Positioning of old and new biologicals and small molecules in the treatment of inflammatory bowel diseases

The past decade has brought substantial advances in the management of inflammatory bowel diseases(IBD). The introduction of tumor necrosis factor(TNF) antagonists, evidence for the value of combination therapy, the recog-nition of targeting lymphocyte trafficking and activation as a viable treatment, and the need for early treatment of high-risk patients are all fundamental concepts for current modern IBD treatment algorithms. In this article, authors review the existing data on approved biologicals and small molecules as well as provide insight on the current positioning of approved therapies. Patient stratification for the selection of specific therapies, therapeutic targets and patient monitoring will be discussed as well. The thera-peutic armamentarium for IBD is expanding as novel and more targeted therapies become available. In the absence of comparative trials, positioning these agents is becoming difficult. Emerging concepts for the future will include an emphasis on the development of algorithms which will facilitate a greater understanding of the positioning of novel biological drugs and small molecules in order to best tailor therapy to the patient. In the interim, anti-TNF therapy remains an important component of IBD therapy with the most real-life evidence and should be considered as first-line therapy in patients with complicated Crohn's disease and in acute-severe ulcerative colitis. The safety and efficacy of these ‘older' anti-TNF therapies can be optimized by adhering to therapeutic algorithms which combine clinical and objective markers of disease severityand response to therapy.

Access to biologicals in Crohn's disease in ten European countries

AIM To analyze access(availability, affordability and acceptability) to biologicals for Crohn's disease(CD) in ten European countries and to explore the associations between these dimensions, the uptake of biologicals and economic development.METHODS A questionnaire-based survey combined with desk research was carried out in May 2016. Gastroenterologists from the Czech Republic, France, Germany, Hungary, Latvia, Poland, Romania, Slovakia, Spain and Sweden were invited to participate and provide data on the availability of biologicals/biosimilars, reimbursement criteria, clinical practice and prices, and use of biologicals. An availability score was developed to evaluate the restrictiveness of eligibility and administrative criteria applied in the countries. Affordability was defined as the annual cost of treatment as a share of gross domestic product(GDP) per capita. Correlations with the uptake of biologicals, dimensions of access and GDP per capita were calculated.RESULTS At the time of the survey, infliximab and adalimumab were reimbursed in all ten countries, and vedolizumab was reimbursed in five countries(France, Germany, Latvia, Slovakia, Sweden). Reimbursement criteria were the least strict in Sweden and Germany, and the strictest in Hungary, Poland and Slovakia. Between countries, the annual cost of different biological treatments differed 1.6-3.3-fold. Treatments were the most affordable in Sweden(13%-37% of the GDP per capita) and the least affordable in the Central and Eastern European countries, especially in Hungary(87%-124%) and Romania(141%-277%). Biosimilars made treatments more affordable by driving down the annual costs. The number of patients with CD on biologicals per 100000 population was strongly correlated with GDP per capita(0.91), although substantial differences were found in the uptake among countries with similar economic development. Correlation between the number of patients with CD on biologicals per 100000 population and the availability and affordability was also strong(-0.75,-0.69 respectively). CONCLUSION Substantial inequalities in access to biologicals were largely associated with GDP. To explain differences in access among countries with similar development needs further research on acceptance.

COVID-19: Considerations about immune suppression and biologicals at the time of SARS-CoV-2 pandemic

The extent of the profound immunological and nonimmunological responses linked to severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection is currently being investigated worldwide due to the large burden associated with death due to SARS-CoV-2 and the short-term consequences of coronavirus disease 2019(COVID-19).It has been hypothesized that patients on immunosuppressive treatments,including biologics,may have an augmented risk of being infected by SARS-CoV-2;however,there are currently no definitive data about biological drugs and COVID-19 in immune-mediated inflammatory diseases.Current epidemiological models developed to understand how long the COVID-19 epidemic may last are not conclusive and range from sustained epidemics to complete elimination.Nevertheless,even in the best-case scenario of apparent elimination,there is concordance about a possible contagion resurgence as late as 2024.Therefore,knowledge of the impact of SARS-CoV-2 on immunemediated diseases and among patients treated with biologicals,together with the results of novel and promising COVID-19 treatment strategies targeting the virus and the host immune response(or both),will help us to best manage our patients during this pandemic over the next few years.

