bluuebunny/crossref_metadata_2025 huggingface dataset:
Ultrasound-Assisted Production of Xylo-Oligosaccharides From Alkali-Solubilized Corncob Bran Using Penicillium janthinellum XAF01 Acidic Xylanase
Authors: Zhou Mingchun , Fan Guangsen , Xia Hanshuo , Zhang Xiaohan , Teng Chao , Li Xiuting
Published: September 2021

A novel treatment involving enzymatic hydrolysis using an acidic xylanase coupled with ultrasound was performed to improve the xylo-oligosaccharides (XOS) yield from corncob bran. The acidic xylanase (XynB) was purified to a most suitable pH, temperature, and operational parameters for ultrasound-assisted hydrolysis were determined. A preliminary mechanistic investigation was performed through circular dichroism (CD) spectroscopy, scanning electron microscope (SEM) and a laser particle size analyzer, and the effects of ultrasound on enzyme (XynB) and substrate (corncob bran) were assessed. The results show that the maximum XOS yield was 20.71% when the reaction pH and temperature were 4.3 and 50°C, the ultrasonic parameters were 50 kHz and 0.40 W/cm2, which was 2.55 fold higher than that obtained using a non-ultrasound-assisted enzymatic preparation. Mechanism studies indicated that ultrasonic pretreatment could reduce the β-fold content and increase the random coil content. Changes in structure and size of substrate were observed. The specific surface area of the XAC molecules is easy to carry out enzymatic reaction, which is beneficial to the production of XOS.
The Core Promoter Is a Regulatory Hub for Developmental Gene Expression
Authors: Sloutskin Anna , Shir-Shapira Hila , Freiman Richard N. , Juven-Gershon Tamar
Published: September 2021

The development of multicellular organisms and the uniqueness of each cell are achieved by distinct transcriptional programs. Multiple processes that regulate gene expression converge at the core promoter region, an 80 bp region that directs accurate transcription initiation by RNA polymerase II (Pol II). In recent years, it has become apparent that the core promoter region is not a passive DNA component, but rather an active regulatory module of transcriptional programs. Distinct core promoter compositions were demonstrated to result in different transcriptional outputs. In this mini-review, we focus on the role of the core promoter, particularly its downstream region, as the regulatory hub for developmental genes. The downstream core promoter element (DPE) was implicated in the control of evolutionarily conserved developmental gene regulatory networks (GRNs) governing body plan in both the anterior-posterior and dorsal-ventral axes. Notably, the composition of the basal transcription machinery is not universal, but rather promoter-dependent, highlighting the importance of specialized transcription complexes and their core promoter target sequences as key hubs that drive embryonic development, differentiation and morphogenesis across metazoan species. The extent of transcriptional activation by a specific enhancer is dependent on its compatibility with the relevant core promoter. The core promoter content also regulates transcription burst size. Overall, while for many years it was thought that the specificity of gene expression is primarily determined by enhancers, it is now clear that the core promoter region comprises an important regulatory module in the intricate networks of developmental gene expression.
Appetite Suppression and Interleukin 17 Receptor Signaling Activation of Colonic Mycobiota Dysbiosis Induced by High Temperature and High Humidity Conditions
Authors: Guo Yinrui , Guo Hongya , Qiu Lingyan , Fu Yuanfei , Zhu Xiangxiang , Zhang Haiting , Wang Jian , Chen Diling
Published: September 2021

It is known that the microbiome affects human physiology, emotion, disease, growth, and development. Most humans exhibit reduced appetites under high temperature and high humidity (HTHH) conditions, and HTHH environments favor fungal growth. Therefore, we hypothesized that the colonic mycobiota may affect the host’s appetite under HTHH conditions. Changes in humidity are also associated with autoimmune diseases. In the current study mice were fed in an HTHH environment (32°C ± 2°C, relative humidity 95%) maintained via an artificial climate box for 8 hours per day for 21 days. Food intake, the colonic fungal microbiome, the feces metabolome, and appetite regulators were monitored. Components of the interleukin 17 pathway were also examined. In the experimental groups food intake and body weight were reduced, and the colonic mycobiota and fecal metabolome were substantially altered compared to control groups maintained at 25°C ± 2°C and relative humidity 65%. The appetite-related proteins LEPT and POMC were upregulated in the hypothalamus (p < 0.05), and NYP gene expression was downregulated (p < 0.05). The expression levels of PYY and O-linked β-N-acetylglucosamine were altered in colonic tissues (p < 0.05), and interleukin 17 expression was upregulated in the colon. There was a strong correlation between colonic fungus and sugar metabolism. In fimo some metabolites of cholesterol, tromethamine, and cadaverine were significantly increased. There was significant elevation of the characteristic fungi Solicoccozyma aeria, and associated appetite suppression and interleukin 17 receptor signaling activation in some susceptible hosts, and disturbance of gut bacteria and fungi. The results indicate that the gut mycobiota plays an important role in the hypothalamus endocrine system with respect to appetite regulation via the gut-brain axis, and also plays an indispensable role in the stability of the gut microbiome and immunity. The mechanisms involved in these associations require extensive further studies.
Can We Improve Antifungal Susceptibility Testing?
Authors: Durand Charlotte , Maubon Danièle , Cornet Muriel , Wang Yan , Aldebert Delphine , Garnaud Cécile
Published: September 2021

