Combinator演算族的π演算语义

以SKI演算作为Combinator演算族的代表,通过形式化的手段给出了SKI演算的π演算语义;通过一个实例验证了所论方法的正确性.所给出的转换方法证明了π演算的表达能力:π演算为图灵完备的.由于高阶函数式语言与Combinator演算族之间存在着自然的转换,所给的转换思想不仅为在π演算的理论框架下研究Combinator演算族提供了基础,也为探讨高阶函数式语言的表示和实现问题提供了新途径.

Combinatorial model of solute transport in porous media

Modeling of solute transport is a key issue in the area of soil physics and hydrogeology. The most common approach (the convection-dispersion equation) considers an average convection flow rate and Fickian-like dispersion. Here,we propose a solute transport model in porous media of continuously expanding scale, according to the combinatorics principle. The model supposed actual porous media as a combinative body of many basic segments. First, we studied the solute transport process in each basic segment body, and then deduced the distribution of pore velocity in each basic segment body by difference approximation, finally assembled the solute transport process of each basic segment body into one of the combinative body. The simulation result coincided with the solute transport process observed in test. The model provides useful insight into the solute transport process of the non-Fickian dispersion in continuously expanding scale.

Bipolar Quantum Logic Gates and Quantum Cellular Combinatorics—A Logical Extension to Quantum Entanglement

Based on bipolar dynamic logic (BDL) and bipolar quantum linear algebra (BQLA) this work introduces bipolar quantum logic gates and quantum cellular combinatorics with a logical interpretation to quantum entanglement. It is shown that: 1) BDL leads to logically definable causality and generic particle-antiparticle bipolar quantum entanglement;2) BQLA makes composite atom-atom bipolar quantum entanglement reachable. Certain logical equivalence is identified between the new interpretation and established ones. A logical reversibility theorem is presented for ubiquitous quantum computing. Physical reversibility is briefly discussed. It is shown that a bipolar matrix can be either a modular generalization of a quantum logic gate matrix or a cellular connectivity matrix. Based on this observation, a scalable graph theory of quantum cellular combinatorics is proposed. It is contended that this work constitutes an equilibrium-based logical extension to Bohr’s particle-wave complementarity principle, Bohm’s wave function and Bell’s theorem. In the meantime, it is suggested that the result may also serve as a resolution, rather than a falsification, to the EPR paradox and, therefore, a equilibrium-based logical unification of local realism and quantum non-locality.

New Operator Identities and Combinatorics Studied by Virtue of IWOP Technique

Using the coherent state representation we derive some new operator identities and study some mathematical relations in comblnatorics. The technique of integral within an ordered product （IWOP） of operators plays an essential role in realizing our goal.

Formal Derivation of the Combinatorics Problems with PAR Method

Partition-and-Recur (PAR) method is a simple and useful formal method. It can be used to design and testify algo-rithmic programs. In this paper, we propose that PAR method is an effective formal method on solving combinatorics problems. Furthermore, we formally derive combinatorics problems by PAR method, which cannot only simplify the process of algorithmic program's designing, but also improve its automatization, standardization and correctness. We develop algorithms for two typical combinatorics problems, the number of string scheme and the number of error per-mutation scheme. Lastly, we obtain accurate C++ programs which are transformed by automatic transforming system of PAR platform.

Mathematical rules for synergistic,additive,and antagonistic effects of multi-drug combinations and their application in research and development of combinatorial drugs and special medical food combinations

Multi-drug(or multi-element)combinations are often prescribed in the practice of clinical medicine and as foods for special medical purposes.The main motivations for these combinations are that most diseases contain multiple related targets and an appropriate combination can maximize benefits while minimizing adverse reactions.As such,it is especially important to derive mathematical models for their quantitative calculation.In this paper,we introduce mathematical rules for the synergistic,additive,and antagonistic effects of multi-drug combinations developed in our laboratory.We have established a“onebelt,one-line”model and provide examples of the quantitative calculation of the synergistic,additive,and antagonistic effects of a combination of multiple components.We also explain how to scientifically and precisely determine the intensity of these synergies,additions and antagonisms,as well as their corresponding dose ranges,thereby laying a solid theoretical foundation for market listing combinatorial drugs and foods for special medical purposes.