TM9SF1 promotes bladder cancer cell growth and infiltration

BACKGROUND Bladder cancer(BC)is the most common urological tumor.It has a high recur-rence rate,displays tutor heterogeneity,and resists chemotherapy.Furthermore,the long-term survival rate of BC patients has remained unchanged for decades,which seriously affects the quality of patient survival.To improve the survival rate and prognosis of BC patients,it is necessary to explore the molecular mechanisms of BC development and progression and identify targets for treatment and intervention.Transmembrane 9 superfamily member 1(TM9SF1),also known as MP70 and HMP70,is a member of a family of nine transmembrane superfamily proteins,which was first identified in 1997.TM9SF1 can be expressed in BC,but its biological function and mechanism in BC are not clear.AIM To investigate the biological function and mechanism of TM9SF1 in BC.Overexpression of TM9SF1 increased the in vitro proliferation,migration,and invasion of BC cells by promoting the entry of BC cells into the G2/M phase.Silencing of TM9SF1 inhibited in vitro proliferation,migration,and invasion of BC cells and blocked BC cells in the G1 phase.CONCLUSION TM9SF1 may be an oncogene in BC.

A critical review on natural compounds interacting with the plant plasma membrane H^(+)-ATPase and their potential as biologicals in agriculture

The plant plasma membrane(PM)H^(+)-ATPase is an essential enzyme controlling plant growth and development.It is an important factor in response to abiotic and biotic stresses and is subject to tight regulation.We are in demand for new sustainable natural growth regulators and as a key enzyme for regulation of transport into the plant cell the PM H^(+)-ATPase is a potential target for these.In this review,we have evaluated the known non-protein natural compounds with regulatory effects on the PM H^(+)-ATPase,focusing on their mechanism of action and their potential as biologicals/growth regulators in plant production of future sustainable agriculture.

Glycine-β-cyclodextrin-assisted cometabolism of phenanthrene and pyrene by Pseudomonas stutzeri DJP 1 from marine sediment

Cometabolic degradation is currently an effective and extensively way to remove high molecular weight polycyclic aromatic hydrocarbons(HMW-PAHs).Unfortunately,due to low bio-accessibility and high biotoxicity,the cometabolic degradation rate of HMW-PAHs is limited.Glycine-β-cyclodextrin(GCD)was obtained through amino modification ofβ-cyclodextrin(BCD)and added to cometabolic system of phenanthrene(PHE)and pyrene(PYR)to assist PYR biodegradation.Results show that the addition of GCD(100 mg/L)effectively improved the removal rate of PYR(20 mg/L)by 42.3%.GCD appeared to increase the bio-accessibility and reduce the biotoxicity of PHE and PYR,and then promoted the growth of Pseudomonas stutzeri DJP1 and stimulated the elevation of dehydrogenase(DHA)and catechol 12 dioxygenase(C12O)activities.The phthalate metabolic pathway was accelerated,which improved the cometabolic degradation.This study provided a new reference for the cometabolic degradation of HMW-PAHs.

The biological functions and metabolic pathways of valine in swine

Valine is an essential amino acid and a type of branched-chain amino acid. Due to the involvement of branchedchain amino acids in various metabolic pathways, there has been a surge of interests in valine nutrition and its role in animal physiology. In pigs, the interactions between valine and other branched-chain amino acids or aromatic amino acids are complex. In this review, we delve into the interaction mechanism, metabolic pathways, and biological functions of valine. Appropriate valine supplementation not only enhances growth and reproductive performances, but also modulates gut microbiota and immune functions. Based on past observations and interpretations, we provide recommended feed levels of valine for weaned piglets, growing pigs, gilts, lactating sows, barrows and entire males. The summarized valine nutrient requirements for pigs at different stages offer valuable insights for future research and practical applications in animal husbandry.