Systemic antifungal agents are increasingly used for prevention or treatment of invasive fungal infections, whose prognosis remains poor. At the same time, emergence of resistant or even multi-resistant strains is of concern as the antifungal arsenal is limited. Antifungal susceptibility testing (AFST) is therefore of key importance for patient management and antifungal stewardship. Current AFST methods, including reference and commercial types, are based on growth inhibition in the presence of an antifungal, in liquid or solid media. They usually enable Minimal Inhibitory Concentrations (MIC) to be determined with direct clinical application. However, they are limited by a high turnaround time (TAT). Several innovative methods are currently under development to improve AFST. Techniques based on MALDI-TOF are promising with short TAT, but still need extensive clinical validation. Flow cytometry and computed imaging techniques detecting cellular responses to antifungal stress other than growth inhibition are also of interest. Finally, molecular detection of mutations associated with antifungal resistance is an intriguing alternative to standard AFST, already used in routine microbiology labs for detection of azole resistance in Aspergillus and even directly from samples. It is still restricted to known mutations. The development of Next Generation Sequencing (NGS) and whole-genome approaches may overcome this limitation in the near future. While promising approaches are under development, they are not perfect and the ideal AFST technique (user-friendly, reproducible, low-cost, fast and accurate) still needs to be set up routinely in clinical laboratories.
Factor-Based Framework for Multivariate and Multi-step-ahead Forecasting of Large Scale Time Series
Authors: De Stefani Jacopo , Bontempi Gianluca
Published: September 2021

State-of-the-art multivariate forecasting methods are restricted to low dimensional tasks, linear dependencies and short horizons. The technological advances (notably the Big data revolution) are instead shifting the focus to problems characterized by a large number of variables, non-linear dependencies and long forecasting horizons. In the last few years, the majority of the best performing techniques for multivariate forecasting have been based on deep-learning models. However, such models are characterized by high requirements in terms of data availability and computational resources and suffer from a lack of interpretability. To cope with the limitations of these methods, we propose an extension to the DFML framework, a hybrid forecasting technique inspired by the Dynamic Factor Model (DFM) approach, a successful forecasting methodology in econometrics. This extension improves the capabilities of the DFM approach, by implementing and assessing both linear and non-linear factor estimation techniques as well as model-driven and data-driven factor forecasting techniques. We assess several method integrations within the DFML, and we show that the proposed technique provides competitive results both in terms of forecasting accuracy and computational efficiency on multiple very large-scale (>102 variables and > 103 samples) real forecasting tasks.
Sedimentary Provenance Changes Constrain the Eocene Initial Uplift of the Central Pamir, NW Tibetan Plateau
Authors: Wang Ping , Liu Dongliang , Li Haibing , Chevalier Marie-Luce , Wang Yadong , Pan Jiawei , Zheng Yong , Ge Chenglong , Bai Mingkun , Wang Shiguang
Published: September 2021

The Pamir Plateau region of the Northwestern Tibetan Plateau forms a prominent tectonic salient, separating the Tajik and Tarim basins. However, the topographic evolution of the Pamir Plateau remains elusive, despite the key role of this region played in the retreat of the Paratethys Ocean and in aridification across Central Asia. Therefore, the SW Tarim and Tajik basins are prime locations to decipher the geological history of the Pamir Plateau. Here, we present detrital zircon U/Pb and apatite fission-track (DAFT) ages from the Keliyang section of the SW Tarim Basin. DAFT ages show that sediments had three components during the Late Cretaceous and two components since the Oligocene. Detrital zircon U/Pb ages mainly cluster between 400 and 500 Ma during the Late Cretaceous, and coincide with ages of the Songpan-Ganzi and the West Kunlun Mountains. In contrast, detrital zircon U/Pb ages in the Eocene sediments are centered at around 200–300 Ma and 40–70 Ma, with a peak at ∼45 Ma, consistent with data from the Central Pamir and the West Kunlun Mountains. The ∼45 Ma peak in detrital zircon U/Pb ages since the Eocene indicates a new sedimentary source from the Central Pamir. Non-metric multi-dimensional scaling (MDS) analyses also show that the sedimentary source was closer to the Central Pamir after the Eocene, when compared to the Late Cretaceous. The result shows a clear Eocene provenance change in the Keliyang area. Moreover, this Eocene provenance shift has been detected in previous studies, in both the Tajik and Tarim basins, suggesting that the entire Central Pamir region likely experienced quasi-simultaneous abrupt uplift and paleo-geomorphological changes during the Eocene.
How to Understand School Refusal
Authors: Havik Trude , Ingul Jo Magne
Published: September 2021