Research to Establish a Set of Combinatorial Indicators to Calculate Flood Vulnerability Index in Thach Han-Ben Hai River Basin, Quang Tri Province, Vietnam

In recent times,approaches to flood prevention and mitigation have changed a lot.These changes are to shift the focus from flood control to flood risk management,in which the assessment of vulnerability to floods caused by each sector and field corresponding to each flood magnitude is typical.Current flood vulnerability assessment studies are basically holistic based on factors affected by floods or in aspects:economy,society and ecological environment,and aspects that are mentioned in all areas of social life.The content of the flood vulnerability assessment method usually considers 3 components:E(Exposure),S(Susceptibility),A(Adaptability-Recovery).Each component will contain many different variables belonging to different objects and different natural-economic-social characteristics in each area.Therefore,for each research area,the evaluation method needs to establish an appropriate set of indicators.A set of indicators used to assess flood vulnerability must:be scientific;be practical;simplify the investigation,collection and synthesis of data.This study has established a set of combinatorial indicators including 27 indicators for the T-BRB(Thach Han-Ben Hai River Basin)on the basis of analysis and synthesis from case studies.

Combinatorial Method with Static Analysis for Source Code Security in Web Applications

Security weaknesses in web applications deployed in cloud architectures can seriously affect its data confidentiality and integrity.The construction of the procedure utilized in the static analysis tools of source code security differs and therefore each tool finds a different number of each weakness type for which it is designed.To utilize the possible synergies different static analysis tools may process,this work uses a new method to combine several source codes aiming to investigate how to increase the performance of security weakness detection while reducing the number of false positives.Specifically,five static analysis tools will be combined with the designed method to study their behavior using an updated benchmark for OWASP Top Ten Security Weaknesses(OWASP TTSW).The method selects specific metrics to rank the tools for different criticality levels of web applications considering different weights in the ratios.The findings show that simply including more tools in a combination is not synonymous with better results;it depends on the specific tools included in the combination due to their different designs and techniques.

COMBINATORIAL DESIGN APPROACHES FOR AUTOMATIC TEST GENERATION

The n-way combination testing is a specification-based testing criterion, which requires that for a system consisted of a few parameters, every combination of valid values of arbitrary n(n >_2) parameters be covered by at least one test. This letter proposed two different test generation algorithms based on combinatorial design for the n-way coverage criterion. The automatic test generators are implemented and some valuable empirical results are obtained.

Cocrystal@protein-anchoring nanococktail for combinatorially treating multidrug-resistant cancer

Multidrug resistance(MDR),the major mechanism by which various cancers develop specific resistance to therapeutic agents,has set up enormous obstacles to many forms of tumor chemotherapy.Traditional cocktail therapy administration,based on the combination of multiple drugs for anti-MDR chemotherapy,often suffers from inconsistent in vivo pharmacokinetic behaviors that cannot act synchronously on the lesions,leading to limited pharmacodynamic outcomes.Despite the emergence of nanomedicines,which has improved chemotherapeutic drugs’bioavailability and therapeutic effect on clinical application,these monotherapy-based nano-formulations still show poor progression in overcoming MDR.Herein,a“one stone and three birds”nanococktail integrated by a cocrystal@protein-anchoring strategy was purposed for triple-payload delivery,which paclitaxel-disulfiram cocrystal-like nanorods(NRs)were anchored with the basic protein drug Cytochrome c(Cyt C),followed by hyaluronic-acid modification.In particular,NRs were utilized as carrier-like particles to synchronously deliver biomacromolecule Cyt C into tumor cells and then promote cell apoptosis.Of note,on A549/Taxol drug-resistant tumor-bearing mice,the system with extraordinarily high encapsulation efficiency demonstrated prolonged in vivo circulation and increased tumor-targeting accumulation,significantly reversing tumor drug resistance and improving therapeutic efficacy.Our mechanistic study indicated that the system induced the apoptosis of Taxol-resistant tumor cells through the signal axis P-glycoprotein/Cyt C/caspase 3.Collectively,this nanococktail strategy offers a promising approach to improve the sensitivity of tumor cells to chemotherapeutic drugs and strengthen intractable drug-resistant oncotherapy.

