bluuebunny/crossref_metadata_2025 huggingface dataset:
SSR‐based DNA fingerprinting of fruit crops
Authors: Testolin Raffaele , Messina Rachele , Cipriani Guido , De Mori Gloria
Published: December 2022

The DNA fingerprinting of fruit crops, based on DNA microsatellite markers that are considered to be the key markers for the molecular analysis of germplasm collections, is reviewed. Simple sequence repeats (SSRs) remain the markers of choice for fingerprinting in humans, animals, plants, and other living organisms. This review, that considers 44 fruit species, provides a set of markers that are suitable for profiling accessions and that should make the databases produced in different laboratories more comparable. Every effort has been made to select SSR markers that are robust and easily scorable considering that such analyses are sometimes used in legal cases. The review first describes the basic protocols, procedures, and methods of data analyses; it then describes the fingerprinting of individual species or groups of species, providing a set of SSR markers and appropriate guidance based on the revised literature and on the authors’ experience.
Emerging point‐of‐care autologous cellular therapy using adipose‐derived stromal vascular fraction for neurodegenerative diseases
Authors: Al‐kharboosh Rawan , Perera Jonathan Jude , Bechtle Alexandra , Bu Guojun , Quinones‐Hinojosa Alfredo
Published: December 2022

Neurodegenerative disorders are characterized by the gradual decline and irreversible loss of cognitive functions and CNS structures. As therapeutic recourse stagnates, neurodegenerative diseases will cost over a trillion dollars by 2050. A dearth of preventive and regenerative measures to hinder regression and enhance recovery has forced patients to settle for traditional therapeutics designed to manage symptoms, leaving little hope for a cure. In the last decade, pre‐clinical animal models and clinical investigations in humans have demonstrated the safety and promise of an emerging cellular product from subcutaneous fat. The adipose‐derived stromal vascular fraction (SVF) is an early intervention and late‐stage novel ‘at point’ of care cellular treatment, demonstrating improvements in clinical applications for Multiple Sclerosis, Alzheimer's disease, and Parkinson's disease. SVF is a heterogeneous fraction of cells forming a robust cellular ecosystem and serving as a novel and valuable source of point‐of‐care autologous cell therapy, providing an easy‐to‐access population that we hypothesize can mediate repair through ‘bi‐directional’ communication in response to pathological cues. We provide the first comprehensive review of all pre‐clinical and clinical findings available to date and highlight major challenges and future directions. There is a greater medical and economic urgency to innovate and develop novel cellular therapy solutions that enable the repair and regeneration of neuronal tissue that has undergone irreversible and permanent damage.
Fluctuations in resource availability shape the competitive balance among non‐native plant species
Authors: Tao Zhibin , Shen Changchao , Qin Wenchao , Nie Baoguo , Chen Pengdong , Wan Jinlong , Zhang Kaoping , Huang Wei , Siemann Evan
Published: December 2022

Fluctuating resource availability plays a critical role in determining non‐native plant invasions through mediating the competitive balance between non‐native and native species. However, the impact of fluctuating resource availability on interactions among non‐native species remains largely unknown. This represents a barrier to understanding invasion mechanisms, particularly in habitats that harbor multiple non‐native species with different responses to fluctuating resource availability. To examine the responses of non‐native plant species to nutrient fluctuations, we compared the growth of each of 12 non‐native species found to be common in local natural areas to nutrients supplied at a constant rate or supplied as a single large pulse in a pot experiment. We found that seven species produced more biomass with pulsed nutrients compared to constant nutrients (hereafter “benefitting species”), while the other five species did not differ between nutrient enrichment treatments (hereafter “non‐benefitting species”). To investigate how nutrient fluctuations influence the interactions among non‐native plant species, we established experimental non‐native communities in the field with two benefitting and two non‐benefitting non‐native species. Compared with constant nutrient supply, the single large pulse of nutrient did not influence community biomass, but strongly increased the biomass and cover of the benefitting species and decreased those of the non‐benefitting species. Furthermore, the benefitting species had higher leaf N content and greater plant height when nutrients were supplied as a single large pulse than at a constant rate, whereas the non‐benefitting species showed no differences in leaf N content and were shorter when nutrients were supplied as a single large pulse than at a constant rate. Our results add to the growing evidence that the individual responses of non‐native species to nutrient fluctuation are species‐specific. More importantly, benefitting species were favored by nutrients coming in a pulse, while non‐benefitting ones were favored by nutrients coming constantly when they grew together. This suggests that nutrient fluctuations can mediate the competitive balance among non‐native plants and may thus determine their invasion success in a community harboring multiple non‐native plant species.
Partial refuges from biological control due to intraspecific variation in protective host traits
Authors: Abram Paul K. , Haye Tim , Clarke Peggy , Grove Emily , Thiessen Jason , Gariepy Tara D.
Published: December 2022

