proteins. HA that is induced to form stable networks has unique biological properties relative to unmodified soluble HA. AlphaLISA assay technology offers a facile and general experimental approach to assay protein-mediated networking of HA in solution. Connections formed between two end-biotinylated 50 kDa HA (bHA) chains can be detected by signal arising from streptavidin-coated donor and acceptor beads being brought into close proximity when the bHA chains are bridged by proteins. We observed that incubation of bHA with the protein TSG-6 (tumor necrosis factor alpha stimulated gene/protein 6, TNFAIP/TSG-6) leads to dimerization or higher order multimerization of HA chains in solution. We compared two different heparin (HP) samples and two heparan sulfate (HS) samples for the ability to disrupt HA crosslinking by TSG-6. Both HP samples had approximately three sulfates per disaccharide, and both were effective in inhibiting HA crosslinking by TSG-6. HS with a relatively high degree of sulfation (1.75 per disaccharide) also inhibited TSG-6 mediated HA networking, while HS with a lower degree of sulfation (0.75 per disaccharide) was less effective. We further identified Proteoglycan 4 (PRG4, lubricin) as a TSG-6 ligand, and found it to inhibit TSG-6-mediated HA crosslinking. The effects of HP, HS, and PRG4 on HA crosslinking by TSG-6 were shown to be due to HP/HS/PRG4 inhibition of HA binding to the Link domain of TSG-6. Using the AlphaLISA platform, we also tested other HA-binding proteins for ability to create HA networks. The G1 domain of versican (VG1) effectively networked bHA in solution but required a higher concentration than TSG-6. Cartilage link protein (HAPLN1) and the HA binding protein segment of aggrecan (HABP, G1-IGD-G2) showed only low and variable magnitude HA networking effects. This study unambiguously demonstrates HA crosslinking in solution by TSG-6 and VG1 proteins, and establishes PRG4, HP and highly sulfated HS as modulators of TSG-6 mediated HA crosslinking.
Identifying well-folded de novo proteins in the new era of accurate structure prediction
Authors: Peñas-Utrilla Daniel , Marcos Enrique
Published: October 2022

Computational de novo protein design tailors proteins for target structures and oligomerisation states with high stability, which allows overcoming many limitations of natural proteins when redesigned for new functions. Despite significant advances in the field over the past decade, it remains challenging to predict sequences that will fold as stable monomers in solution or binders to a particular protein target; thereby requiring substantial experimental resources to identify proteins with the desired properties. To overcome this, here we leveraged the large amount of design data accumulated in the last decade, and the breakthrough in protein structure prediction from last year to investigate on improved ways of selecting promising designs before experimental testing. We collected de novo proteins from previous studies, 518 designed as monomers of different folds and 2112 as binders against the Botulinum neurotoxin, and analysed their structures with AlphaFold2, RoseTTAFold and fragment quality descriptors in combination with other properties related to surface interactions. These features showed high complementarity in rationalizing the experimental results, which allowed us to generate quite accurate machine learning models for predicting well-folded monomers and binders with a small set of descriptors. Cross-validating designs with varied orthogonal computational techniques should guide us for identifying design imperfections, rescuing designs and making more robust design selections before experimental testing.
Practice effects in cognitive assessments three years later in non-carriers but not in symptom-free mutation carriers of autosomal-dominant Alzheimer's disease: Exemplifying procedural learning and memory?
Authors: Almkvist Ove , Graff Caroline
Published: October 2022

Practice effects (PEs) defined as an improvement of performance in cognition due to repeated assessments between sessions are well known in unimpaired individuals, while less is known about impaired cognition and particularly in latent brain disease as autosomal-dominant Alzheimer's disease. The purpose was to evaluate the general (across tests/domains) and domain-specific PE calculated as the annual rate of change (ARC) in relation to years to the estimated disease onset (YECO) and in four groups of AD: asymptomatic mutation carriers (aAD, n = 19), prodromal, i.e., symptomatic mutation carriers, criteria for AD diagnosis not fulfilled (pAD, n = 4) and mutation carriers diagnosed with AD (dAD, n = 6) as well as mutation non-carriers from the AD families serving as a healthy comparison group (HC, n = 35). Cognition was assessed at baseline and follow-up about 3 years later by 12 tests covering six domains. The aAD and HC groups were comparable at baseline in demographic characteristics (age, gender, and education), when they were in their early forties, while the pAD and dAD groups were older and cognitively impaired. The results on mean ARC for the four groups were significantly different, small, positive, and age-insensitive in the HC group, while ARC was negative and declined with time/disease advancement in AD. The differences between HC and aAD groups in mean ARC and domain-specific ARC were not significant, indicating a subtle PE in aAD in the early preclinical stage of AD. In the symptomatic stages of AD, there was no PE probably due to cognitive disease-related progression. PEs were the largest in the verbal domain in both the HC and aAD groups, indicating a relationship with cognitive vulnerability. The group-related difference in mean ARC was predominant in timekeeping tests. To conclude, the practice effect in over 3 years was suggested to be linked to procedural learning and memory.
Multi-compartment diffusion magnetic resonance imaging models link tract-related characteristics with working memory performance in healthy older adults
Authors: Bauer Christopher E. , Zachariou Valentinos , Maillard Pauline , Caprihan Arvind , Gold Brian T.
Published: October 2022