Enhancing tylosin production by combinatorial overexpression of efflux,SAM biosynthesis,and regulatory genes in hyperproducing Streptomyces xinghaiensis strain

Tylosin is a 16-membered macrolide antibiotic widely used in veterinary medicine to control infections caused by Gram-positive pathogens and mycoplasmas.To improve the fermentation titer of tylosin in the hyperproducing Streptomyces xinghaiensis strain TL01,we sequenced its whole genome and identified the biosynthetic gene cluster therein.Overexpression of the tylosin efflux gene tlrC,the cluster-situated S-adenosyl methionine(SAM)synthetase gene metK_(cs),the SAM biosynthetic genes adoK_(cs)-metFcs,or the pathway-specific activator gene tylR enhanced tylosin production by 18%,12%,11%,and 11%in the respective engineered strains TLPH08-2,TLPH09,TLPH10,and TLPH12.Co-overexpression of metK_(cs)and adoK_(cs)-metFcs as two transcripts increased tylosin production by 22%in the resultant strain TLPH11 compared to that in TL01.Furthermore,combinational overexpression of tlrC,metK_(cs),adoK_(cs)-metFcs,and tylR as four transcripts increased tylosin production by 23%(10.93g/L)in the resultant strain TLPH17 compared to that in TL01.However,a negligible additive effect was displayed upon combinational overexpression in TLPH17 as suggested by the limited increment of fermentation titer compared to that in TLPH08-2.Transcription analyses indicated that the expression of tlrC and three SAM biosynthetic genes in TLPH17 was considerably lower than that of TLPH08-2 and TLPH11.Based on this observation,the five genes were rearranged into one or two operons to coordinate their overexpression,yielding two engineered strains TLPH23 and TLPH24,and leading to further enhancement of tylosin production over TLPH17.In particular,the production of TLPH23 reached 11.35 g/L.These findings indicated that the combinatorial strategy is a promising approach for enhancing tylosin production in high-yielding industrial strains.

Circulating proteomic biomarkers for diagnosing sporadic amyotrophic lateral sclerosis:a cross-sectional study

Biomarke rs are required for the early detection,prognosis prediction,and monitoring of amyotrophic lateral sclerosis,a progressive disease.Proteomics is an unbiased and quantitative method that can be used to detect neurochemical signatures to aid in the identification of candidate biomarke rs.In this study,we used a label-free quantitative proteomics approach to screen for substantially differentially regulated proteins in ten patients with sporadic amyotrophic lateral scle rosis compared with five healthy controls.Su bstantial upregulation of serum proteins related to multiple functional clusters was observed in patients with spo radic amyotrophic lateral sclerosis.Potential biomarke rs were selected based on functionality and expression specificity.To validate the proteomics profiles,blood samples from an additional cohort comprising 100 patients with sporadic amyotrophic lateral sclerosis and 100 healthy controls were subjected to enzyme-linked immunosorbent assay.Eight substantially upregulated serum proteins in patients with spora dic amyotrophic lateral sclerosis were selected,of which the cathelicidin-related antimicrobial peptide demonstrated the best discriminative ability between patients with sporadic amyotrophic lateral sclerosis and healthy controls(area under the curve[AUC]=0.713,P<0.0001).To further enhance diagnostic accuracy,a multi-protein combined discriminant algorithm was developed incorporating five proteins(hemoglobin beta,cathelicidin-related antimicrobial peptide,talin-1,zyxin,and translationally-controlled tumor protein).The algo rithm achieved an AUC of 0.811 and a P-value of<0.0001,resulting in 79%sensitivity and 71%specificity for the diagnosis of sporadic amyotrophic lateral scle rosis.Subsequently,the ability of candidate biomarkers to discriminate between early-stage amyotrophic lateral sclerosis patients and controls,as well as patients with different disease severities,was examined.A two-protein panel comprising talin-1 and translationally-controlled tumor protein effectively distinguished early-stage amyotrophic lateral sclerosis patients from controls(AUC=0.766,P<0.0001).Moreove r,the expression of three proteins(FK506 binding protein 1A,cathelicidin-related antimicrobial peptide,and hemoglobin beta-1)was found to increase with disease progression.The proteomic signatures developed in this study may help facilitate early diagnosis and monitor the progression of sporadic amyotrophic lateral sclerosis when used in co mbination with curre nt clinical-based parameters.