Silencing transformer and transformer-2 in Zeugodacus cucurbitae causes defective sex determination with inviability of most pseudomales

transformer is a switch gene for sex determination in many insects, which cooperates with transformer-2 that is expressed in both sexes to regulate female differentiation, particularly in dipterans. Zeugodacus cucurbitae(Coquillett) is a very destructive pest worldwide, however, its sex determination pathway remains largely uncharacterized. Here, we show that the female sex ratio is sharply reduced with knockdown of either transformer or transformer-2 by RNA interference in early embryos of Z. cucurbitae. Most of the males grown from the embryos with transient transformer and transformer-2 suppression mated with wild-type females and produced mixed sex progeny, with one exception that produced only female progeny, and all of the few remaining males failed to mate with wild-type females and produced no progeny. The exceptional male and those males with mating failure were XX pseudomales as determined by the detection of Y chromosome-linked Maleness-on-the-Y, indicating that most XX pseudomales are not viable. The phenotypes of transformer and transformer-2 suggest that they play a key role in regulating sex determination and are required for female sexual development of Z. cucurbitae. Our results will be beneficial to the understanding of sex determination in Z. cucurbitae and can facilitate the development of genetic sexing strains for its biological control.

Assessment of the Characteristics of Demersal Fish Communities Using Species-and Trait-Based Approaches in the Coastal Habitats Along Rongcheng Bay,Shandong Peninsula,China

Biodiversity declines have motivated many studies on the relationship between species diversity and ecosystem functioning.In this study,we described the spatial-temporal characteristics of demersal fish communities along a coastal habitat in Rongcheng Bay,Shandong Peninsula,China with both species-based and biological trait-based approaches.The field survey was carried out monthly using traps from April to October of 2018,and divided into three seasons(spring:April and May;summer:June,July and August;autumn:September,October and November).The study area included five distinct habitats:seagrass bed,natural rocky reef,bare sand,artificial reef together with natural rocky reef,and artificial reef together with bare sand.We analyzed the fish communities with three taxonomic diversity indices,including Shannon-Wiener,Simpson,and Pielou Evenness,as well as four functional diversity indices,including FRic,FEve,FDiv,and FDis,based on 7 functional groups which are categorized into 27 traits.The results showed that there were no significant differences in taxonomic diversity indices among different habitats in the three seasons.However,significant differences were found in the functional richness of fish communities among different habitats in three seasons.Seagrass bed represented the highest functional richness in spring and autumn.This study demonstrates that seagrass bed is very important in enhancing the functional diversity of fish communities in a complex habitat.The study also indicates that the combination of taxonomic diversity and functional diversity will provide a more detailed description of the characteristics of fish communities.

EjGASA6 promotes flowering and root elongation by enhancing gibberellin biosynthesis

The Gibberellic Acid-stimulated Arabidopsis(GASA)gene family is involved in the regulation of gene expression and plant growth,development,and stress responses.To investigate the function of loquat GASA genes in the growth and developmental regulation of plants,a loquat EjGASA6 gene homologous to Arabidopsis AtGASA6 was cloned.EjGASA6 expression was induced by gibberellin,and ectopic transgenic plants containing this gene exhibited earlier bloom and longer primary roots since these phenotypic characteristics are related to higher gibberellin content.Transcriptome analysis and qRT-PCR results showed that the expression levels of GA3ox1 and GA20ox1,which encode key enzymes in gibberellin biosynthesis,were significantly increased.Furthermore,we confirmed that EjGASA6 could promote the expression of GA20ox1 via the luciferase reporter system.Overall,our results suggest that EjGASA6 promotes blooming and main-root elongation by positively regulating gibberellin biosynthesis.These findings broaden our understanding of the role of GASAs in plant development and growth,and lay the groundwork for future research into the functions of EjGASA6 in regulating loquat growth and development.

