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.

Biolog代谢表型技术解析小菜蛾肠道细菌河生肠杆菌的生物学特性

河生肠杆菌Enterobacter amnigenus为小菜蛾Plutella xylostella幼虫肠道优势可培养格兰氏阴性细菌,本文系统地阐述了河生肠杆菌在养分需求和环境适应力上的生物学特性。采用Biolog代谢表型技术,系统地研究了E.amnigenus的碳、氮、磷、硫需求及其在各种环境下的适应力。河生肠杆菌具有广泛的营养需求,可代谢38.42%的供试碳源、98.42%的供试氮源,以及100%的硫源和100%的磷源;高效代谢的碳源和氮源分别为有机酸类和糖类、及氨基酸类和肽类化合物。它表现出95种生物合成途径。河生肠杆菌具有广泛的环境适应力,能分别在高达6.5%氯化钠、5%硫酸钠、6%氯化钾、20%乙二醇、6%甲酸钠、4%尿素、10%乳酸钠、50 mmol/L苯甲酸钠(pH5.2)、200 mmol/L磷酸钠(pH7.0)、100 mmol/L硫酸铵(pH8.0)、100 mmol/L亚硝酸钠和100 mmol/L硝酸钠的渗透溶液中生长,而不能在11%~12%的乳酸钠渗透溶液中生长;其适应pH值范围为4.5~10.0,最适约为9.0。在多种氨基酸的作用下,河生肠杆菌具有脱羧酶和脱氨酶活性。小菜蛾肠道细菌河生肠杆菌具有广泛营养需求特性、渗透压与pH环境适应力。

Surgery for Crohn's disease in the era of biologicals:A reduced need or delayed verdict?

Crohn's disease(CD) is a chronic inflammatory bowel disease that can affect the entire gastrointestinal tract.Ultimately,up to 70% of all patients will need surgery,despite optimized medical therapy.Moreover,about half of the patients will need redo-surgery because of disease recurrence.The introduction of anti-tumor necrosis factor(TNF) drugs(Infliximab in 1998) revolutionized the treatment of CD.Different randomized trials assessed the efficacy of anti-TNF treatment not only to induce,but also to maintain,steroid-free remission.Furthermore,these agents can rapidly lead to mucosal healing.This aspect is important,as it is a major predictor for long-term disease control.Subgroup analyses of responding patients seemed to suggest a reduction in the need for surgery at median-term follow up(1-3 years).However if one looks at population surveys,one does not observe any decline in the need for surgery since the introduction of Infliximab in 1998.The short follow-up term and the exclusion of patients with imminent surgical need in the randomized trials could bias the results.Only 60% of patients respond to induction of anti-TNF therapy,moreover,some patients will actually develop resistance to biologicals.Many patients are diagnosed when stenosing disease has already occurred,obviating the need for biological therapy.In a further attempt to change the actual course of the disease,top down strategies have been progressively implemented.Whether this will indeed obviate surgery for a substantial group of patients remains unclear.For the time being,surgery will still play a pivotal role in the treatment of CD.

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.

Na^(+)/K^(+)-ATPase:ion pump,signal transducer,or cytoprotective protein,and novel biological functions

Na^(+)/K^(+)-ATPase is a transmembrane protein that has important roles in the maintenance of electrochemical gradients across cell membranes by transporting three Na^(+)out of and two K^(+)into cells.Additionally,Na^(+)/K^(+)-ATPase participates in Ca^(2+)-signaling transduction and neurotransmitter release by coordinating the ion concentration gradient across the cell membrane.Na^(+)/K^(+)-ATPase works synergistically with multiple ion channels in the cell membrane to form a dynamic network of ion homeostatic regulation and affects cellular communication by regulating chemical signals and the ion balance among different types of cells.Therefo re,it is not surprising that Na^(+)/K^(+)-ATPase dysfunction has emerged as a risk factor for a variety of neurological diseases.However,published studies have so far only elucidated the important roles of Na^(+)/K^(+)-ATPase dysfunction in disease development,and we are lacking detailed mechanisms to clarify how Na^(+)/K^(+)-ATPase affects cell function.Our recent studies revealed that membrane loss of Na^(+)/K^(+)-ATPase is a key mechanism in many neurological disorders,particularly stroke and Parkinson's disease.Stabilization of plasma membrane Na^(+)/K^(+)-ATPase with an antibody is a novel strategy to treat these diseases.For this reason,Na^(+)/K^(+)-ATPase acts not only as a simple ion pump but also as a sensor/regulator or cytoprotective protein,participating in signal transduction such as neuronal autophagy and apoptosis,and glial cell migration.Thus,the present review attempts to summarize the novel biological functions of Na^(+)/K^(+)-ATPase and Na^(+)/K^(+)-ATPase-related pathogenesis.The potential for novel strategies to treat Na^(+)/K^(+)-ATPase-related brain diseases will also be discussed.

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.