Combination treatment of inflammatory bowel disease:Present status and future perspectives

The treatment of patients with inflammatory bowel disease(IBD),especially those with severe or refractory disease,represents an important challenge for the clinical gastroenterologist.It seems to be no exaggeration to say that in these patients,not only the scientific background of the gastroenterologist is tested,but also the abundance of“gifts”that he should possess(insight,intuition,determ-ination,ability to take initiative,etc.)for the successful outcome of the treatment.In daily clinical practice,depending on the severity of the attack,IBD is treated with one or a combination of two or more pharmaceutical agents.These combin-ations include not only the first-line drugs(e.g.,mesalazine,corticosteroids,antibiotics,etc)but also second-and third-line drugs(immunosuppressants and biologic agents).It is a fact that despite the significant therapeutic advances there is still a significant percentage of patients who do not satisfactorily respond to the treatment applied.Therefore,a part of these patients are going to surgery.In recent years,several small-size clinical studies,reviews,and case reports have been published combining not only biological agents with other drugs(e.g.,immunosuppressants or corticosteroids)but also the combination of two biologi-cal agents simultaneously,especially in severe cases.In our opinion,it is at least a strange(and largely unexplained)fact that we often use combinations of drugs in a given patient although studies comparing the simultaneous administration of two or more drugs with monotherapy are very few.As mentioned above,there is a timid tendency in the literature to combine two biological agents in severe cases unresponsive to the applied treatment or patients with severe extraintestinal manifestations.The appropriate dosage,the duration of the administration,the suitable timing for checking the clinical and laboratory outcome,as well as the treatment side-effects,should be the subject of intense clinical research shortly.In this editorial,we attempt to summarize the existing data regarding the already applied combination therapies and to humbly formulate thoughts and suggestions for the future application of the combination treatment of biological agents in a well-defined category of patients.We suggest that the application of biomarkers and artificial intelligence could help in establishing new forms of treatment using the available modern drugs in patients with IBD resistant to treatment.

Dynamic simulation analysis of molten salt reactor-coupled air-steam combined cycle power generation system

A nonlinear dynamic simulation model based on coordinated control of speed and flow rate for the molten salt reactor and combined cycle systems is proposed here to ensure the coordination and stability between the molten salt reactor and power system.This model considers the impact of thermal properties of fluid variation on accuracy and has been validated with Simulink.This study reveals the capability of the control system to compensate for anomalous situations and maintain shaft stability in the event of perturbations occurring in high-temperature molten salt tank outlet parameters.Meanwhile,the control system’s impact on the system’s dynamic characteristics under molten salt disturbance is also analyzed.The results reveal that after the disturbance occurs,the controlled system benefits from the action of the control,and the overshoot and disturbance amplitude are positively correlated,while the system power and frequency eventually return to the initial values.This simulation model provides a basis for utilizing molten salt reactors for power generation and maintaining grid stability.