Attending school is usually seen as a precondition for academic, social, and emotional learning. However, school absenteeism is a problem in many countries and covers different types of authorized or unauthorized absences and a myriad of reasons. An authorized absence is when there is a satisfactory explanation for the youth’s absence, while unauthorized absence is usually understood as school attendance problems (SAPs). The main aim of this article is first to investigate define, describe, and discuss school refusal (SR) and how SR differs from other concepts of SAPs, and the secondary aim is to understand SR using different theoretical perspectives. The article outlines this aim based upon a review of international research in this field and uses the systemic integrated cognitive approach and school alienation theories to explain how SR might emerge and develop. The review indicates that SAPs involve many types, concepts, definitions, and reasons. The most frequently used concepts are school refusal behavior, truancy, school refusal, and school withdrawal. Based on the review, the article argues for a common understanding of these concepts among all stakeholders. We suggest a narrow definition of SR to enhance clarity and agreement and propose that the systemic integrated cognitive approach and school alienation theory are relevant to the understanding of SR. A common understanding among all stakeholders is the importance of identifying and intervening in specific types of SAPs. By using a systemic integrated cognitive approach and school alienation theory, identification and interventions can be targeted at an early stage of the development process of SR.
Biohydrogen Production From Biomass Sources: Metabolic Pathways and Economic Analysis
Authors: Ahmed Shams Forruque , Rafa Nazifa , Mofijur M. , Badruddin Irfan Anjum , Inayat Abrar , Ali Md Sawkat , Farrok Omar , Yunus Khan T. M.
Published: September 2021

The commercialization of hydrogen as a fuel faces severe technological, economic, and environmental challenges. As a method to overcome these challenges, microalgal biohydrogen production has become the subject of growing research interest. Microalgal biohydrogen can be produced through different metabolic routes, the economic considerations of which are largely missing from recent reviews. Thus, this review briefly explains the techniques and economics associated with enhancing microalgae-based biohydrogen production. The cost of producing biohydrogen has been estimated to be between $10 GJ-1 and $20 GJ−1, which is not competitive with gasoline ($0.33 GJ−1). Even though direct biophotolysis has a sunlight conversion efficiency of over 80%, its productivity is sensitive to oxygen and sunlight availability. While the electrochemical processes produce the highest biohydrogen (>90%), fermentation and photobiological processes are more environmentally sustainable. Studies have revealed that the cost of producing biohydrogen is quite high, ranging between $2.13 kg−1 and 7.24 kg−1via direct biophotolysis, $1.42kg−1 through indirect biophotolysis, and between $7.54 kg−1 and 7.61 kg−1via fermentation. Therefore, low-cost hydrogen production technologies need to be developed to ensure long-term sustainability which requires the optimization of critical experimental parameters, microalgal metabolic engineering, and genetic modification.
Examining Signatures of Natural Selection in Antifungal Resistance Genes Across Aspergillus Fungi
Authors: dos Santos Renato Augusto Corrêa , Mead Matthew E. , Steenwyk Jacob L. , Rivero-Menéndez Olga , Alastruey-Izquierdo Ana , Goldman Gustavo Henrique , Rokas Antonis
Published: September 2021

Certain Aspergillus fungi cause aspergillosis, a set of diseases that typically affect immunocompromised individuals. Most cases of aspergillosis are caused by Aspergillus fumigatus, which infects millions of people annually. Some closely related so-called cryptic species, such as Aspergillus lentulus, can also cause aspergillosis, albeit at lower frequencies, and they are also clinically relevant. Few antifungal drugs are currently available for treating aspergillosis and there is increasing worldwide concern about the presence of antifungal drug resistance in Aspergillus species. Furthermore, isolates from both A. fumigatus and other Aspergillus pathogens exhibit substantial heterogeneity in their antifungal drug resistance profiles. To gain insights into the evolution of antifungal drug resistance genes in Aspergillus, we investigated signatures of positive selection in 41 genes known to be involved in drug resistance across 42 susceptible and resistant isolates from 12 Aspergillus section Fumigati species. Using codon-based site models of sequence evolution, we identified ten genes that contain 43 sites with signatures of ancient positive selection across our set of species. None of the sites that have experienced positive selection overlap with sites previously reported to be involved in drug resistance. These results identify sites that likely experienced ancient positive selection in Aspergillus genes involved in resistance to antifungal drugs and suggest that historical selective pressures on these genes likely differ from any current selective pressures imposed by antifungal drugs.
Using Molecular Transmission Networks to Reveal the Epidemic of Pretreatment HIV-1 Drug Resistance in Guangxi, China
Authors: Zhang Fei , Liang Bingyu , Liang Xu , Lin Zhaosen , Yang Yuan , Liang Na , Yang Yao , Liang Huayue , Jiang Jiaxiao , Huang Jiegang , Huang Rongye , Zhong Shanmei , Qin Cai , Jiang Junjun , Ye Li , Liang Hao
Published: September 2021

Introduction

Pretreatment drug resistance (PDR) is becoming an obstacle to the success of ART. This study investigated the prevalence of PDR and the transmission clusters (TCs) of drug resistance mutations (DRMs) in two cities where drug abuse used to be high to describe the local HIV-1 transmission dynamics.

Methods

Plasma samples were obtained from 1,027 ART-naïve patients in Guangxi. Viral subtypes and DRMs were identified. Transmission network and related factors were also determined.