Predicting how much of a host or prey population may be attacked by their natural enemies is fundamental to several subfields of applied ecology, particularly biological control of pest organisms. Hosts or prey can occupy refuges that prevent them from being killed by natural enemies, but habitat or ecological refuges are challenging or impossible to predict in a laboratory setting—which is often where efficacy and specificity testing of candidate biological control agents is done. Here we explore how intraspecific variation in continuous traits of individuals or groups that confer some protection from natural enemy attack—even after the natural enemy has encountered the prey—could provide partial refuges. The size of these trait‐based refuges (i.e., the proportion of prey that survive natural enemy encounters due to protective traits) should depend on the relationship between trait values and host/prey susceptibility to natural enemy attack and on how common different trait values are within a host/prey population. These can be readily estimated in laboratory testing of natural enemy impact on target or nontarget prey or hosts as long as sufficient host material is available. We provide a general framework for how intraspecific variation in protective host traits could be integrated into biological control research, specifically with reference to nontarget testing as part of classical biological control programs. As a case study, we exposed different host clutch sizes of target (pest) and nontarget (native species) stink bug (Hemiptera: Pentatomidae) species to a well‐studied exotic biocontrol agent, the egg parasitoid Trissolcus japonicus (Hymenoptera: Scelionidae). We predicted that the smallest and largest clutches would occupy trait‐based refuges from parasitism. Although we observed several behavioral and reproductive responses to variation in host egg mass size by T. japonicus, they did not translate to increases in host survival large enough to change the conclusions of nontarget testing. We encourage researchers to investigate intraspecific variation in a wider variety of protective host and prey traits and their consequences for refuge size.
Optimizing the use of suppression zones for containment of invasive species
Authors: Lampert Adam , Liebhold Andrew M.
Published: December 2022

Despite efforts to prevent their establishment, many invasive species continue to spread and threaten food production, human health, and natural biodiversity. Slowing the spread of established species is often a preferred strategy; however, it is also expensive and necessitates treatment over large areas. Therefore, it is critical to examine how to distribute management efforts over space cost‐effectively. Here we consider a continuous‐space bioeconomic model and we develop a novel algorithm to find the most cost‐effective allocation of treatment efforts throughout a landscape. We show that the optimal strategy often comprises eradication in the yet‐uninvaded area, and under certain conditions, it also comprises maintaining a “suppression zone,” an area between the invaded and the uninvaded areas, where treatment reduces the invading population but without eliminating it. We examine how the optimal strategy depends on the demographic characteristics of the species and reveal general criteria for deciding when a suppression zone is cost effective.
Identifying and protecting macroalgae detritus sinks toward climate change mitigation
Authors: Queirós Ana M. , Tait Karen , Clark James R. , Bedington Michael , Pascoe Christine , Torres Ricardo , Somerfield Paul J. , Smale Dan A.
Published: December 2022

Harnessing natural solutions to mitigate climate change requires an understanding of carbon fixation, flux, and sequestration across ocean habitats. Recent studies have suggested that exported seaweed particulate organic carbon is stored within soft‐sediment systems. However, very little is known about how seaweed detritus disperses from coastlines, or where it may enter seabed carbon stores, where it could become the target of conservation efforts. Here, focusing on regionally dominant seaweed species, we surveyed environmental DNA (eDNA) from natural coastal sediments, and studied their connectivity to seaweed habitats using a particle tracking model parameterized to reproduce seaweed detritus dispersal behavior based on laboratory observations of seaweed fragment degradation and sinking. Experiments showed that seaweed detritus density changed over time, differently across species. This, in turn, modified distances traveled by released fragments until they reached the seabed for the first time, during model simulations. Dispersal pathways connected detritus from the shore to the open ocean but, importantly, also to coastal sediments, and this was reflected by field eDNA evidence. Dispersion pathways were also affected by hydrodynamic conditions, varying in space and time. Both the properties and timing of released detritus, individual to each macroalgal population, and short‐term near‐seabed and medium‐term water‐column transport pathways, are thus seemingly important in determining the connectivity between seaweed habitats and potential sedimentary sinks. Studies such as this one, supported by further field verification of sedimentary carbon sequestration rates and source partitioning, are still needed to help quantify the role of seaweed in the ocean carbon cycle. Such studies will provide vital evidence to inform on the potential need to develop blue carbon conservation mechanisms, beyond wetlands.
Investigating peak dispersion in free‐flow counterflow gradient focusing due to electroosmotic flow
Authors: Courtney Matthew , Glawdel Tomasz , Ren Carolyn L.
Published: December 2022

Free‐flow electrophoresis (FFE) has the ability to continuously separate charged solutes from complex biological mixtures. Recently, a free‐flow counterflow gradient focusing mechanism has been introduced to FFE, and it offers the potential for improved resolution and versatility. However, further investigation is needed to understand the solute dispersion at the focal position. Therefore, the goal of this work is to model the impact of electroosmotic flow, which is found to produce a pressure‐driven backflow to maintain the fixed counterflow inputs. Like the counterflow, this backflow has a parabolic velocity profile that must be considered when predicting the concentration distribution of a given solute. After the model is established, preliminary experimental results are presented for a qualitative comparison. Results demonstrate a reasonable agreement at low applied voltages and provide a strong framework for future experimental validation.
The impact of environmental contaminants on extracellular vesicles and their key molecular regulators: A literature and database‐driven review
Authors: Carberry Celeste K. , Rager Julia E.
Published: December 2022