Multi-compartment diffusion MRI metrics [such as metrics from free water elimination diffusion tensor imaging (FWE-DTI) and neurite orientation dispersion and density imaging (NODDI)] may reflect more specific underlying white-matter tract characteristics than traditional, single-compartment metrics [i.e., metrics from Diffusion Tensor Imaging (DTI)]. However, it remains unclear if multi-compartment metrics are more closely associated with age and/or cognitive performance than single-compartment metrics. Here we compared the associations of single-compartment [Fractional Anisotropy (FA)] and multi-compartment diffusion MRI metrics [FWE-DTI metrics: Free Water Eliminated Fractional Anisotropy (FWE-FA) and Free Water (FW); NODDI metrics: Intracellular Volume Fraction (ICVF), Orientation Dispersion Index (ODI), and CSF-Fraction] with both age and working memory performance. A functional magnetic resonance imaging (fMRI) guided, white matter tractography approach was employed to compute diffusion metrics within a network of tracts connecting functional regions involved in working memory. Ninety-nine healthy older adults (aged 60–85) performed an in-scanner working memory task while fMRI was performed and also underwent multi-shell diffusion acquisition. The network of white matter tracts connecting functionally-activated regions was identified using probabilistic tractography. Diffusion metrics were extracted from skeletonized white matter tracts connecting fMRI activation peaks. Diffusion metrics derived from both single and multi-compartment models were associated with age (ps≤ 0.011 for FA, FWE-FA, ICVF and ODI). However, only multi-compartment metrics, specifically FWE-FA (p= 0.045) and ICVF (p= 0.020), were associated with working memory performance. Our results suggest that while most current diffusion metrics are sensitive to age, several multi-compartment metrics (i.e., FWE-FA and ICVF) appear more sensitive to cognitive performance in healthy older adults.
Behavior is movement only but how to interpret it? Problems and pitfalls in translational neuroscience—a 40-year experience
Authors: Lipp Hans-Peter , Wolfer David P.
Published: October 2022

Translational research in behavioral neuroscience seeks causes and remedies for human mental health problems in animals, following leads imposed by clinical research in psychiatry. This endeavor faces several problems because scientists must read and interpret animal movements to represent human perceptions, mood, and memory processes. Yet, it is still not known how mammalian brains bundle all these processes into a highly compressed motor output in the brain stem and spinal cord, but without that knowledge, translational research remains aimless. Based on some four decades of experience in the field, the article identifies sources of interpretation problems and illustrates typical translational pitfalls. (1) The sensory world of mice is different. Smell, hearing, and tactile whisker sensations dominate in rodents, while visual input is comparatively small. In humans, the relations are reversed. (2) Mouse and human brains are equated inappropriately: the association cortex makes up a large portion of the human neocortex, while it is relatively small in rodents. The predominant associative cortex in rodents is the hippocampus itself, orchestrating chiefly inputs from secondary sensorimotor areas and generating species-typical motor patterns that are not easily reconciled with putative human hippocampal functions. (3) Translational interpretation of studies of memory or emotionality often neglects the ecology of mice, an extremely small species surviving by freezing or flight reactions that do not need much cognitive processing. (4) Further misinterpretations arise from confounding neuronal properties with system properties, and from rigid mechanistic thinking unaware that many experimentally induced changes in the brain do partially reflect unpredictable compensatory plasticity. (5) Based on observing hippocampal lesion effects in mice indoors and outdoors, the article offers a simplistic general model of hippocampal functions in relation to hypothalamic input and output, placing hypothalamus and the supraspinal motor system at the top of a cerebral hierarchy. (6) Many translational problems could be avoided by inclusion of simple species-typical behaviors as end-points comparable to human cognitive or executive processing, and to rely more on artificial intelligence for recognizing patterns not classifiable by traditional psychological concepts.
Galectin-3 (MAC-2) controls phagocytosis and macropinocytosis through intracellular and extracellular mechanisms
Authors: Rotshenker Shlomo
Published: October 2022