Biological soil crusts and their potential applications in the sand land over Qinghai-Tibet Plateau

The Qinghai-Tibet Plateau is now experiencing ecological degradation risks as a result of climate change and human activities.The alpine grassland ecology in permafrost zones is fragile and susceptible to deterioration due to its high altitude,low temperature,and limited oxygen,which complicates the repair of damaged land.Biological soil crusts(BSCs)are crucial for land restoration in plateau regions because they can thrive in harsh conditions and have environmentally beneficial traits.Inoculated biological soil crust(IBSC)has shown success in low-altitude desert regions,but may not be easily duplicated to the plateau environment.Therefore,it is essential to do a comprehensive and multifaceted analysis of the basic theoretical comprehension and practical application of BSCs on the Tibetan Plateau.This review article aims to provide a brief summary of the ecological significance and the mechanisms related to the creation,growth,and progression of BSCs.It discusses the techniques used for cultivating BSCs in laboratories and using them in the field,focusing on the Qinghai-Tibet Plateau circumstance.We thoroughly discussed the potential and the required paths for further studies.This study may be used as a basis for selecting suitable microbial strains and accompanying supplemental actions for implementing IBSCs in the Qinghai-Tibet Plateau.

Plant growth and metabolism of exotic and native Crotalaria species for mine land rehabilitation in the Amazon

Despite its enormous benefits,mining is respon-sible for intense changes to vegetation and soil properties.Thus,after extraction,it is necessary to rehabilitate the mined areas,creating better conditions for the establishment of plant species which is challenging.This study evaluated mineral and organic fertilization on the growth,and carbon and nitrogen(N)metabolism of two Crotalaria species[Cro-talaria spectabilis(exotic species)and Crotalaria maypu-rensis(native species from Carajás Mineral Province(CMP)]established on a waste pile from an iron mine in CMP.A control(without fertilizer application)and six fertilization mixtures were tested(i=NPK;ii=NPK+micronutrients;iii=NPK+micronutrients+organic compost;iv=PK;v=PK+micronutrients;vi=PK+micronutrients+organic compost).Fertilization contributed to increased growth of both species,and treatments with NPK and micronutrients had the best results(up to 257%cf.controls),while organic fertilization did not show differences.Exotic Crotalaria had a greater number of nodules,higher nodule dry mass,chlorophyll a and b contents and showed free ammonium as the predominant N form,reflecting greater increments in biomass compared to native species.Although having lower growth,the use of this native species in the rehabilitation of mining areas should be considered,mainly because it has good development and meets current government legislation as an opportunity to restore local biodiversity.

Bioactive compounds in Hericium erinaceus and their biological properties:a review

Hericium erinaceus is a nutritious edible and medicinal fungi,rich in a variety of functional active ingredients,with various physiological functions such as antioxidation,anticancer,and enhancing immunity.It is also effective in protecting the digestive system and preventing neurodegenerative diseases.In this review paper,we summarize the sources,structures and efficacies of the main active components in H.erinaceus fruiting body,mycelium,and culture media,and update the latest research progress on their biological activities and the related molecular mechanisms.Based on this information,we provide detailed challenges in current research,industrialization and information on the active ingredients of H.erinaceus.Perspectives for future studies and new applications of H.erinaceus are proposed.

Comparative proteomics reveals the response and adaptation mechanisms of white Hypsizygus marmoreus against the biological stress caused by Penicillium

White Hypsizygus marmoreus is a popular edible mushroom.Its mycelium is easy to be contaminated by Penicillium,which leads to a decrease in its quality and yield.Penicillium could compete for limited space and nutrients through rapid growth and produce a variety of harmful gases,such as benzene,aldehydes,phenols,etc.,to inhibit the growth of H.marmoreus mycelium.A series of changes occurred in H.marmoreus proteome after contamination when detected by the label-free tandem mass spectrometry(MS/MS)technique.Some proteins with up-regulated expression worked together to participate in some processes,such as the non-toxic transformation of harmful gases,glutathione metabolism,histone modification,nucleotide excision repair,clearing misfolded proteins,and synthesizing glutamine,which were mainly used in response to biological stress.The proteins with down-regulated expression are mainly related to the processes of ribosome function,protein processing,spliceosome,carbon metabolism,glycolysis,and gluconeogenesis.The reduction in the function of these proteins affected the production of the cell components,which might be an adjustment to adapt to growth retardation.This study further enhanced the understanding of the biological stress response and the growth restriction adaptation mechanisms in edible fungi.It also provided a theoretical basis for protein function exploration and edible mushroom food safety research.