Exposure to environmental chemicals is now well recognized as a significant factor contributing to the global burden of disease; however, there remain critical gaps in understanding the types of biological mechanisms that link environmental chemicals to adverse health outcomes. One type of mechanism that remains understudied involves extracellular vesicles (EVs), representing small cell‐derived particles capable of carrying molecular signals such as RNAs, miRNAs, proteins, lipids, and chemicals through biological fluids and imparting beneficial, neutral, or negative effects on target cells. In fact, evidence is just now starting to grow that supports the role of EVs in various disease etiologies. This review aims to (1) Provide a landscape of the current understanding of the functional relationship between EVs and environmental chemicals; (2) Summarize current knowledge of EV regulatory processes including production, packaging, and release; and (3) Conduct a database‐driven analysis of known chemical–gene interactions to predict and prioritize environmentally relevant chemicals that may impact EV regulatory genes and thus EV regulatory processes. This approach to predicting environmentally relevant chemicals that may alter EVs provides a novel method for evidence‐based hypothesis generation for future studies evaluating the link between environmental exposures and EVs.
Scaling of waiting time distribution in northern Chile
Authors: Siegel Cristián E. , Toledo Patricio , Madariaga Raul , Campos Jaime M.
Published: December 2022

In this study, we compare the scaling of waiting time distributions in
Northern Chile Subduction context. For this, we analized 7-yr high
spatial resolution and low complete- ness magnitude IPOC seismic catalog
and 45-yr USGS catalog. A unified moment-epicentral area linear
dimension-time scaling relation is empirically evaluated by calculating
wait- ing times for different ranges of magnitude and epicentral area
linear dimension and es- timating associated scaling coefficients, β
analog to b-value and γ, the correlation frac- tal dimension. We find a
scaling function that can be characterized with 3 distinct re- gions,
regions whose behaviour depend on whether seismicity is in the coastal
area or from intermediate depth. Moreover, high resolution localizations
from IPOC catalog al- lows us to further observe differences in coastal
seismicity, with lower plane seismicity behaviour alike intermediate
depth. Thus, waiting time distribution primarily depends on whether
seismicity is associated with subduction interface interaction or not,
having respectively high/low correlated behaviour in the short scale
region, non-exponential/exponential decay in the transition middle
region and in all cases long-term clustering with a slower than
exponential decay in the long scale.
Quantitative evaluation of the lunar seismic scattering and comparison between the Earth, Mars, and the Moon
Authors: Onodera Keisuke , Kawamura Taichi , Tanaka Satoshi , Ishihara Yoshiaki , Maeda Takuto
Published: December 2022

The intense seismic scattering seen in Apollo lunar seismic data is one
of the most characteristic features, making the seismic signals much
different from those observed on the Earth. The scattering is considered
to be attributed to subsurface heterogeneity. While the heterogeneous
structure of the Moon reflects the past geological activities and
evolution processes from the formation, the detailed description remains
an open issue. Here we present a new model of the subsurface
heterogeneity within the upper lunar crust derived through a full 3D
seismic wave propagation simulation. Our simulation successfully
reproduced the Apollo seismic observations, leading to a significant
update of the scattering properties of the Moon. The results showed that
the scattering intensity of the Moon is about ten times higher than that
of the heterogeneous region on the Earth. The quantified scattering
parameters could give us a constraint on the surface evolution process
on the Moon and enable the comparative study for answering a fundamental
question of why the seismological features are different on various
planetary bodies.
Empirically-based production environment soil health goals
Authors: Amsili Joseph , Es Harold van , Aller Deborah , Schindelbeck Robert
Published: December 2022

Soil health metrics in agricultural systems require edaphic context,
notably climate, soil type (soil texture and classification), as well as
cropping system. Soil samples (n=1,334) from New York State (USA) with
both texture and cropping system information were analyzed for eight
physical and biological soil health indicators (soil organic matter,
permanganate-oxidizable carbon, respiration, protein, available water
capacity, wet aggregate stability, and penetration resistance from 0-15
and 15-45 cm), and population distribution functions were determined.
Production environment soil health (PESH) goals were derived for four
soil texture groups and six cropping systems by proposing the 75th and
90th percentile for each factorial class. Finer-textured soils and
Pasture and Mixed Vegetable systems generally have higher values for
soil health goals followed by Dairy Crop and Orchard systems, then
Annual Grain, and Processing Vegetable systems. A comparison between
Long Island and the rest of New York State demonstrated that soil
organic matter PESH goals for Long Island were on average 0.8 % lower
than those from the rest of the state. This indicates that regional PESH
goals within a state or region may be warranted if edaphic context is
considerably different.
Visualizing the deep cerebellar nuclei using quantitative susceptibility mapping: An application in healthy controls, Parkinson's disease patients and essential tremor patients
Authors: Zhang Youmin , Huang Pei , Wang Xinhui , Xu Qiuyun , Liu Yu , Jin Zhijia , Li Yan , Cheng Zenghui , Tang Rongbiao , Chen Shengdi , He Naying , Yan Fuhua , Haacke E. Mark
Published: December 2022