Results

A total of 1,025 eligible sequences were obtained from Qinzhou (65.8%) and Baise (34.2%) cities. The predominant HIV-1 genotype was CRF08_BC (45.0%), followed by CRF01_AE (40.9%). The overall prevalence of PDR was 8.3%, and resistance to NNRTI was the most common. Putative links with at least one other sequence were found in 543/1,025 (53.0%) sequences, forming 111 clusters (2–143 individuals). The most prevalent shared DRMs included V106I (45.35%), V179D (15.1%), and V179E (15.1%). Clusters related to shared DRMs were more frequent and larger in CRF08_BC. The prevalence of shared DRMs increased with time, while the proportion of PDR gradually decreased. Age > 50 years was associated with clustering. Subtype CRF08_BC was more likely to have DRMs, PDR propagation, and DRM sharing.

Conclusion

PDR prevalence is moderate in this region. The association between PDR and subtype CRF08_BC suggested that DRMs spreading from injection drug users (IDUs) to heterosexuals (HETs) might be the major source of PDR in this region. Our findings highlight the significance of continuous surveillance of PDR.
Spatial Management to Reduce Entanglement Risk to North Atlantic Right Whales in Fishing Gear: A Case Study of U.S. Northeast Lobster Fishery 2002–2009
Authors: Bisack Kathryn D. , Magnusson Gisele M.
Published: September 2021

Despite the use of gear requirements and access restrictions to manage lobster fishery interactions with north Atlantic right whales since 1997, the population is likely below 370 animals. The Dynamic Area Management (DAM) program (2002–2009) used “real-time” right whale sightings data to provide temporary protection using closures or whale-modified-gear to reduce entanglement. Our ex-post evaluation uses a flexible framework to identify strengths and weaknesses of the program. Biological and economic implications of the program are evaluated using a relative risk of entanglement index (RREI) calculated with spatially and temporally explicit data on density of right whales and fishing effort. An illustrative closure optimization model demonstrates the trade-offs between the non-monetary benefits of risk reduction and the opportunity cost of closures under alternative decision rules (benefit-ranking and cost-effectiveness). Annual aerial sampling to detect DAM areas was low (<3%), yet in some months’ the 17% of area covered by all northeast right whale management areas encompassed up to 70% of the region’s population. Despite their small spatial footprint, dynamic and static measures may have reduced total risk by 6.5% on average, and DAM zones may have created an indirect economic incentive for some fishers to adopt the whale-modified-gear. Similar RREI index values in some months with inverse levels of fishing effort and whale presence highlight the need to consider fishing and whales jointly to reduce risk. These temporal-spatial patterns are critical in policy instrument design. Further, optimization results illustrate how different decision rules can attain equivalent non-monetary benefits of risk reduction at different opportunity costs to industry; the implications of whale-modified-gear and compliance factors are explored. We recommend that DAMs be considered as part of a suite of policy instruments, and highlight how recent technological advances may support lower cost data collection and faster implementation given limited public sector budgets. This case study highlights the need for evaluation of past policy instruments with a lens beyond biological outcomes, and sets the stage for further empirical analysis to better understand harvester responses to management measures designed to protect right whales and the resulting private and public sector trade-offs.
Internal Wave Dynamics Over Isolated Seamount and Its Influence on Coral Larvae Dispersion
Authors: Stashchuk Nataliya , Vlasenko Vasiliy
Published: September 2021

The internal wave dynamics over Rosemary Bank Seamount (RBS), North Atlantic, were investigated using the Massachusetts Institute of Technology general circulation model. The model was forced by M2-tidal body force. The model results are validated against the in-situ data collected during the 136th cruise of the RRS “James Cook” in June 2016. The observations and the modeling experiments have shown two-wave processes developed independently in the subsurface and bottom layers. Being super-critical topography for the semi-diurnal internal tides, RBS does not reveal any evidence of tidal beams. It was found that below 800-m depth, the tidal flow generates bottom trapped sub-inertial internal waves propagated around RBS. The tidal flow interacting with a cluster of volcanic origin tall bottom cones generates short-scale internal waves located in 100 m thick seasonal pycnocline. A weakly stratified layer separates the internal waves generated in two waveguides. Parameters of short-scale sub-surface internal waves are sensitive to the season stratification. It is unlikely they can be observed in the winter season from November to March when seasonal pycnocline is not formed. The deep-water coral larvae dispersion is mainly controlled by bottom trapped tidally generated internal waves in the winter season. A Lagrangian-type passive particle tracking model is used to reproduce the transport of generic deep-sea water invertebrate species.
Isolation and Characterization of High-Efficiency Rhizobia From Western Kenya Nodulating With Common Bean
Authors: Wekesa Clabe Simiyu , Furch Alexandra C. U. , Oelmüller Ralf
Published: September 2021

Common bean is one of the primary protein sources in third-world countries. They form nodules with nitrogen-fixing rhizobia, which have to be adapted to the local soils. Commercial rhizobial strains such asRhizobium tropiciCIAT899 are often used in agriculture. However, this strain failed to significantly increase the common bean yield in many places, including Kenya, due to the local soils’ low pH. We isolated two indigenous rhizobial strains from the nodules of common bean from two fields in Western Kenya that have never been exposed to commercial inocula. We then determined their ability to fix nitrogen in common beans, solubilize phosphorus, and produce indole acetic acid. In greenhouse experiments, common bean plants inoculated with two isolates, B3 and S2 in sterile vermiculite, performed better than those inoculated with CIAT899 or plants grown with nitrogen fertilizer alone. In contrast to CIAT899, both isolates grew in the media with pH 4.8. Furthermore, isolate B3 had higher phosphate solubilization ability and produced more indole acetic acid than the other two rhizobia. Genome analyses revealed that B3 and S2 are different strains ofRhizobium phaseoli. We recommend fieldwork studies in Kenyan soils to test the efficacy of the two isolates in the natural environment in an effort to produce inoculants specific for these soils.
Mycobacterium lepromatosis as a Second Agent of Hansen’s Disease
Authors: Deps Patrícia , Collin Simon M.
Published: September 2021

