bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ultra-fast insulin-pramlintide co-formulation for improved glucose management in diabetic rats
Authors: Maikawa Caitlin L. , Chen Peyton C. , Vuong Eric T. , Nguyen Leslee T. , Mann Joseph L. , d’Aquino Andrea I. , Lal Rayhan A. , Maahs David M. , Buckingham Bruce A. , Appel Eric A. 
Published: April 2021

ABSTRACTDual-hormone replacement therapy with insulin and amylin in patients with type 1 diabetes has the potential to improve glucose management. Unfortunately, currently available formulations require burdensome separate injections at mealtimes and have disparate pharmacokinetics that do not mimic endogenous co-secretion. Here, we use amphiphilic acrylamide copolymers to create a stable co-formulation of monomeric insulin and amylin analogues (lispro and pramlintide) with synchronous pharmacokinetics and ultra-rapid action. The co-formulation is stable for over 16 hours under stressed aging conditions, whereas commercial insulin lispro (Humalog) aggregates in 8 hours. The faster pharmacokinetics of monomeric insulin in this co-formulation resulted in increased insulin-pramlintide overlap of 75 ± 6% compared to only 47 ± 7% for separate injections. The co-formulation resulted in similar delay in gastric emptying compared to pramlintide delivered separately. In a glucose challenge, in rats the co-formulation reduced deviation from baseline glucose compared to insulin only, or separate insulin and pramlintide administrations. Further, comparison of interspecies pharmacokinetics of monomeric pramlintide suggests that pharmacokinetics observed for the co-formulation will be well preserved in future translation to humans. Together these results suggest that the co-formulation has the potential to improve mealtime glucose management and reduce patient burden in the treatment of diabetes.
Plasma exosomal miRNA analysis of Alzheimer’s disease reveals the dysfunction of a neural network
Authors: Sun Yuzhe , Hefu Zhen , Lifang Wang , Li Benchao , Zhijie Song , Deng Yan , Zhili Liu , Ding Jiahong , Li Tao , Zhang Wenwei , Chao Nie , Rong Shuang 
Published: April 2021

AbstractExosomal microRNA (miRNA) is an emerging source for biomarkers of Alzheimer’s disease (AD). Here, we profiled miRNA expression in AD, mild cognitive impairment (MCI), and controls. The assessment and validation of differentially expressed miRNA represented their potential to be novel biomarkers for AD and MCI. We conducted 13 co-expression networks and a miRNA network module linked to neural function emerged as the most significantly associated with AD diagnosis. The conservation analysis revealed the M1 was highly preserved in controls but dysfunction in AD and MCI. The module pattern between MCI and NC was similar, but significantly differed from AD, suggesting that the neural network regulated by miRNA changed during the mild cognitive stage, and the total miRNA expression altered in AD stage. Additionally, 24 out of 26 M1 hub-miRNAs were derived from brain tissue, and 15 had been reported as AD biomarkers. We consequently proposed the other 11 miRNAs could play important roles in AD. Our study highlights that co-expression network analysis can provide a new path for finding novel biomarkers.
Host poly(A) polymerases PAPD5 and PAPD7 provide two layers of protection that ensure the integrity and stability of hepatitis B virus RNA
Authors: Liu Fei , Lee Amy C.H. , Guo Fang , Kondratowicz Andrew S. , Micolochick Steuer Holly M. , Miller Angela , Bailey Lauren D. , Wang Xiaohe , Chen Shuai , Kultgen Steven G. , Cuconati Andrea , Cole Andrew G. , Gotchev Dimitar , Dorsey Bruce D. , Rijnbrand Rene , Lam Angela M. , Sofia Michael J. , Gao Min 
Published: April 2021