Chronic Hepatitis B Virus Infection: Biological Parameters in Patients Treated with Tenofovir Disoproxil Fumarate

Chronic hepatitis B causes a liver disease characterized by inflammation of the liver parenchyma. The aim of this study was to investigate the evolution of biological parameters in patients treated with Tenofovir for chronic B infection at the Commune V referral health center in Bamako. We obtained a prevalence of 14.15%. The most represented age group was 31 - 40 years, with 36.8%. The sex ratio was 1.44 in favour of men. Viral load was undetectable after 18 months of treatment in 25 patients (42.37%). Tenofovir, the 1st-line drug in Mali, is effective on the biological parameters monitored in patients.

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.

Secondary Metabolites of Entomopathogenic Fungi, Biological Alternative for the Control of Agricultural Pests and Disease: Present and Perspectives

The use of entomopathogenic fungi (EF) in recent years has been highly effective against the different orders of insects considered pests of agricultural importance and their conidia have been commonly applied, but it has been reported that these are sensitive to the environmental conditions. For this reason, biopesticides products have been formulated based on secondary metabolites, recently. These biomolecules participate as biological control agent, such as: cyclic depsipeptides, amino acids, polyketides, polyphenols and terpenoids, affecting their morphology, life cycle and insect behavior. The use of secondary metabolites of entomopathogenic fungi opens the possibility of application in a more efficient way for the control of agricultural pests in a compatible with the environment and human health;therefore, it is important to know, analyzing the type of molecules, their effects, and their different methods of application.

Evaluation of the Efficacy of an Aloe barbadensis Based Biological Insecticide against Pests of Abelmochus esculentus for Promoting Ecological Agriculture (Far-North, Cameroon)

Chemical insecticides have been considered as a means to combat crop pests. Although their effectiveness is evident, their impact on the environment is increasingly being discussed. The aim of this study is to determine the agro-ecological potential of a biological insecticide (C25H32O12) based on Aloe barbadensis in a Sahelian context. For this purpose, a completely randomized block experimental design with 3 replications and 4 treatments was set up to experiment with Aloe barbadensis as a bioinsecticide against pests of Abelmoschus esculentus. However, data were collected using an observation and parameter monitoring grid. This includes the cultivation of Abelmoschus esculentus, soil preparation, seeding and watering, plot labeling, preparation of the bioinsecticide (selection and preparation of raw materials, grinding of Aloe barbadensis miller and extraction of the crude bioinsecticide, quantification of treatment doses and dilution, and obtaining the formulated bioinsecticide), plant watering, plant treatment, and finally parameter monitoring. The results obtained reveal that the level of damage is significantly high in the control treatment T0 (63%) compared to the other treatments, with 29% for treatment T1, 7% for T2, and 1% for T3, implying a strong action capability of this insecticide against pests of Abelmoschus esculentus. Therefore, it can be concluded that for a normal growing season of Abelmoschus esculentus, this biological insecticide should be sprayed 12 times. Furthermore, this biological insecticide is unique in that it does not inflict any gastric toxicity on the pests, which gives it the characteristic of being a repellent. It is a biological insecticide whose efficacy period has been tested, with a minimum duration of 21 days. In conclusion, this formulated bioinsecticide based on Aloe barbadensis demonstrates significant efficacy against pests of Abelmoschus esculentus. In the future, we will consider experimenting with its effectiveness against pests of other plants.

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.

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.

Hyperhomocysteinemia and Associated Biological Markers in a Congolese Population of Type 2 Diabetes Mellitus in Brazzaville

The search for new biomarkers predictive of type 2 diabetes currently constitutes a research avenue in Bioclinical. Total homocysteine remains a preferred target due to its involvement in the occurrence of degenerative complications in type 2 diabetics. The aim of this work was to study hyperhomocysteinemia and other biochemical markers associated with T2D in the Congolese population. This was an analytical case-control study carried out between October 2022 and October 2023. The study population consisted of 150 subjects including 100 T2D patients and 50 control subjects. The main clinical data were collected on a pre-established form. Homocysteine determination was carried out by the sandwich ELISA method. The other biochemical markers were measured by colorimetric enzymatic methods. Hyperhomocysteinemia was present in 27.3% (41/150) of the entire study population. Type 2 diabetics had a frequency of hyperhomocysteinemia of 36% (36/100) and control 10% (5/50) (p = 0.001). The mean hyperhomocysteinemia concentration was 31.9 μmol/l with extremes ranging from 18 to 103 μmol/l. Means of biological markers between diabetics and controls showed a statistically significant difference (p = 0.01). The risk factors associated with this HHcy were: sex (OR = 3.5), age (OR = 9.4), sedentary lifestyle (OR = 3.4) and glycosylated hemoglobin (OR = 12) with a p-value <0.05 respectively. Our results suggest that hyperhomocysteinemia can be considered as a predictive biomarker in the bioclinic of Congolese type 2 diabetic patients.