Mycobacterium lepromatosis was identified as a new species and second causal agent of Hansen’s disease (HD, or leprosy) in 2008, 150years after the disease was first attributed to Mycobacterium leprae. M. lepromatosis has been implicated in a small number of HD cases, and clinical aspects of HD caused by M. lepromatosis are poorly characterized. HD is a recognized zoonosis through transmission of M. leprae from armadillos, but the role of M. lepromatosis as a zoonotic agent of HD is unknown. M. lepromatosis was initially associated with diffuse lepromatous leprosy, but subsequent case reports and surveys have linked it to other forms of HD. HD caused by M. lepromatosis has been reported from three endemic countries: Brazil, Myanmar, and Philippines, and three non-endemic countries: Mexico, Malaysia, and United States. Contact with armadillos in Mexico was mentioned in 2/21 M. lepromatosis HD case reports since 2008. M. lepromatosis in animals has been investigated only in non-endemic countries, in squirrels and chipmunks in Europe, white-throated woodrats in Mexico, and armadillos in the United States. To date, there have only been a small number of positive findings in Eurasian red squirrels in Britain and Ireland. A single study of environmental samples found no M. lepromatosis in soil from a Scottish red squirrel habitat. Future studies must focus on endemic countries to determine the true proportion of HD cases caused by M. lepromatosis, and whether viable M. lepromatosis occurs in non-human sources.
Autophagy as a Mechanism for Adaptive Prediction-Mediated Emergence of Drug Resistance
Authors: Nivedita Nivedita , Aitchison John D. , Baliga Nitin S.
Published: September 2021

Drug resistance is a major problem in treatment of microbial infections and cancers. There is growing evidence that a transient drug tolerant state may precede and potentiate the emergence of drug resistance. Therefore, understanding the mechanisms leading to tolerance is critical for combating drug resistance and for the development of effective therapeutic strategy. Through laboratory evolution of yeast, we recently demonstrated that adaptive prediction (AP), a strategy employed by organisms to anticipate and prepare for a future stressful environment, can emerge within 100 generations by linking the response triggered by a neutral cue (caffeine) to a mechanism of protection against a lethal agent (5-fluoroorotic acid, 5-FOA). Here, we demonstrate that mutations selected across multiple laboratory-evolved lines had linked the neutral cue response to core genes of autophagy. Across these evolved lines, conditional activation of autophagy through AP conferred tolerance, and potentiated subsequent selection of mutations in genes specific to overcoming the toxicity of 5-FOA. These results offer a new perspective on how extensive genome-wide genetic interactions of autophagy could have facilitated the emergence of AP over short evolutionary timescales to potentiate selection of 5-FOA resistance-conferring mutations.
Regulation of Biofilm Exopolysaccharide Production by Cyclic Di-Guanosine Monophosphate
Authors: Poulin Myles B. , Kuperman Laura L.
Published: September 2021

Many bacterial species in nature possess the ability to transition into a sessile lifestyle and aggregate into cohesive colonies, known as biofilms. Within a biofilm, bacterial cells are encapsulated within an extracellular polymeric substance (EPS) comprised of polysaccharides, proteins, nucleic acids, lipids, and other small molecules. The transition from planktonic growth to the biofilm lifecycle provides numerous benefits to bacteria, such as facilitating adherence to abiotic surfaces, evasion of a host immune system, and resistance to common antibiotics. As a result, biofilm-forming bacteria contribute to 65% of infections in humans, and substantially increase the energy and time required for treatment and recovery. Several biofilm specific exopolysaccharides, including cellulose, alginate, Pel polysaccharide, and poly-N-acetylglucosamine (PNAG), have been shown to play an important role in bacterial biofilm formation and their production is strongly correlated with pathogenicity and virulence. In many bacteria the biosynthetic machineries required for assembly of these exopolysaccharides are regulated by common signaling molecules, with the second messenger cyclic di-guanosine monophosphate (c-di-GMP) playing an especially important role in the post-translational activation of exopolysaccharide biosynthesis. Research on treatments of antibiotic-resistant and biofilm-forming bacteria through direct targeting of c-di-GMP signaling has shown promise, including peptide-based treatments that sequester intracellular c-di-GMP. In this review, we will examine the direct role c-di-GMP plays in the biosynthesis and export of biofilm exopolysaccharides with a focus on the mechanism of post-translational activation of these pathways, as well as describe novel approaches to inhibit biofilm formation through direct targeting of c-di-GMP.
Detection of Alu Exonization Events in Human Frontal Cortex From RNA-Seq Data
Authors: Florea Liliana , Payer Lindsay , Antonescu Corina , Yang Guangyu , Burns Kathleen
Published: September 2021