AbstractNoncanonical poly(A) polymerases PAPD5 and PAPD7 (PAPD5/7) stabilize HBV RNA via the interaction with the viral post-transcriptional regulatory element (PRE), representing new antiviral targets to control HBV RNA metabolism, HBsAg production and viral replication. Inhibitors targeting these proteins are being developed as antiviral therapies, therefore it is important to understand how PAPD5/7 coordinate to stabilize HBV RNA. Here, we utilized a potent small-molecule AB-452 as a chemical probe, along with genetic analyses to dissect the individual roles of PAPD5/7 in HBV RNA stability. AB-452 inhibits PAPD5/7 enzymatic activities and reduces HBsAg bothin vitro(EC50ranged from 1.4 to 6.8 nM) andin vivoby 0.93 log10. Our genetic studies demonstrate that the stem-loop alpha sequence within PRE is essential for both maintaining HBV poly(A) tail integrity and determining sensitivity towards the inhibitory effect of AB-452. Although neither single knock-out (KO) ofPAPD5norPAPD7reduces HBsAg RNA and protein production,PAPD5KO does impair poly(A) tail integrity and confers partial resistance to AB-452. In contrast,PAPD7KO could not result in any measurable phenotypic changes, but displays a similar antiviral effect as AB-452 treatment whenPAPD5is depleted simultaneously.PAPD5/7double KO confers complete resistance to AB-452 treatment. Our results thus indicate that PAPD5 plays a dominant role in stabilizing viral RNA by protecting the integrity of its poly(A) tail, while PAPD7 serves as a second line of protection. These findings inform PAPD5 targeted therapeutic strategies and open avenues for further investigating PAPD5/7 in HBV replication.ImportanceChronic hepatitis B affects more than 250 million patients and is a major public health concern worldwide. HBsAg plays a central role in maintaining HBV persistence and as such, therapies reducing HBsAg have been extensively investigated. PAPD5/7 targeting inhibitors, with oral bioavailability, represent an opportunity to reduce both HBV RNA and HBsAg. Here we uncover that the SLα sequence is required for HBV poly(A) tail integrity and RNA stability, and that the antiviral activity of AB-452 mimics the SLα mutants. Although PAPD5 and PAPD7 regulate HBV RNA stability, it remains unclear how they coordinate in stabilizing HBV RNA. Based on our studies, PAPD5 plays a dominant role to stabilize viral RNA by protecting the integrity of its poly(A) tail, while PAPD7 serves as a backup protection mechanism. Our studies may point out a direction towards developing PAPD5-selective inhibitors that could be used effectively to treat chronic hepatitis B.
HspB8 prevents aberrant phase transitions of FUS by chaperoning its folded RNA binding domain
Authors: Boczek Edgar E. , Fürsch Julius , Jawerth Louise , Jahnel Marcus , Niedermeier Marie Laura , Ruer-Gruß Martine , Kammer Kai-Michael , Mediani Laura , Wang Jie , Yan Xiao , Pozniakovski Andrej , Poser Ina , Mateju Daniel , Carra Serena , Alberti Simon , Hyman Anthony A. , Stengel Florian 
Published: April 2021

SummaryAberrant liquid-to-solid phase transitions of biomolecular condensates have been linked to various neurodegenerative diseases. However, the underlying molecular interactions that drive aging remain enigmatic. Here, we develop quantitative time-resolved crosslinking mass spectrometry to monitor protein interactions and dynamics inside condensates formed by the protein fused in sarcoma (FUS). We identify misfolding of the RNA recognition motif (RRM) of FUS as a key driver of condensate ageing. We demonstrate that the small heat shock protein HspB8 partitions into FUS condensates via its intrinsically disordered domain and prevents condensate hardening via condensate-specific interactions that are mediated by its α-crystallin domain (αCD). These αCD-mediated interactions are altered in a disease-associated mutant of HspB8, which abrogates the ability of HspB8 to prevent condensate hardening. We propose that stabilizing aggregation-prone folded RNA-binding domains inside condensates by molecular chaperones may be a general mechanism to prevent aberrant phase transitions.
A simple model explains the cell cycle-dependent assembly of centromeric nucleosomes in holocentric species
Authors: Câmara Amanda Souza , Schubert Veit , Mascher Martin , Houben Andreas 
Published: April 2021

ABSTRACTCentromeres are essential for chromosome movement. In independent taxa, species with holocentric chromosomes exist. In contrast to monocentric species, where no obvious dispersion of centromeres occurs during interphase, the organization of holocentromeres differs between condensed and decondensed chromosomes. During interphase, centromeres are dispersed into a large number of CENH3-positive nucleosome clusters in a number of holocentric species. With the onset of chromosome condensation, the centromeric nucleosomes join and form line-like holocentromeres. Using polymer simulations, we propose a mechanism, relying on the interaction between centromeric nucleosomes and Structural Maintenance of Chromosomes (SMC) proteins. All simulations represented a ~20 Mbp-long chromosome, corresponding to ~100,000 nucleosomes. Different sets of molecular dynamic simulations were evaluated by testing four parameters: 1) the concentration of Loop Extruders (LEs) corresponding to SMCs; 2) the distribution and number of centromeric nucleosomes; 3) the effect of centromeric nucleosomes on interacting LEs; and 4) the assembly of kinetochores bound to centromeric nucleosomes. We observed the formation of a line-like holocentromere, due to the aggregation of the centromeric nucleosomes when the chromosome was compacted into loops. A groove-like holocentromere structure formed after a kinetochore complex was simulated along the centromeric line. Similar mechanisms may also organize a monocentric chromosome constriction, and its regulation may cause different centromere types during evolution.
Optofluidic Fiber Component for Separation and counting of Micron-Sized Particles
Authors: Kumar T. , Harish A.V. , Etcheverry S. , Margulis W. , Laurell F. , Russom A. 
Published: April 2021