Study of the Constraints of Millet Production (Pennisetum glaucum (L.) R. Br.) and the Peasant Perception of Biological Control in the Tahoua Region

Millet (Pennisetum glaucum (L.) R. Br.) is the Sahelian crop par excellence due to its adaptation to the particular production conditions in this region. Unfortunately, in recent years this crop has been threatened by very strong parasitic pressure and drought during the production period. The objective of this study is to analyze the main constraints of millet production and the solutions known to producers. A survey was carried out in November 2022 with a sample of 298 producers in five municipalities in the Tahoua region. The main constraints are drought and pressure from crop pests (locust, millet ear miner, floricultural insects) according to 57.9% of respondents. The millet ear miner is the most formidable pest according to 55% of respondents. Thus, the average yield obtained in a year of good production without the leafminer is 194 kg/ha and that obtained in a year of millet ear leafminer is around 27 kg to 43 kg/ha depending on the municipality. The yield obtained this last campaign after the attack of this leafminer varies from 64 to 77 kg/ha depending on the municipalities compared to a potential yield of over 1000 kg/ha. More than half of producers (58.1%) are unaware of the existence of biological control compared to only 12.5% who are aware of this alternative method. Work to popularize this technology is necessary in the five municipalities and the entire region in general.

Progress in the Use of Glucocorticoids and Biological Agents in Non-Infectious Uveitis

One of the main immune-mediated diseases that lead to avoidable blindness is non-infectious uveitis. Glucocorticoids are the first-line therapy choice for noninfectious uveitis;however, biologics are also showing promise in the management of this condition. The description of glucocorticoid and biologic usage in non-infectious uveitis is the main topic of this paper.

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.

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.

Bibliometric analysis of the status and trend of biological soil crusts research from 1912 to 2023

Biological soil crusts(BSCs)play an important role in soil development and ecological function,and it is more important for quantitatively analyzing the processes and trends of BSCs to identify the advantages and disadvantages of BSCs research for the development and application of BSCs theory.Bibliometric analysis of 2,186 BSCs literatures from Web of Science showed an exponential growth trend,as China and the United States as the top 2 in terms of publication volume.High quality publications are mainly from European and American countries,such as the United States,Germany and Spain.The top 3 publishers are Journal of Arid Environments,Soil Biology&Biochemistry and Plant and Soil,and disciplines include ecology,environmental science,and soil science,etc..Research institutions mainly affiliate to the Chinese Academy of Sciences,United States Department of the Interior,United States Geological Survey,Hebrew University of Jerusalem,Consejo Superior de Investigaciones Cientificas,and Universidad Rey Juan Carlos.Authors mainly come from United States,Israel,Spain and China.Funds are mainly from the National Natural Science Foundation of China,Spanish Government,Chinese Academy of Sciences,and National Science Foundation of the United States.Biological soil crusts(biocrusts,cyanobacteria,lichens,moss crusts,bryophytes),drylands,climate change,photosynthesis and desert are high-frequency keywords.Future research will focus on the driving mechanisms of BSCs on global biogeochemical cycles,maintaining global biodiversity on important ecological processes,global C,N,and P cycles.The impact on biological invasion,sandstorms,and water balance,multifunctional and reciprocal mechanisms for maintaining the stability of desert and sandy ecosystems,and impact on the formulation of management policies for arid ecosystems,corresponding to global climate change,and the estimation of regional,local,and microscale distribution of BSCs based on machine deep learning modeling gradually focus on.The ecosystem service functions of BSCs,the soil and water conservation and soil stability mediated by BSCs in arid and semi-arid regions,and the excavation of stress resistant genes for BSCs will be emphasized.

Recent advances in zwitterionic nanoscale drug delivery systems to overcome biological barriers

Nanoscale drug delivery systems(nDDS)have been employed widely in enhancing the therapeutic efficacy of drugs against diseases with reduced side effects.Although several nDDS have been successfully approved for clinical use up to now,biological barriers between the administration site and the target site hinder the wider clinical adoption of nDDS in disease treatment.Polyethylene glycol(PEG)-modification(or PEGylation)has been regarded as the gold standard for stabilising nDDS in complex biological environment.However,the accelerated blood clearance(ABC)of PEGylated nDDS after repeated injections becomes great challenges for their clinical applications.Zwitterionic polymer,a novel family of antifouling materials,have evolved as an alternative to PEG due to their super-hydrophilicity and biocompatibility.Zwitterionic nDDS could avoid the generation of ABC phenomenon and exhibit longer blood circulation time than the PEGylated analogues.More impressively,zwitterionic nDDS have recently been shown to overcome multiple biological barriers such as nonspecific organ distribution,pressure gradients,impermeable cell membranes and lysosomal degradation without the need of any complex chemical modifications.The realization of overcoming multiple biological barriers by zwitterionic nDDS may simplify the current overly complex design of nDDS,which could facilitate their better clinical translation.Herein,we summarise the recent progress of zwitterionic nDDS at overcoming various biological barriers and analyse their underlyingmechanisms.Finally,prospects and challenges are introduced to guide the rational design of zwitterionic nDDS for disease treatment.