Alu exonization events functionally diversify the transcriptome, creating alternative mRNA isoforms and accounting for an estimated 5% of the alternatively spliced (skipped) exons in the human genome. We developed computational methods, implemented into a software called Alubaster, for detecting incorporation of Alu sequences in mRNA transcripts from large scale RNA-seq data sets. The approach detects Alu sequences derived from both fixed and polymorphic Alu elements, including Alu insertions missing from the reference genome. We applied our methods to 117 GTEx human frontal cortex samples to build and characterize a collection of Alu-containing mRNAs. In particular, we detected and characterized Alu exonizations occurring at 870 fixed Alu loci, of which 237 were novel, as well as hundreds of putative events involving Alu elements that are polymorphic variants or rare alleles not present in the reference genome. These methods and annotations represent a unique and valuable resource that can be used to understand the characteristics of Alu-containing mRNAs and their tissue-specific expression patterns.
Effects of Aging on the Neural Mechanisms Underlying the Recollection of Memories Encoded by Social Interactions With Persons in the Same and Different Age Groups
Authors: Tsuruha Eri , Tsukiura Takashi
Published: September 2021

Memories related to ingroup members are remembered more accurately than those related to outgroup members. However, little is known about the age-dependent differences in neural mechanisms underlying the retrieval of memories shared with ingroup or outgroup members that are categorized by age-group membership. The present functional magnetic resonance imaging (fMRI) study investigated this issue. Healthy young and older adults participated in a 2-day experiment. On the first day outside fMRI, participants were presented with words by unfamiliar persons in movie clips and exchanged each word with persons belonging to the same age group (SAG) or different age group (DAG). On the second day during fMRI, participants were randomly presented with learned and new words one by one, and they judged whether each word had been encoded with either SAG or DAG members or neither. fMRI results demonstrated that an age-dependent decrease in successful retrieval activation of memories presented by DAG was identified in the anterior temporal lobe (ATL) and hippocampus, whereas with memories presented by SAG, an age-dependent decrease in activation was not found in any regions. In addition, an age-dependent decrease in functional connectivity was significant between the hippocampus/ATL and posterior superior temporal sulcus (pSTS) during the successful retrieval of memories encoded with the DAG people. The “other”-related mechanisms including the hippocampus, ATL, and pSTS with memories learned with the outgroup members could decrease in older adults, whereas with memories learned with the ingroup members, the “self”-related mechanisms could be relatively preserved in older adults.
Acute Secondary Prevention of Ischemic Stroke: Overlooked No Longer
Authors: Bulwa Zachary B. , Mendelson Scott J. , Brorson James R.
Published: September 2021

Recent studies of interventions initiated acutely following onset of minor ischemic stroke or transient ischemic attack (TIA) have disclosed early stroke recurrence rates that are substantially higher than long-term recurrence rates and that can be reduced by acute antiplatelet treatment interventions. These observations, bolstered by analysis based on kinetic modeling of the time course of recurrence following initial events, suggest that acute stroke patients experience an underlying vulnerable state that quickly transitions to a more stable state. Some evidence also supports the benefits of early treatment with direct-acting oral anticoagulants in cardioembolic stroke and of continuation or early initiation of statin therapy in atherosclerotic stroke. Treatment of ischemic stroke should address the transient vulnerable state that follows the initial event, employing measures aiming to avert early recurrence of thromboembolism and to promote stabilization of vulnerable arterial plaque. These measures constitute acute secondary prevention following ischemic stroke.
Bone Mineral Density in Adults With Cerebral Palsy
Authors: Won Jun Hee , Jung Se Hee
Published: September 2021

Low bone mineral density (BMD) is an emerging health issue in adults with cerebral palsy (CP). This cross-sectional study aimed to describe the characteristics of BMD in adults with CP, and to elucidate the risk factors for low BMD in this population. People aged ≥20 years and diagnosed with CP were recruited from February 2014 to November 2014. We assessed BMD using dual-energy X-ray absorptiometry (DXA) for the lumbar spine, femoral neck, and total femur. Moreover, the body composition was assessed using DXA. We included a total of 87 adults with CP (mean age 42.01 years; 52 men). The prevalence of low BMD was 25.3%. Male sex and age were associated with lower BMD. BMD was significantly lower in the non-ambulatory group than that in the ambulatory group for both lumbar spine and femoral neck. The total fat mass demonstrated a positive correlation with the Z-score and BMD for the femur neck and total femur. Body mass index (BMI) and total fat mass were positively correlated with BMD in the lumbar spine, femoral neck, and total femur. However, the Gross Motor Function Classification Scale levels were negatively correlated with BMD at the aforementioned three sites. In conclusion, adults with CP revealed decreased BMD, which was associated with male sex, age, decreased gross motor function, loss of ambulatory function, low BMI, decreased total fat mass, and decreased total fat-free mass.
Computerized Music-Reading Intervention Improves Resistance to Unisensory Distraction Within a Multisensory Task, in Young and Older Adults
Authors: Karagiorgis Alexandros T. , Chalas Nikolas , Karagianni Maria , Papadelis Georgios , Vivas Ana B. , Bamidis Panagiotis , Paraskevopoulos Evangelos
Published: September 2021