The visualization and identification of the deep cerebellar nuclei (DCN) (dentate [DN], interposed [IN] and fastigial nuclei [FN]) are particularly challenging. We aimed to visualize the DCN using quantitative susceptibility mapping (QSM), predict the contrast differences between QSM and T2* weighted imaging, and compare the DCN volume and susceptibility in movement disorder populations and healthy controls (HCs). Seventy‐one Parkinson's disease (PD) patients, 39 essential tremor patients, and 80 HCs were enrolled. The PD patients were subdivided into tremor dominant (TD) and postural instability/gait difficulty (PIGD) groups. A 3D strategically acquired gradient echo MR imaging protocol was used for each subject to obtain the QSM data. Regions of interest were drawn manually on the QSM data to calculate the volume and susceptibility. Correlation analysis between the susceptibility and either age or volume was performed and the intergroup differences of the volume and magnetic susceptibility in all the DCN structures were evaluated. For the most part, all the DCN structures were clearly visualized on the QSM data. The susceptibility increased as a function of volume for both the HC group and disease groups in the DN and IN (p < .001) but not the FN (p = .74). Only the volume of the FN in the TD‐PD group was higher than that in the HCs (p = .012), otherwise, the volume and susceptibility among these four groups did not differ significantly. In conclusion, QSM provides clear visualization of the DCN structures. The results for the volume and susceptibility of the DCN can be used as baseline references in future studies of movement disorders.
Excess healthcare costs of psychological distress in young women: Evidence from linked national Medicare claims data
Authors: Jayawardana Danusha , Gannon Brenda , Doust Jenny , Mishra Gita D.
Published: December 2022

The prevalence of mental health disorders in young adults is increasing, yet there is limited empirical evidence on its economic consequences. We contribute to the literature by estimating the healthcare costs of psychological distress using panel data of young women (aged 18–23 years with a 5‐year follow‐up) from the Australian Longitudinal Study on Women's Health and linked administrative data from Medicare Australia. Our empirical strategy is based on the classical two‐part model of healthcare costs with individual specific fixed‐effects. We complement our analysis with a test for selection on unobservables to address potential concerns of endogeneity. We find that young women with psychological distress have 15% higher annual healthcare costs (excluding hospital costs) than women with no psychological distress. A large proportion of these costs is driven by the use of antidepressants and the services of psychiatrists and psychologists. We further find that women with psychological distress have higher out‐of‐pocket costs on these mental health related services compared to non‐mental health specific services. Additionally, we show that the effect of psychological distress on healthcare costs is highest during the first 6 months of onset, which gradually decreases afterwards. The findings justify the importance of policy initiatives towards early prevention and treatment of psychological distress, especially among young women.
Celecoxib promotes the efficacy of STING‐targeted therapy by increasing antitumor CD8+ T‐cell functions via modulating glucose metabolism of CD11b+Ly6G+ cells
Authors: Kosaka Akemi , Yajima Yuki , Yasuda Shunsuke , Komatsuda Hiroki , Nagato Toshihiro , Oikawa Kensuke , Kobayashi Hiroya , Ohkuri Takayuki
Published: December 2022

Recent studies have shown that activation of the cGAS‐STING pathway is a key process in antitumor immune responses and various kinds of STING agonists have been developed for cancer immunotherapy. Despite promising preclinical studies, preliminary clinical results have shown only a modest effect of STING agonists. There is therefore a need to develop more effective treatment strategies. Based on previous observations that COX‐2 is frequently overexpressed not only in a variety of cancers but also in tumor myeloid cells and that it suppresses antitumor immunity and promotes tumor survival by producing PGE2, we investigated the antitumor effects of combination therapy with a STING agonist cGAMP and the selective COX‐2 inhibitor celecoxib in mouse models. Combination treatment with cGAMP and celecoxib inhibited tumor growth compared with either monotherapy, and the combination therapy induced both local and systemic antitumor immunity. cGAMP treatment decreased PD‐1 expression on tumor‐infiltrating T‐cells and enhanced T‐cell activation in tumor‐draining lymph nodes regardless of the presence of celecoxib. Meanwhile, although celecoxib treatment did not alter the frequency of CD4+CD25+Foxp3+ regulatory T‐cells, it enhanced the expression of costimulatory molecules and glycolysis‐associated genes in tumor‐infiltrating CD11b+Ly6G+ cells. Moreover, we also found that celecoxib decreased lactate efflux and increased the frequency of IFN‐γ‐ and TNF‐α‐producing CD8+ T‐cells in the tumor microenvironment. Taken together, our findings suggest that combined treatment with celecoxib may be an effective strategy to improve the antitumor efficacy of STING agonists.
Impact of medication optimization and recommendations by clinical pharmacists embedded in a memory disorder clinic
Authors: Coli Katherine G. , Lee Monica , Aladeen Traci S. , Mattle Anna G. , Ajtai Bela , Rainka Michelle M.
Published: December 2022

Introduction

Older patients with dementia or mild cognitive impairment (MCI) are particularly vulnerable to adverse effects from potentially inappropriate medications (PIMs). Previous studies demonstrated that pharmacist interventions may reduce PIMs, but the impact of pharmacists embedded in an outpatient memory care clinic has not been adequately studied.

Objective

To determine the impact of pharmacist recommendations on PIM reduction in older adults with dementia or MCI.

Methods

This prospective observational study within an outpatient neurology center included patients at least 65 years old diagnosed with dementia or MCI. Pharmacists utilized the American Geriatrics Society Beers Criteria, the Screening Tool of Older Persons' Potentially Inappropriate Prescriptions, and the Anticholinergic Burden Scale (ACB) to identify PIMs and reviewed patient charts to make pharmacologic and nonpharmacologic recommendations to prescribers when appropriate per clinical judgment. Primary outcomes included frequency and prevalence of PIMs before versus after pharmacist intervention and rate of acceptance of pharmacy recommendations. Additional outcomes included ACB scores before versus after intervention.