AbstractAn all-fiber separation component capable of sorting and counting micron-sized particles based on size is presented. A sequence of silica fiber capillaries with various diameters and longitudinal cavities were used to fabricate the component for separation and detection in an uninterrupted flow. Fluorescence microparticles of 1 μm and 10 μm sizes are mixed in a visco-elastic fluid and infused into the all-fiber separation component. Elasto-inertial forces focus the larger particle to the center of the silica capillary, while the smaller microparticles exit from a side capillary. Analysis of the separated particles at the output showed a separation efficiency of 100% for the 10 μm and 97% for the 1 μm particles. In addition, the counting of the larger particles is demonstrated in the same flow. The separated 10 μm particles are further routed through another all-fiber component for counting. A counting speed of ~1400 particles/min and with the variation in amplitude of 10% is achived. A combination of separation and counting can be powerful tool may find several applications in biology and medicine, such as separation and analysis of exosomes, bacteria, and blood cell sub-populations.
Computational modeling and quantitative physiology reveal central parameters for brassinosteroid-regulated early cell physiological processes linked to elongation growth of theArabidopsisroot
Authors: Großeholz Ruth , Wanke Friederike , Rohr Leander , Glöckner Nina , Rausch Luiselotte , Scholl Stefan , Scacchi Emanuele , Spazierer Amelie-Jette , Shabala Lana , Shabala Sergey , Schumacher Karin , Kummer Ursula , Harter Klaus 
Published: April 2021

AbstractBrassinosteroids (BR) are key hormonal regulators of plant development. However, whereas the individual components of BR perception and signaling are well characterized experimentally, the question of how they can act and whether they are sufficient to carry out the critical function of cellular elongation remains open. Here, we combined computational modeling with quantitative cell physiology to understand the dynamics of the plasma membrane (PM)-localized BR response pathway during the initiation of cellular responses in the epidermis of theArabidopsisroot tip that are be linked to cell elongation. The model, consisting of ordinary differential equations, comprises the BR induced hyperpolarization of the PM, the acidification of the apoplast and subsequent cell wall swelling. We demonstrate that the competence of the root epidermal cells for the BR response predominantly depends on the amount and activity of H+-ATPases in the PM. The model further predicts that an influx of cations is required to compensate for the shift of positive charges caused by the apoplastic acidification. A potassium channel was subsequently identified and experimentally characterized, fulfilling this function. Thus, we established the landscape of components and parameters for physiological processes potentially linked to cell elongation, a central process in plant development.
Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells
Authors: Aaron Nicole , Kraakman Michael J. , Zhou Qiuzhong , Liu Qiongming , Yang Jing , Liu Longhua , Yu Lexiang , Wang Liheng , He Ying , Fan Lihong , Hirakawa Hiroyuki , Ding Lei , Lo James C , Wang Weidong , Zhao Baohong , Edward Guo X , Sun Lei , Rosen Clifford J. , Qiang Li 
Published: April 2021