Incoming information from multiple sensory channels compete for attention. Processing the relevant ones and ignoring distractors, while at the same time monitoring the environment for potential threats, is crucial for survival, throughout the lifespan. However, sensory and cognitive mechanisms often decline in aging populations, making them more susceptible to distraction. Previous interventions in older adults have successfully improved resistance to distraction, but the inclusion of multisensory integration, with its unique properties in attentional capture, in the training protocol is underexplored. Here, we studied whether, and how, a 4-week intervention, which targets audiovisual integration, affects the ability to deal with task-irrelevant unisensory deviants within a multisensory task. Musically naïve participants engaged in a computerized music reading game and were asked to detect audiovisual incongruences between the pitch of a song’s melody and the position of a disk on the screen, similar to a simplistic music staff. The effects of the intervention were evaluated via behavioral and EEG measurements in young and older adults. Behavioral findings include the absence of age-related differences in distraction and the indirect improvement of performance due to the intervention, seen as an amelioration of response bias. An asymmetry between the effects of auditory and visual deviants was identified and attributed to modality dominance. The electroencephalographic results showed that both groups shared an increase in activation strength after training, when processing auditory deviants, located in the left dorsolateral prefrontal cortex. A functional connectivity analysis revealed that only young adults improved flow of information, in a network comprised of a fronto-parietal subnetwork and a multisensory temporal area. Overall, both behavioral measures and neurophysiological findings suggest that the intervention was indirectly successful, driving a shift in response strategy in the cognitive domain and higher-level or multisensory brain areas, and leaving lower level unisensory processing unaffected.
Social Deficits and Repetitive Behaviors Are Improved by Early Postnatal Low-Dose VPA Intervention in a Novel shank3-Deficient Zebrafish Model
Authors: Liu Chunxue , Wang Yi , Deng Jingxin , Lin Jia , Hu Chunchun , Li Qiang , Xu Xiu
Published: September 2021

Mutations of the SHANK3 gene are found in some autism spectrum disorder (ASD) patients, and animal models harboring SHANK3 mutations exhibit a variety of ASD-like behaviors, presenting a unique opportunity to explore the underlying neuropathological mechanisms and potential pharmacological treatments. The histone deacetylase (HDAC) valproic acid (VPA) has demonstrated neuroprotective and neuroregenerative properties, suggesting possible therapeutic utility for ASD. Therefore, SHANK3-associated ASD-like symptoms present a convenient model to evaluate the potential benefits, therapeutic window, and optimal dose of VPA. We constructed a novel shank3-deficient (shank3ab–/–) zebrafish model through CRISPR/Cas9 editing and conducted comprehensive morphological and neurobehavioral evaluations, including of core ASD-like behaviors, as well as molecular analyses of synaptic proteins expression levels. Furthermore, different VPA doses and treatment durations were examined for effects on ASD-like phenotypes. Compared to wild types (WTs), shank3ab–/– zebrafish exhibited greater developmental mortality, more frequent abnormal tail bending, pervasive developmental delay, impaired social preference, repetitive swimming behaviors, and generally reduced locomotor activity. The expression levels of synaptic proteins were also dramatically reduced in shank3ab–/– zebrafish. These ASD-like behaviors were attenuated by low-dose (5 μM) VPA administered from 4 to 8 days post-fertilization (dpf), and the effects persisted to adulthood. In addition, the observed underexpression of grm5, encoding glutamate metabotropic receptor 5, was significantly improved in VPA-treated shank3ab–/– zebrafish. We report for the first time that low-dose VPA administered after neural tube closure has lasting beneficial effects on the social deficits and repetitive behavioral patterns in shank3-deficient ASD model zebrafish. These findings provide a promising strategy for ASD clinical drug development.
Novel Angiotensin-I Converting Enzyme Inhibitory Peptides Isolated From Rice Wine Lees: Purification, Characterization, and Structure-Activity Relationship
Authors: He Zeqi , Liu Guo , Qiao Zijiao , Cao Yong , Song Mingyue
Published: September 2021

The bioactive peptides that can inhibit angiotensin-I converting enzyme (ACE, EC. 3. 4.15.1) are considered as possible cures of hypertension. Food-derived angiotensin-I converting enzyme inhibitory (ACEi) peptides have gained more attention because of their reduced side effects. In this study, we reported the method for purifying ACEi peptides from the lees of traditional Chinese rice wine and evaluated the product's biochemical properties. After three steps of reversed-phase high-performance liquid chromatography (RP-HPLC), for the first time, we isolated, purified, and identified two novel peptides: LIIPQH and LIIPEH, both of which showed strong ACEi activity (IC50-values of 120.10 ± 9.31 and 60.49±5.78 μg/ml, respectively). They were further categorized as mixed-type ACE inhibitors and were stable against both ACE and gastrointestinal enzymes during in vitro digestion. Together, these results suggest that the rice wine lees that produced as a by-product during rice wine production can be utilized in various fields related to functional foods and antihypertensive medicine.
Effectiveness of Canakinumab Treatment in Colchicine Resistant Familial Mediterranean Fever Cases
Authors: Yücel Burcu Bozkaya , Aydog Ozlem , Nalcacioglu Hulya , Yılmaz Ayşegül
Published: September 2021