Results

A total of 180 patients were included. Pharmacists made recommendations for 49% of patients, most commonly laboratory monitoring recommendations and medication discontinuations or substitutions. Out of 192 total pharmacist recommendations, 61 (32%) were accepted by providers within the memory clinic. After pharmacist intervention, the frequency and prevalence of PIMs were reduced from average 1.8 to 1.7 PIMs per patient and from 78% to 74% of patients with at least one PIM (p < 0.05). ACB scores were reduced from average 1.5 to 1.3 (p < 0.01).

Conclusion

Pharmacist intervention resulted in a reduction in PIMs and ACB scores in patients with dementia or MCI. Future studies should incorporate a controlled prospective design with scheduled clinical outcomes assessments such as cognitive testing to examine the clinical benefit of pharmacist intervention and explore methods to improve multidisciplinary collaboration between pharmacists and prescribers.
STAT3/Mitophagy Axis Coordinates Macrophage NLRP3 Inflammasome Activation and Inflammatory Bone Loss
Authors: Zhu Lingxin , Wang Zijun , Sun Xiaoyue , Yu Jingjing , Li Ting , Zhao Huan , Ji Yaoting , Peng Bin , Du Minquan
Published: December 2022

Signal transducer and activator of transcription 3 (STAT3), a cytokine-responsive transcription factor, is known to play a role in immunity and bone remodeling. However, whether and how STAT3 impacts macrophage NLR family pyrin domain containing 3 (NLRP3) inflammasome activation associated with inflammatory bone loss remains unknown. Here, STAT3 signaling is hyperactivated in macrophages in the context of both non-sterile and sterile inflammatory osteolysis, and this was highly correlated with the cleaved interleukin-1β (IL-1β) expression pattern. Strikingly, pharmacological inhibition of STAT3 markedly blocks macrophage NLRP3 inflammasome activation in vitro, thereby relieving inflammatory macrophage-amplified osteoclast formation and bone-resorptive activity. Mechanistically, STAT3 inhibition in macrophages triggers PTEN-induced kinase 1 (PINK1)-dependent mitophagy that eliminates dysfunctional mitochondria, reverses mitochondrial membrane potential collapse, and inhibits mitochondrial reactive oxygen species release, thus inactivating the NLRP3 inflammasome. In vivo, STAT3 inhibition effectively protects mice from both infection-induced periapical lesions and aseptic titanium particle-mediated calvarial bone erosion with potent induction of PINK1 and downregulation of inflammasome activation, macrophage infiltration, and osteoclast formation. This study reveals the regulatory role of the STAT3/mitophagy axis at the osteo-immune interface and highlights a potential therapeutic intervention to prevent inflammatory bone loss. © 2022 American Society for Bone and Mineral Research (ASBMR).

Abstract

Schematic illustration. In both non-sterile and sterile inflammatory osteolysis, macrophage hyperactivated STAT3 is highly correlated with the cleaved IL-1β expression. Targeting STAT3 using stattic blocks macrophage NLRP3 inflammasome activation through triggering PINK1-dependent mitophagy that eliminates dysfunctional mitochondria, thereby relieving inflammatory macrophage-amplified osteoclast formation in vitro and protecting mouse inflammatory osteolysis in vivo.
FK506 binding protein 51: Its role in the adipose organ and beyond
Authors: Galigniana Natalia M. , Ruiz Marina C. , Piwien‐Pilipuk Graciela
Published: December 2022

There is a great body of evidence that the adipose organ plays a central role in the control not only of energy balance, but importantly, in the maintenance of metabolic homeostasis. Interest in the study of different aspects of its physiology grew in the last decades due to the pandemic of obesity and the consequences of metabolic syndrome. It was not until recently that the first evidence for the role of the high molecular weight immunophilin FK506 binding protein (FKBP) 51 in the process of adipocyte differentiation have been described. Since then, many new facets have been discovered of this stress‐responsive FKBP51 as a central node for precise coordination of many cell functions, as shown for nuclear steroid receptors, autophagy, signaling pathways as Akt, p38 MAPK, and GSK3, as well as for insulin signaling and the control of glucose homeostasis. Thus, the aim of this review is to integrate and discuss the recent advances in the understanding of the many roles of FKBP51 in the adipose organ.
Drug repurposing toward the inhibition of RNA‐dependent RNA polymerase of various flaviviruses through computational study
Authors: Murali Aarthy , Kumar Sushil , Akshaya Srinivasan , Singh Sanjeev K.
Published: December 2022