Back to the drawing board:Overview of the next generation of combination therapy for inflammatory bowel disease

Inflammatory bowel disease(IBD)is entering a potentially new era of combined therapeutics.Triantafillidis et al provide an insightful review of the current state of combination therapy,with a focus on the use of a combined biologic and immunomodulator,as well as emerging data on the future potential of dual-biologic therapy(DBT).While current evidence for DBT is limited,encouraging safety profiles and ongoing trials suggest a brighter future for this approach.The importance of controlled trials should be stressed in establishing new treatment paradigms.Ongoing prospective randomized trials of DBT and perhaps future combinations of biologics and small molecule therapies will hopefully guide the next generation of IBD care.

Mechanical responses of anchoring structure under triaxial cyclic loading

Dynamic load on anchoring structures(AS)within deep roadways can result in cumulative damage and failure.This study develops an experimental device designed to test AS under triaxial loads.The device enables the investigation of the mechanical response,failure mode,instability assessment criteria,and anchorage effect of AS subjected to combined cyclic dynamic-static triaxial stress paths.The results show that the peak bearing strength is positively correlated with the anchoring matrix strength,anchorage length,and edgewise compressive strength.The bearing capacity decreases significantly when the anchorage direction is severely inclined.The free face failure modes are typically transverse cracking,concave fracturing,V-shaped slipping and detachment,and spallation detachment.Besides,when the anchoring matrix strength and the anchorage length decrease while the edgewise compressive strength,loading rate,and anchorage inclination angle increase,the failure intensity rises.Instability is determined by a negative tangent modulus of the displacement-strength curve or the continued deformation increase against the general downward trend.Under cyclic loads,the driving force that breaks the rock mass along the normal vector and the rigidity of the AS are the two factors that determine roadway stability.Finally,a control measure for surrounding rock stability is proposed to reduce the internal driving force via a pressure relief method and improve the rigidity of the AS by full-length anchorage and grouting modification.

PRaG 3.0 therapy for human epidermal growth factor receptor 2-positive metastatic pancreatic ductal adenocarcinoma:A case report

BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly fatal disease with limited effective treatment especially after first-line chemotherapy.The human epidermal growth factor receptor 2(HER-2)immunohistochemistry(IHC)positive is associated with more aggressive clinical behavior and shorter overall survival in PDAC.CASE SUMMARY We present a case of multiple metastatic PDAC with IHC mismatch repair proficient but HER-2 IHC weakly positive at diagnosis that didn’t have tumor regression after first-line nab-paclitaxel plus gemcitabine and PD-1 inhibitor treatment.A novel combination therapy PRaG 3.0 of RC48(HER2-antibody-drug conjugate),radio-therapy,PD-1 inhibitor,granulocyte-macrophage colony-stimulating factor and interleukin-2 was then applied as second-line therapy and the patient had confirmed good partial response with progress-free-survival of 6.5 months and overall survival of 14.2 month.She had not developed any grade 2 or above treatment-related adverse events at any point.Percentage of peripheral CD8^(+) Temra and CD4^(+) Temra were increased during first two activation cycles of PRaG 3.0 treatment containing radiotherapy but deceased to the baseline during the maintenance cycles containing no radiotherapy.CONCLUSION PRaG 3.0 might be a novel strategy for HER2-positive metastatic PDAC patients who failed from previous first-line approach and even PD-1 immunotherapy but needs more data in prospective trials.

Immunotherapy for esophageal cancer:Where are we now and where can we go

Immune checkpoint inhibitor therapy has dramatically improved patient prognosis,and thereby transformed the treatment in various cancer types including esophageal squamous cell carcinoma(ESCC)in the past decade.Monoclonal antibodies that selectively inhibit programmed cell death-1(PD-1)activity has now become standard of care in the treatment of ESCC in metastatic settings,and has a high expectation to provide clinical benefit during perioperative period.Further,anti-cytotoxic T-lymphocyte–associated protein 4(CTLA-4)monoclonal antibody has also been approved in the treatment of recurrent/metastatic ESCC in combination with anti-PD-1 antibody.Well understanding of the existing evidence of immune-based treatments for ESCC,as well as recent clinical trials on various combinations with chemotherapy for different clinical settings including neoadjuvant,adjuvant,and metastatic diseases,may provide future prospects of ESCC treatment for better patient outcomes.