Metabolomic Analysis in Saliva and Different Brain Regions of Older Mice with Postoperative Delirium Behaviors

Objective Postoperative delirium(POD)has become a critical challenge with severe consequences and increased incidences as the global population ages.However,the underlying mechanism is yet unknown.Our study aimed to explore the changes in metabolites in three specific brain regions and saliva of older mice with postoperative delirium behavior and to identify potential non-invasive biomarkers.Methods Eighteen-month-old male C57/BL6 mice were randomly assigned to the anesthesia/surgery or control group.Behavioral tests were conducted 24 h before surgery and 6,9,and 24 h after surgery.Complement C3(C3)and S100 calcium-binding protein B protein(S100beta)levels were measured in the hippocampus,and a metabolomics analysis was performed on saliva,hippocampus,cortex,and amygdala samples.Results In total,43,33,38,and 14 differential metabolites were detected in the saliva,hippocampus,cortex,and amygdala,respectively.“Pyruvate”“alpha-linolenic acid”and“2-oleoyl-1-palmitoy-snglycero-3-phosphocholine”are enriched in one common pathway and may be potential non-invasive biomarkers for POD.Common changes were observed in the three brain regions,with the upregulation of 1-methylhistidine and downregulation of D-glutamine.Conclusion Dysfunctions in energy metabolism,oxidative stress,and neurotransmitter dysregulation are implicated in the development of POD.The identification of changes in the level of salivary metabolite biomarkers could aid in the development of noninvasive diagnostic methods for POD.

A novel small-animal locomotor activity recording device for biological clock research

The rodent running-wheel recording apparatus is a reliable approach for studying cir-cadian rhythm.This study demonstrated how to construct a simple and intelligent running-wheel recording system.The running wheel was attached to the cage's base,whereas the Hall sensor was attached to the cage's cover.Then,the RJ25 adaptor relayed the running signal to the main control board.Finally,the main control board was connected to the USB port of the computer with the USB connection.Data were collected using the online-accessible,self-created software Magturning.Through Magturning,generated data were saved and exported in real time.Afterward,the device was validated by collecting data on the locomotor activities of mice under dif-ferent light conditions.In conclusion,this new device can record circadian activity of rodents.Our device is appropriate for interdisciplinary investigations related to biological clock research.

Potential Secretory Transporters and Biosynthetic Precursors of Biological Nitrification Inhibitor 1,9-Decanediol in Rice as Revealed by Transcriptome and Metabolome Analyses

Biological nitrification inhibitors(BNIs)are released from plant roots and inhibit the nitrification activity of microorganisms in soils,reducing NO_(3)^(‒)leaching and N2O emissions,and increasing nitrogenuse efficiency(NUE).Several recent studies have focused on the identification of new BNIs,yet little is known about the genetic loci that govern their biosynthesis and secretion.We applied a combined transcriptomic and metabolomic analysis to investigate possible biosynthetic pathways and transporters involved in the biosynthesis and release of BNI 1,9-decanediol(1,9-D),which was previously identified in rice root exudates.Our results linked four fatty acids,icosapentaenoic acid,linoleate,norlinolenic acid,and polyhydroxy-α,ω-divarboxylic acid,with 1,9-D biosynthesis and three transporter families,namely the ATP-binding cassette protein family,the multidrug and toxic compound extrusion family,and the major facilitator superfamily,with 1,9-D release from roots into the soil medium.Our finding provided candidates for further work on the genes implicated in the biosynthesis and secretion of 1,9-D and pinpoint genetic loci for crop breeding to improve NUE by enhancing 1,9-D secretion,with the potential to reduce NO_(3)^(‒)leaching and N2O emissions from agricultural soils.