ABSTRACTBackgroundBone marrow (BM) adipose tissue (BMAT) has been shown to be vital for regulating metabolism and maintaining skeletal homeostasis in the marrow niche. As a reflection of BM remodeling, BMAT is highly responsive to nutrient fluctuations, hormonal changes and metabolic disturbances such as obesity and diabetes mellitus. Expansion of BMAT has also been strongly associated with bone loss in mice and humans. However, the regulation of BM plasticity remains poorly understood, as does the mechanism that links changes in marrow adiposity with bone remodeling.MethodsUsing C57BL/6 mice as a model, we employed the bone-protected PPARγ constitutive deacetylation (2KR), Adipsin, and its downstream effector, C3, knockout mice. These mice were challenged to thiazolidinedione treatment, calorie restriction, or aging in order to induce bone loss and MAT expansion. Analysis of bone density and marrow adiposity was performed using a μCT scanner and by RNA analysis to assess adipocyte and osteoblast markers. Forin vitrostudies, primary bone marrow stromal cells (BMSCs) were isolated and subjected to osteoblastogenic or adipogenic differentiation or chemical treatment followed by morphological and molecular analyses. Clinical data was obtained from samples of a previous clinical trial of fasting and high calorie diet in healthy human volunteers.ResultsWe have shown that Adipsin is the most up-regulated adipokine during BMAT expansion in mice and humans, in a PPARγ acetylation-dependent manner. Ablation of Adipsin in mice specifically inhibited BMAT expansion but not peripheral adipose depots, and improved bone mass during calorie restriction, thiazolidinedione treatment, and aging. These effects were mediated through its downstream effector, complement component C3, to prime common progenitor cells toward adipogenesis rather than osteoblastogenesis through inhibiting Wnt/β- catenin signaling.ConclusionsAdipsin promotes new adipocyte formation and affects skeletal remodeling in the BM niche. Our study reveals a novel mechanism whereby the BM sustains its own plasticity through paracrine and endocrine actions of a unique adipokine.FundingThis work was supported by the National Institutes of Health T32DK007328 (NA), F31DK124926 (NA), R01DK121140 (JCL), R01AR068970 (BZ), R01AR071463 (BZ), R01DK112943 (LQ), and P01HL087123 (LQ).
Artificial selection of stable rhizosphere microbiota leads to heritable plant phenotype changes
Authors: Jacquiod Samuel , Spor Aymé , Wei Shaodong , Munkager Victoria , Bru David , Sørensen Søren J. , Salon Christophe , Philippot Laurent , Blouin Manuel 
Published: April 2021

AbstractResearch on artificial selection of microbial community has become popular due to perspectives in improving plant and animal health1-4. However, reported results still lack consistency5-8. We hypothesized that artificial selection may provide desired outcomes provided that microbial community structure has stabilized along the selection process. In a ten-generation artificial selection experiment involving 1,800 plants, we selected rhizosphere microbiota ofBrachypodium distachyonthat were associated with high or low levels of leaf greenness, a proxy for plant health9. Monitoring of the rhizosphere microbiota dynamics showed strong oscillations in community structure during an initial transitory phase of five generations, with no heritability in the selected property. In the last five generations, the structure of microbial communities displayed signs of stabilization, concomitantly to the appearance of heritability in leaf greenness. Selection pressure, initially ineffective, became successful in changing the greenness index in the intended direction, especially toward high greenness values. We showed a remarkable congruence between plant traits and selected microbial community structures, highlighting two phylogenetically distinct microbial sub-communities correlating with leaf greenness, whose abundance was significantly steered by directional artificial selection. Understanding microbial community structure stabilization can thus help improve the reliability of artificial microbiota selection.Short SentenceStable microbiota selection enables trait heritability
Identifying planktonic foraminiferal morphospecies: which are the important images?
Authors: Scott George H. 
Published: April 2021

AbstractSelection of imagery that promotes accurate identification of morphotaxa is viewed as a significant problem in the taxonomy of planktonic foraminifera. Currently, imagery of taxa is sparse, apparently selected by visual judgement, and presented without information about its typicality. What is required are impartially selected images which embrace population variation to serve as training sets for reliable identification of taxa. Outlined here is a simple morphometrically-based solution, applied to the shape of shells in two orientations, in which shape variation is resolved onto three principal component axes. On the premise that the best-adapted shells are the commonest, specimens within 1 standard deviation (sd) of the trivariate mean are recognized as population exemplars suitable for use as trainers. Specimens which project at ≥2 sd onto at least one axis are mapped as boundary specimens whose identity might be questioned. This procedure is trialled on samples ofTruncorotalia crassaformis. Exemplars from the Equatorial Atlantic and Caribbean compare closely; they partially overlap with those from a Holocene Southwest Pacific population provisionally interpreted as a subtaxon,Truncorotalia crassaformis hessi.
Interaction of the Causal Agent of Apricot bud gallAcalitus phloeocoptes(Nalepa) with Apricot: Implications in Infested Tissues
Authors: Li Shijuan , Khurshid Muhammad , Yao Junsheng , Dawuda Mohammed Mujitaba , Zhang Jin , Hassan Zeeshan , Ahmad Shahbaz , Xu Bingliang 
Published: April 2021