Galectin-3 (Gal-3; formally named MAC-2) is a β-galactoside-binding lectin. Various cell types produce Gal-3 under either normal conditions and/or pathological conditions. Gal-3 can be present in cells' nuclei and cytoplasm, secreted from producing cells, and associated with cells' plasma membranes. This review focuses on how Gal-3 controls phagocytosis and macropinocytosis. Intracellular and extracellular Gal-3 promotes the phagocytosis of phagocytic targets/cargo (e.g., tissue debris and apoptotic cells) in “professional phagocytes” (e.g., microglia and macrophages) and “non-professional phagocytes” (e.g., Schwann cells and astrocytes). Intracellularly, Gal-3 promotes phagocytosis by controlling the “eat me” signaling pathways that phagocytic receptors generate, directing the cytoskeleton to produce the mechanical forces that drive the structural changes on which phagocytosis depends, protrusion and then retraction of filopodia and lamellipodia as they, respectively, engulf and then internalize phagocytic targets. Extracellularly, Gal-3 promotes phagocytosis by functioning as an opsonin, linking phagocytic targets to phagocytic receptors, activating them to generate the “eat me” signaling pathways. Macropinocytosis is a non-selective endocytic mechanism that various cells use to internalize the bulk of extracellular fluid and included materials/cargo (e.g., dissolved nutrients, proteins, and pathogens). Extracellular and intracellular Gal-3 control macropinocytosis in some types of cancer. Phagocytosed and macropinocytosed targets/cargo that reach lysosomes for degradation may rupture lysosomal membranes. Damaged lysosomal membranes undergo either repair or removal by selective autophagy (i.e., lysophagy) that intracellular Gal-3 controls.
GABAA signaling, focal epileptiform synchronization and epileptogenesis
Authors: Avoli Massimo , de Curtis Marco , Lévesque Maxime , Librizzi Laura , Uva Laura , Wang Siyan
Published: October 2022

Under physiological conditions, neuronal network synchronization leads to different oscillatory EEG patterns that are associated with specific behavioral and cognitive functions. Excessive synchronization can, however, lead to focal or generalized epileptiform activities. It is indeed well established that in both epileptic patients and animal models, focal epileptiform EEG patterns are characterized by interictal and ictal (seizure) discharges. Over the last three decades, employing in vitro and in vivo recording techniques, several experimental studies have firmly identified a paradoxical role of GABAA signaling in generating interictal discharges, and in initiating—and perhaps sustaining—focal seizures. Here, we will review these experiments and we will extend our appraisal to evidence suggesting that GABAA signaling may also contribute to epileptogenesis, i.e., the development of plastic changes in brain excitability that leads to the chronic epileptic condition. Overall, we anticipate that this information should provide the rationale for developing new specific pharmacological treatments for patients presenting with focal epileptic disorders such as mesial temporal lobe epilepsy (MTLE).
A neural network model for timing control with reinforcement
Authors: Wang Jing , El-Jayyousi Yousuf , Ozden Ilker
Published: October 2022

How do humans and animals perform trial-and-error learning when the space of possibilities is infinite? In a previous study, we used an interval timing production task and discovered an updating strategy in which the agent adjusted the behavioral and neuronal noise for exploration. In the experiment, human subjects proactively generated a series of timed motor outputs. Positive or negative feedback was provided after each response based on the timing accuracy. We found that the sequential motor timing varied at two temporal scales: long-term correlation around the target interval due to memory drifts and short-term adjustments of timing variability according to feedback. We have previously described these two key features of timing variability with an augmented Gaussian process, termed reward-sensitive Gaussian process (RSGP). In a nutshell, the temporal covariance of the timing variable was updated based on the feedback history to recreate the two behavioral characteristics mentioned above. However, the RSGP was mainly descriptive and lacked a neurobiological basis of how the reward feedback can be used by a neural circuit to adjust motor variability. Here we provide a mechanistic model and simulate the process by borrowing the architecture of recurrent neural networks (RNNs). While recurrent connection provided the long-term serial correlation in motor timing, to facilitate reward-driven short-term variations, we introduced reward-dependent variability in the network connectivity, inspired by the stochastic nature of synaptic transmission in the brain. Our model was able to recursively generate an output sequence incorporating internal variability and external reinforcement in a Bayesian framework. We show that the model can generate the temporal structure of the motor variability as a basis for exploration and exploitation trade-off. Unlike other neural network models that search for unique network connectivity for the best match between the model prediction and observation, this model can estimate the uncertainty associated with each outcome and thus did a better job in teasing apart adjustable task-relevant variability from unexplained variability. The proposed artificial neural network model parallels the mechanisms of information processing in neural systems and can extend the framework of brain-inspired reinforcement learning (RL) in continuous state control.
Neurological disorders associated with glutamic acid decarboxylase 65 antibodies: Clinical spectrum and prognosis of a cohort from China
Authors: Bai Lin , Ren Haitao , Liang Menglin , Lu Qiang , Lin Nan , Liu Mange , Fan Siyuan , Cui Ruixue , Guan Hongzhi
Published: October 2022