Numerous pathogens affecting human is present in the flavivirus family namely west nile, dengue, yellow fever, and zika which involves in development of global burden and distressing the environment economically. Till date, no approved drugs are available for targeting these viruses. The threat which urged the identification of small molecules for the inhibition of these viruses is the spreading of serious viral diseases. The recent outbreak of zika and dengue infections postured a solemn risk to worldwide public well‐being. RNA‐dependent RNA polymerase (RdRp) is the supreme adaptable enzymes of all the RNA viruses which is responsible for the replication and transcription of genome among the structural and nonstructural proteins of flaviviruses. It is understood that the RdRp of the flaviviruses are similar stating that the japanese encephalitis and west nile shares 70% identity with zika whereas the dengue serotype 2 and 3 shares the identity of 76% and 81%, respectively. In this study, we investigated the binding site of four flaviviral RdRp and provided insights into various interaction of the molecules using the computational approach. Our study helps in recognizing the potent compounds that could inhibit the viral protein as a common inhibitor. Additionally, with the conformational stability analysis, we proposed the possible mechanism of inhibition of the identified common small molecule toward RdRp of flavivirus. Finally, this study could be an initiative for the identification of common inhibitors and can be explored further for understanding the mechanism of action through in vitro studies for the study on efficacy.
Characterization of advanced glycation end products and aggregates of irisin: Multispectroscopic and microscopic approaches
Authors: Waseem Rashid , Shamsi Anas , Khan Tanzeel , Anwer Ayesha , Shahid Mohammad , Kazim Syed Naqui , Hassan Md. Imtaiyaz , Islam Asimul
Published: December 2022

Glycation of proteins leading to the formation of advanced glycation end products (AGEs) has been demonstrated to contribute to the pathogenesis of several diseases. Irisin is a clinically significant protein, putatively involved in obesity, diabetes, and neurological disorders. This study aimed to monitor the methyl‐glyoxal (MG) induced AGEs and aggregate formation of irisin, as a function of time, employing multispectroscopic and microscopic approaches. ANS fluorescence suggested a molten globule‐like state on Day 6, followed by the formation of irisin AGEs adducts, as confirmed by AGE‐specific fluorescence. Glycation of irisin led to aggregate formation, which was characterized by Thioflavin T fluorescence, CD spectroscopy, and microscopic studies. These aggregates were confirmed by exploiting fluorescence microscopy, confocal, and transmission electron microscopy. Molecular docking was performed to determine the crucial residues of irisin involved in irisin‐MG interaction. Usually, MG is present in trace amounts as a metabolic by‐product in the body, which is found to be elevated in diseased conditions viz. diabetes and Alzheimer's disease. This study characterized the AGEs and aggregates of clinically important protein, irisin; and since MG level has been found to be increased in various pathological conditions, this study provides a clinical perspective. There is a possibility that elevated MG concentrations might glycate irisin resulting in reduced irisin levels as reported in pathological conditions. However, further investigations are required to prove it.
Differential gene expression analysis of RAGE‐S100A6 complex for target selection and the design of novel inhibitors for anticancer drug discovery
Authors: Faruqui Tabrez , Singh Garima , Khan Salman , Khan Mohd Sajid , Akhter Yusuf
Published: December 2022

Receptor for advanced glycation end products (RAGE), a member of the immunoglobulin family, interactions with its ligands trigger downstream signaling and induce an inflammatory response linked to diabetes, inflammation, carcinogenesis, cardiovascular disease, and a variety of other human disorders. The interaction of RAGE and S100A6 has been associated with a variety of malignancies. For the control of RAGE‐related illnesses, there is a great demand for more specialized drug options. To identify the most effective target for combating human malignancies associated with RAGE‐S100A6 complex, we conducted single and differential gene expression analyses of S100A6 and RAGE, comparing normal and malignant tissues. Further, a structure‐based virtual screening was conducted using the ZINC15 database. The chosen compounds were then subjected to a molecular docking investigation on the RAGE active site region, recognized by the various cancer‐related RAGE ligands. An optimized RAGE structure was screened against a library of drug‐like molecules. The screening results suggested that three promising compounds were presented as the top acceptable drug‐like molecules with a high binding affinity at the RAGE V‐domain catalytic region. We depicted that these compounds may be potential RAGE inhibitors and could be used to produce a successful medication against human cancer and other RAGE‐related diseases based on their various assorted parameters, binding energy, hydrogen bonding, ADMET characteristics, etc. MD simulation on a time scale of 50 ns was used to test the stability of the RAGE‐inhibitor complexes. Therefore, targeting RAGE and its ligands using these drug‐like molecules may be an effective therapeutic approach.
Discovery of octahydropyrrolo [3,2‐b] pyridin derivative as a highly selective Type I inhibitor of FGFR3 over VEGFR2 by high‐throughput virtual screening
Authors: Wang Xin , Ye Cheng‐hao , Li En‐min , Xu Li‐yan , Lin Wang‐qiang , Chen Guang‐hui
Published: December 2022