Real-world efficacy and safety of tofacitinib treatment in Asian patients with ulcerative colitis

BACKGROUND Real-world data on tofacitinib(TOF)covering a period of more than 1 year for a sufficient number of Asian patients with ulcerative colitis(UC)are scarce.AIM To investigate the long-term efficacy and safety of TOF treatment for UC,including clinical issues.METHODS We performed a retrospective single-center observational analysis of 111 UC patients administered TOF at Hyogo Medical University as a tertiary inflammatory bowel disease center.All consecutive UC patients who received TOF between May 2018 and February 2020 were enrolled.Patients were followed up until August 2020.The primary outcome was the clinical response rate at week 8.Secondary outcomes included clinical remission at week 8,cumulative persistence rate of TOF administration,colectomy-free survival,relapse after tapering of TOF and predictors of clinical response at week 8 and week 48.RESULTS The clinical response and remission rates were 66.3%and 50.5%at week 8,and 47.1%and 43.5%at week 48,respectively.The overall cumulative clinical remission rate was 61.7%at week 48 and history of anti-tumor necrosis factor-alpha(TNF-α)agents use had no influence(P=0.25).The cumulative TOF persistence rate at week 48 was significantly lower in patients without clinical remission than in those with remission at week 8(30.9%vs 88.1%;P<0.001).Baseline partial Mayo Score was significantly lower in responders vs non-responders at week 8(odds ratio:0.61,95%confidence interval:0.45-0.82,P=0.001).Relapse occurred in 45.7%of patients after TOF tapering,and 85.7%of patients responded within 4 wk after re-increase.All 6 patients with herpes zoster(HZ)developed the infection after achieving remission by TOF.CONCLUSION TOF was more effective in UC patients with mild activity at baseline and its efficacy was not affected by previous treatment with anti-TNF-αagents.Most relapsed patients responded again after re-increase of TOF and nearly half relapsed after tapering off TOF.Special attention is needed for tapering and HZ.

Biomedical rare-earth magnesium alloy:Current status and future prospects

Biomedical magnesium(Mg)alloys have garnered significant attention because of their unique biodegradability,favorable biocompatibility,and suitable mechanical properties.The incorporation of rare earth(RE)elements,with their distinct physical and chemical properties,has greatly contributed to enhancing the mechanical performance,degradation behavior,and biological performance of biomedical Mg alloys.Currently,a series of RE-Mg alloys are being designed and investigated for orthopedic implants and cardiovascular stents,achieving substantial and encouraging research progress.In this work,a comprehensive summary of the state-of-the-art in biomedical RE-Mg alloys is provided.The physiological effects and design standards of RE elements in biomedical Mg alloys are discussed.Particularly,the degradation behavior and mechanical properties,including their underlying action are studied in-depth.Furthermore,the preparation techniques and current application status of RE-Mg alloys are reviewed.Finally,we address the ongoing challenges and propose future prospects to guide the development of high-performance biomedical Mg-RE alloys.

Impacts of road on plant invasions in the Middle Mountain region of central Nepal

Biological invasion is triggered by human development activities such as the construction and expansion of road networks.Road verges serve as important habitats and corridors for the distribution of invasive alien plant species(IAPS)between geographically distant habitats.However,the trajectory of plant invasion and the data regarding the impact of roads on IAPS distribution are relatively poor in Nepal.Here,we surveyed two road types(main roads and feeder road)in the Middle Mountain region of central Nepal in order to investigate how different road types are driving the dispersal of IAPS along road verges and the adjacent natural habitats.Systematic sampling was conducted at ca 2.5 km intervals along the roads.At each sampling site,paired plots(25 m×4 m)were sampled:one adjacent to and along the road,and another 20 m away and parallel to it in the interior habitat.Our results revealed that the main road verges had a higher cover(33%)and a larger number of IAPS(14 species)than the feeder road(25%;10 species).The IAPS cover and richness were significantly higher along verges than in the adjacent interior habitats for both road types,indicating that roads are contributing as corridors for the dispersal of IAPS in the Middle Mountain areas of central Nepal.Further,elevation,tree canopy,and disturbances(grazing/mowing/trampling)were found to be the key factors that determine spatial distribution of IAPS along road verges.We emphasize that regular monitoring of vegetation along the road verges can help with the early detection and control of potential IAPS in the region before they become problematic.