ABSTRACTApricot bud gall mite,Acalitus phloeocoptes(Nalepa), is a destructive arthropod pest that causes significant economic losses to apricot trees worldwide. Infested bud examination revealed that the starch granules in the bud axon were extended at the onset of the attack. During the later stages of the attack, the cytoplasm was distributed in apricot. The results also demonstrated that the accumulation of large amounts of cytokinin (zeatin, ZT) and auxin (indoleacetic acid, IAA) led to rapid bud proliferation during the rapid growth period. Abscisic acid (ABA) controls the development of gall buds and plays a vital role in gall bud maturity. The reduction of gibberellic acid (GA3) content led to rapid lignification at the later phase of bud development. Our results reveal the mechanism underlying the interaction of apricot bud gall with its parasite and provide reliable information for designing valuable breeding programs. This study will be quite useful for pest management and will provide a comprehensive evaluation of ecology-based cost-effective control, life history and demographic parameters ofA. phloeocoptes.
Siderophore fromTalaromyces trachyspermus:augmentation and characterization
Authors: Sahu Sharda , Prakash Anil 
Published: April 2021

AbstractIn the present study, a siderophore compound produced by an endophytic fungus,Talaromyces trachyspermuswas optimized for maximum production, 88.9 % SU by applying Plackett-Burman design and Response Surface Methodology through Central Composite Design that showed the succinic acid (1.141 g/L), sucrose (31.028 g/L) and temperature (27.475 °C) as significant factors. On scale up, a further increase in siderophore yield was obtained (by 3%) The compound was extracted, purified and detected chemically as catecholate siderophore showing max. λ absorbance at 279nm. Contained of hydroxy benzene as shown by GC-MS analysis and further identified as berberine by HRLC-MS studies. The compound berberine is clinically a very important drug with several ethnobotanical properties. This is rare to report fungal catecholate and first to report the production of berberine fromTalaromyces species.
PhosIDP: a web tool to visualize the location of phosphorylation sites in disordered regions
Authors: Nicolaou Sonia T. , Hebditch Max , Jonathan Owen J. , Verma Chandra S. , Warwicker Jim 
Published: April 2021

AbstractCharge is a key determinant of intrinsically disordered protein (IDP) and intrinsically disordered region (IDR) properties. IDPs and IDRs are enriched in sites of phosphorylation, which alters charge. Visualizing the degree to which phosphorylation modulates the charge profile of a sequence would assist in the functional interpretation of IDPs and IDRs. PhosIDP is a web tool that shows variation of charge and fold propensity upon phosphorylation. In combination with the displayed location of protein domains, the information provided by the web tool can lead to functional inferences for the consequences of phosphorylation. IDRs are components of many proteins that form biological condensates. It is shown that IDR charge, and its modulation by phosphorylation, is more tightly controlled for proteins that are essential for condensate formation than for those present in condensates but inessential.
The Effects of Unilateral Transcranial Direct Current Stimulation on Unimanual Laparoscopic Peg-Transfer Task
Authors: Hadi Zaeem , Umbreen Aysha , Anwar Muhammad Nabeel , Navid Muhammad Samran 
Published: April 2021

ABSTRACTIntroductionEfficient training methods are required for laparoscopic surgical skills training to reduce the time needed for proficiency. Transcranial direct current stimulation (tDCS) is widely used to enhance motor skill acquisition and can be used to supplement the training of laparoscopic surgical skill acquisition. The aim of this study was to investigate the effect of anodal tDCS over the primary motor cortex (M1) on the performance of a unimanual variant of the laparoscopic peg-transfer task.MethodsFifteen healthy subjects participated in this randomized, double-blinded crossover study involving an anodal tDCS and a sham tDCS intervention separated by 48 hours. On each intervention day, subjects performed a unimanual variant of laparoscopic peg-transfer task in three sessions (baseline, tDCS, post-tDCS). The tDCS session consisted of 10 minutes of offline tDCS followed by 10 minutes of online tDCS. The scores based on the task completion time and the number of errors in each session were used as a primary outcome measure. A linear mixed-effects model was used for the analysis.ResultsWe found that the scores increased over sessions (p<0.001). However, we found no effects of stimulation (anodal tDCS vs. sham tDCS) and no interaction of stimulation and sessions.ConclusionThis study suggests that irrespective of the type of current stimulation (anodal and sham) over M1, there was an improvement in the performance of the unimanual peg-transfer task, implying that there was motor learning over time. The results would be useful in designing efficient training paradigms and further investigating the effects of tDCS on laparoscopic peg-transfer tasks.