Anti-interleukin 1 agents are used successfully in colchicine-resistant or intolerant Familial Mediterranean Fever (FMF) patients. Sixty-five patients with FMF who received canakinumab treatment for at least 6 months due to colchicine resistance or intolerance between 2016 and 2020 in our department were retrospectively analyzed. Canakinumab treatment was given subcutaneously every 4 weeks. After completing monthly canakinumab therapy over 12 months, in patients with complete remission, the dosing interval was extended to every 1.5 months for 6 months, then every 2 months for 6 months, and finally every 3 months for a year. In patients without disease activation, canakinumab treatment was discontinued at the end of 3 years and followed up with colchicine treatment. Patients who had a flare switched to the previous dosing interval. In patients with renal amyloidosis, monthly canakinumab treatment was continued without extending the dose intervals. The mean duration of canakinumab use in our patients was 31.4 ± 10.57 months (6–52 months). The mean age at onset of symptoms was 4.65 ± 3.84 (range, 1–18) years, and the mean age at diagnosis was 5.59 ± 3.9 (range, 4–19) years. Complete remission was achieved in 57 (87.6%) and partial remission in seven (10.7%) patients. One patient was unresponsive to treatment. Canakinumab treatment was discontinued in three patients with complete remission and one patient with drug resistance. Erythrocyte sedimentation rate (ESR) (51.85 ± 15.7 vs. 27.80 ± 13.73 mm/h) and C-reactive protein (CRP) [26 (3-73) vs. 5 (1–48) mg/L] values were compared before and after canakinumab treatment in attack-free periods, a significant decrease was found after canakinumab treatment (p < 0.001, p < 0.001, respectively). Bodyweight Z-scores (respectively −0.80 ± 0.86 vs. −0.49 ± 0.92) were compared, similarly, a statistically significant increase after canakinumab treatment (p < 0.001), but no significant increase in height Z scores (−1.00 ± 0.88 vs. −0.96 ± 0.94) (p = 0.445) was detected. Four patients had FMF-related renal amyloidosis. The decrease in proteinuria with canakinumab treatment was not statistically significant (p = 0.068). Cervical lymphadenitis developed in one and local reactions in two patients. No severe adverse effects requiring discontinuation of canakinumab treatment were observed. Our study showed that canakinumab treatment was highly effective, well-tolerated in pediatric FMF patients, and controlled extension of the canakinumab dose interval was safe.
Global Pattern of CD8+ T-Cell Infiltration and Exhaustion in Colorectal Cancer Predicts Cancer Immunotherapy Response
Authors: Tian Sun , Wang Fulong , Zhang Rongxin , Chen Gong
Published: September 2021

Background: The MSI/MSS status does not fully explain cancer immunotherapy response in colorectal cancer. Thus, we developed a colorectal cancer-specific method that predicts cancer immunotherapy response.

Methods: We used gene expression data of 454 samples (MSI = 131, MSI-L = 23, MSS = 284, and Unknown = 16) and developed a TMEPRE method that models signatures of CD8+ T-cell infiltration and CD8+ T-cell exhaustion states in the tumor microenvironment of colorectal cancer. TMEPRE model was validated on three RNAseq datasets of melanoma patients who received pembrolizumab or nivolumab and one RNAseq dataset of purified CD8+ T cells in different exhaustion states.

Results: TMEPRE showed predictive power in three datasets of anti-PD1-treated patients (p = 0.056, 0.115, 0.003). CD8+ T-cell exhaustion component of TMEPRE model correlates with anti-PD1 responding progenitor exhausted CD8+ T cells in both tumor and viral infection (p = 0.048, 0.001). The global pattern of TMEPRE on 454 colorectal cancer samples indicated that 10.6% of MSS patients and 67.2% of MSI patients show biological characteristics that can potentially benefit from anti-PD1 treatment. Within MSI nonresponders, approximately 50% showed insufficient tumor-infiltrating CD8+ T cells and 50% showed terminal exhaustion of CD8+ T cells. These terminally exhausted CD8+ T cells coexisted with signatures of myeloid-derived suppressor cells in colorectal cancer.

Conclusion: TMEPRE is a colorectal cancer-specific method. It captures characteristics of CD8+ T-cell infiltration and CD8+ T-cell exhaustion state and predicts cancer immunotherapy response. A subset of MSS patients could potentially benefit from anti-PD1 treatment. Anti-PD1 resistance MSI patients with insufficient infiltration of CD8+ T cells or terminal exhaustion of CD8+ T cells need different treatment strategies.
Orphan Drugs, Compounded Medication and Pharmaceutical Commons
Authors: Hendrickx Kim , Dooms Marc
Published: September 2021

Regulatory agencies installed orphan drug regulations to stimulate research and development of new innovative treatments for life-threatening diseases with a low prevalence (rare diseases). We established a list of well-known food-related ingredients with clinical evidence for rare diseases in the open medical literature that obtained marketing authorization as an expensive “orphan drug”, protected by intellectual property (IP) rights. We show that these ingredients are part of an established practice of medicinal compounding—a form of point of care manufacturing. We argue that these ingredients should be considered as “pharmaceutical commons”, and that regulatory incentives for private companies and market protection mechanisms such as IP rights are not justified in this case.