Although the aberrant activity of fibroblast growth factor receptor 3 (FGFR3) is implicated in various cancers, the reported kinase inhibitors of FGFR3 tend to cause side effects resulting from the inhibitory activity on vascular endothelial growth factor receptor 2 (VEGFR2). Therefore, it is necessary to find a novel high‐selective inhibitor of FGFR3 over VEGFR2 from the small‐molecule compound database. In this study, integrated virtual screening protocols were established to screen for selective inhibitors of FGFR3 over VEGFR2 in Drugbank and Asinex databases by combining three‐dimensional pharmacophore model, molecular docking, molecular dynamics (MD) simulation, and molecular mechanics Poisson–Boltzmann surface area (MMPBSA) calculations. Finally, it is found that Asinex‐5082, as an octahydropyrrolo[3,2‐b] pyridin derivative, has larger binding free energy with FGFR3 (−39.3 kcal/mol) than reference drug Erdafitinib (−29.9 kcal/mol), while cannot bind with VEGFR2, resulting in considerable inhibitory selectivity. This is because Asinex‐5082, unlike Erdafitinib, has not m‐dimethoxybenzene with large steric hindrance, thus can enter the larger ATP‐binding pocket of FGFR3 with DFG‐in conformation to form hydrophobic interaction with residues Met529, Ile539, and Tyr557 as well as hydrogen bond with Ala558. On the other hand, due to the fact that the benzodioxane and N‐heterocyclic rings are connected by carbonyl (C=O), Asinex‐5082 cannot rotate freely so as to enter the smaller ATP binding pocket of VEGFR2 on the DFG‐out conformation. The lead molecule Asinex‐5082 may facilitate the rational design and development of novel selective inhibitors of FGFR3 over VEGFR2 as anticancer drugs.
Phosphorylation states greatly regulate the activity and gating properties of Cav3.1 T‐type Ca2+ channels
Authors: Jeong Sua , Shim Ji Seon , Sin Seok Kyo , Park Kang‐Sik , Lee Jung‐Ha
Published: December 2022

Cav3.1 T‐type Ca2+ channels play pivotal roles in neuronal low‐threshold spikes, visceral pain, and pacemaker activity. Phosphorylation has been reported to potently regulate the activity and gating properties of Cav3.1 channels. However, systematic identification of phosphorylation sites (phosphosites) in Cav3.1 channel has been poorly investigated. In this work, we analyzed rat Cav3.1 protein expressed in HEK‐293 cells by mass spectrometry, identified 30 phosphosites located at the cytoplasmic regions, and illustrated them as a Cav3.1 phosphorylation map which includes the reported mouse Cav3.1 phosphosites. Site‐directed mutagenesis of the phosphosites to Ala residues and functional analysis of the phospho‐silent Cav3.1 mutants expressed in Xenopus oocytes showed that the phospho‐silent mutation of the N‐terminal Ser18 reduced its current amplitude with accelerated current kinetics and negatively shifted channel availability. Remarkably, the phospho‐silent mutations of the C‐terminal Ser residues (Ser1924, Ser2001, Ser2163, Ser2166, or Ser2189) greatly reduced their current amplitude without altering the voltage‐dependent gating properties. In contrast, the phosphomimetic Asp mutations of Cav3.1 on the N‐ and C‐terminal Ser residues reversed the effects of the phospho‐silent mutations. Collectively, these findings demonstrate that the multiple phosphosites of Cav3.1 at the N‐ and C‐terminal regions play crucial roles in the regulation of the channel activity and voltage‐dependent gating properties.
Na,K‐ATPase: A murzyme facilitating thermodynamic equilibriums at the membrane‐interface
Authors: Manoj Kelath Murali , Gideon Daniel A. , Bazhin Nikolai M. , Tamagawa Hirohisa , Nirusimhan Vijay , Kavdia Mahendra , Jaeken Laurent
Published: December 2022

The redox metabolic paradigm of murburn concept advocates that diffusible reactive species (DRS, particularly oxygen‐centric radicals) are mainstays of physiology, and not mere pathological manifestations. The murburn purview of cellular function also integrates the essential principles of bioenergetics, thermogenesis, homeostasis, electrophysiology, and coherence. In this context, any enzyme that generates/modulates/utilizes/sustains DRS functionality is called a murzyme. We have demonstrated that several water‐soluble (peroxidases, lactate dehydrogenase, hemogoblin, etc.) and membrane‐embedded (Complexes I–V in mitochondria, Photosystems I/II in chloroplasts, rhodopsin/transducin in rod cells, etc.) proteins serve as murzymes. The membrane protein of Na,K‐ATPase (NKA, also known as sodium‐potassium pump) is the focus of this article, owing to its centrality in neuro‐cardio‐musculo electrophysiology. Herein, via a series of critical queries starting from the geometric/spatio‐temporal considerations of diffusion/mass transfer of solutes in cells to an update on structural/distributional features of NKA in diverse cellular systems, and from various mechanistic aspects of ion‐transport (thermodynamics, osmoregulation, evolutionary dictates, etc.) to assays/explanations of inhibitory principles like cardiotonic steroids (CTS), we first highlight some unresolved problems in the field. Thereafter, we propose and apply a minimalist murburn model of trans‐membrane ion‐differentiation by NKA to address the physiological inhibitory effects of trans‐dermal peptide, lithium ion, volatile anesthetics, confirmed interfacial DRS + proton modulators like nitrophenolics and unsaturated fatty acid, and the diverse classes of molecules like CTS, arginine, oximes, etc. These explanations find a pan‐systemic connectivity with the inhibitions/uncouplings of other membrane proteins in cells.
Topography of pleural epithelial structure enabled by en face isolation and machine learning
Authors: Liu Betty S. , Valenzuela Cristian D. , Mentzer Katherine L. , Wagner Willi L. , Khalil Hassan A. , Chen Zi , Ackermann Maximilian , Mentzer Steven J.
Published: December 2022