Objective

To describe clinical phenotypes and prognosis of neurological autoimmunity related to glutamic acid decarboxylase 65 (GAD65) antibodies in China.

Method

In this retrospective observational study from Peking Union Medical College Hospital, we identified patients with neurological disorders related to GAD65 antibodies (cell-based assay) from May 2015 to September 2021. Clinical manifestations, immunotherapy responsiveness, and outcomes were collected after obtaining informed consent from all patients.

Results

Fifty-five patients were included: 40 (72.73%) were women and initial neurological symptoms developed at 42(34-55) years of age. The median time to the nadir of the disease was 5 months (range from 1 day to 48 months). The clinical syndromes included limbic encephalitis (LE) or epilepsy (Ep) (n= 34, 61.82%), stiff-person syndromes (SPS) (n= 18, 32.73%), autoimmune cerebellar ataxia (ACA) (n= 11, 20%), and overlap syndrome in eight (14.55%) patients. Thirty-two (58.2%) patients had comorbidities of other autoimmune diseases, including Hashimoto thyroiditis (n= 17, 53.13%), T1DM (n= 11, 34.78%), vitiligo (n= 6, 18.75%), and others (n=5, 15.63%). Two (3.64%) patients had tumors, including thymoma and small cell lung cancer. Fifty-one (92.7%) patients received first-line immunotherapy (glucocorticoids and/or IV immunoglobulin), and 4 (7.3%) received second-line immunotherapy (rituximab). Long-term immunotherapy (mycophenolate mofetil) was administered to 23 (41.8%) patients. At the median time of 15 months (IQR 6–33.75 month, range 3–96 month) of follow-up, the patients' median modified Rankin Score (mRS) had declined from 2 to 1. Thirty-eight (70.4%) patients experienced clinical improvement (mRS declined ≥1), 47 (87%) had favorable clinical outcomes (mRS ≤2), and nine were symptom-free (16.7%). The sustained response to immunotherapy ranged from 7/15 (63.63%) in ACA patients and 22/34 (64.7%) in LE/Ep patients to 14/17 (82.35%) in SPS patients.

Conclusions

LE/Ep was the most common neurological phenotype of GAD65 antibody neurological autoimmunity in our cohort. Most patients had comorbidities of other autoimmune diseases, but underlying tumors were rare. Most patients responded to immunotherapy. However, the long-term prognosis varied among different clinical phenotypes.
Brain-Computer Interface using neural network and temporal-spectral features
Authors: Wang Gan , Cerf Moran
Published: October 2022

Brain-Computer Interfaces (BCIs) are increasingly useful for control. Such BCIs can be used to assist individuals who lost mobility or control over their limbs, for recreational purposes such as gaming or semi-autonomous driving, or as an interface toward man-machine integration. Thus far, the performance of algorithms used for thought decoding has been limited. We show that by extracting temporal and spectral features from electroencephalography (EEG) signals and, following, using deep learning neural network to classify those features, one can significantly improve the performance of BCIs in predicting which motor action was imagined by a subject. Our movement prediction algorithm uses Sequential Backward Selection technique to jointly choose temporal and spectral features and a radial basis function neural network for the classification. The method shows an average performance increase of 3.50% compared to state-of-the-art benchmark algorithms. Using two popular public datasets our algorithm reaches 90.08% accuracy (compared to an average benchmark of 79.99%) on the first dataset and 88.74% (average benchmark: 82.01%) on the second dataset. Given the high variability within- and across-subjects in EEG-based action decoding, we suggest that using features from multiple modalities along with neural network classification protocol is likely to increase the performance of BCIs across various tasks.