Pleural epithelial adaptations to mechanical stress are relevant to both normal lung function and parenchymal lung diseases. Assessing regional differences in mechanical stress, however, has been complicated by the nonlinear stress–strain properties of the lung and the large displacements with ventilation. Moreover, there is no reliable method of isolating pleural epithelium for structural studies. To define the topographic variation in pleural structure, we developed a method of en face harvest of murine pleural epithelium. Silver‐stain was used to highlight cell borders and facilitate imaging with light microscopy. Machine learning and watershed segmentation were used to define the cell area and cell perimeter of the isolated pleural epithelial cells. In the deflated lung at residual volume, the pleural epithelial cells were significantly larger in the apex (624 ± 247 μm2) than in basilar regions of the lung (471 ± 119 μm2) (p < 0.001). The distortion of apical epithelial cells was consistent with a vertical gradient of pleural pressures. To assess epithelial changes with inflation, the pleura was studied at total lung capacity. The average epithelial cell area increased 57% and the average perimeter increased 27% between residual volume and total lung capacity. The increase in lung volume was less than half the percent change predicted by uniform or isotropic expansion of the lung. We conclude that the structured analysis of pleural epithelial cells complements studies of pulmonary microstructure and provides useful insights into the regional distribution of mechanical stresses in the lung.
Lysosome signaling in cell survival and programmed cell death for cellular homeostasis
Authors: Patra Srimanta , Patil Shankargouda , Klionsky Daniel J. , Bhutia Sujit K.
Published: December 2022

Recent developments in lysosome biology have transformed our view of lysosomes from static garbage disposals that can also act as suicide bags to decidedly dynamic multirole adaptive operators of cellular homeostasis. Lysosome‐governed signaling pathways, proteins, and transcription factors equilibrate the rate of catabolism and anabolism (autophagy to lysosomal biogenesis and metabolite pool maintenance) by sensing cellular metabolic status. Lysosomes also interact with other organelles by establishing contact sites through which they exchange cellular contents. Lysosomal function is critically assessed by lysosomal positioning and motility for cellular adaptation. In this setting, mechanistic target of rapamycin kinase (MTOR) is the chief architect of lysosomal signaling to control cellular homeostasis. Notably, lysosomes can orchestrate explicit cell death mechanisms, such as autophagic cell death and lysosomal membrane permeabilization‐associated regulated necrotic cell death, to maintain cellular homeostasis. These lines of evidence emphasize that the lysosomes serve as a central signaling hub for cellular homeostasis.
Neural crest cells development and neuroblastoma progression: Role of Wnt signaling
Authors: Ahmad Mir Hilal , Ghosh Balaram , Rizvi Moshahid Alam , Ali Mansoor , Kaur Loveleena , Mondal Amal Chandra
Published: December 2022

Neuroblastoma (NB) is one of the most common heterogeneous extracranial cancers in infancy that arises from neural crest (NC) cells of the sympathetic nervous system. The Wnt signaling pathway, both canonical and noncanonical pathway, is a highly conserved signaling pathway that regulates the development and differentiation of the NC cells during embryogenesis. Reports suggest that aberrant activation of Wnt ligands/receptors in Wnt signaling pathways promote progression and relapse of NB. Wnt signaling pathways regulate NC induction and migration in a similar manner; it regulates proliferation and metastasis of NB. Inhibiting the Wnt signaling pathway or its ligands/receptors induces apoptosis and abrogates proliferation and tumorigenicity in all major types of NB cells. Here, we comprehensively discuss the Wnt signaling pathway and its mechanisms in regulating the development of NC and NB pathogenesis. This review highlights the implications of aberrant Wnt signaling in the context of etiology, progression, and relapse of NB. We have also described emerging strategies for Wnt‐based therapies against the progression of NB that will provide new insights into the development of Wnt‐based therapeutic strategies for NB.
miRNA in Parkinson's disease: From pathogenesis to theranostic approaches
Authors: Elangovan Ajay , Venkatesan Dhivya , Selvaraj Priyanka , Pasha Md. Younus , Babu Harysh Winster Suresh , Iyer Mahalaxmi , Narayanasamy Arul , Subramaniam Mohana Devi , Valsala Gopalakrishnan Abilash , Kumar Nachimuthu Senthil , Vellingiri Balachandar
Published: December 2022

Parkinson's disease (PD) is an age associated neurological disorder which is specified by cardinal motor symptoms such as tremor, stiffness, bradykinesia, postural instability, and non‐motor symptoms. Dopaminergic neurons degradation in substantia nigra region and aggregation of αSyn are the classic signs of molecular defects noticed in PD pathogenesis. The discovery of microRNAs (miRNA) predicted to have a pivotal part in various processes regarding regularizing the cellular functions. Studies on dysregulation of miRNA in PD pathogenesis has recently gained the concern where our review unravels the role of miRNA expression in PD and its necessity in clinical validation for therapeutic development in PD. Here, we discussed how miRNA associated with ageing process in PD through molecular mechanistic approach of miRNAs on sirtuins, tumor necrosis factor‐alpha and interleukin‐6, dopamine loss, oxidative stress and autophagic dysregulation. Further we have also conferred the expression of miRNAs affected by SNCA gene expression, neuronal differentiation and its therapeutic potential with PD. In conclusion, we suggest more rigorous studies should be conducted on understanding the mechanisms and functions of miRNA in PD which will eventually lead to discovery of novel and promising therapeutics for PD.