Grain Yield,Biomass Accumulation,and Leaf Photosynthetic Characteristics of Rice under Combined Salinity-Drought Stress

Simultaneous stresses of salinity and drought often coincide during rice-growing seasons in saline lands,primarily due to insufficient water resources and inadequate irrigation facilities.Consequently,combined salinity-drought stress poses a major threat to rice production.In this study,two salinity levels(NS,non-salinity;HS,high salinity)along with three drought treatments(CC,control condition;DJ,drought stress imposed at jointing;DH,drought stress imposed at heading)were performed to investigate their combined influences on leaf photosynthetic characteristics,biomass accumulation,and rice yield formation.Salinity,drought,and their combination led to a shortened growth period from heading to maturity,resulting in a reduced overall growth duration.Grain yield was reduced under both salinity and drought stress,with a more substantial reduction under the combined salinity-drought stress.The combined stress imposed at heading caused greater yield losses in rice compared with the stress imposed at jointing.Additionally,the combined salinity-drought stress induced greater decreases in shoot biomass accumulation from heading to maturity,as well as in shoot biomass and nonstructural carbohydrate(NSC)content in the stem at heading and maturity.However,it increased the harvest index and NSC remobilization reserve.Salinity and drought reduced the leaf area index and SPAD value of flag leaves and weakened the leaf photosynthetic characteristics as indicated by lower photosynthetic rates,transpiration rates,and stomatal conductance.These reductions were more pronounced under the combined stress.Salinity,drought,and especially their combination,decreased the activities of ascorbate peroxidase,catalase,and superoxide dismutase,while increasing the contents of malondialdehyde,hydrogen peroxide,and superoxide radical.Our results indicated a more significant yield loss in rice when subjected to combined salinity-drought stress.The individual and combined stresses of salinity and drought diminished antioxidant enzyme activities,inhibited leaf photosynthetic functions,accelerated leaf senescence,and subsequently lowered assimilate accumulation and grain yield.

Erlotinib combination with a mitochondria-targeted ubiquinone effectively suppresses pancreatic cancer cell survival

BACKGROUND Pancreatic cancer is a leading cause of cancer-related deaths.Increased activity of the epidermal growth factor receptor(EGFR)is often observed in pancreatic cancer,and the small molecule EGFR inhibitor erlotinib has been approved for pancreatic cancer therapy by the food and drug administration.Nevertheless,erlotinib alone is ineffective and should be combined with other drugs to improve therapeutic outcomes.We previously showed that certain receptor tyrosine kinase inhibitors can increase mitochondrial membrane potential(Δψm),facilitate tumor cell uptake ofΔψm-sensitive agents,disrupt mitochondrial homeostasis,and subsequently trigger tumor cell death.Erlotinib has not been tested for this effect.AIM To determine whether erlotinib can elevateΔψm and increase tumor cell uptake ofΔψm-sensitive agents,subsequently triggering tumor cell death.METHODSΔψm-sensitive fluorescent dye was used to determine how erlotinib affectsΔψm in pancreatic adenocarcinoma(PDAC)cell lines.The viability of conventional and patient-derived primary PDAC cell lines in 2D-and 3D cultures was measured after treating cells sequentially with erlotinib and mitochondria-targeted ubiquinone(MitoQ),aΔψm-sensitive MitoQ.The synergy between erlotinib and MitoQ was then analyzed using SynergyFinder 2.0.The preclinical efficacy of the twodrug combination was determined using immune-compromised nude mice bearing PDAC cell line xenografts.RESULTS Erlotinib elevatedΔψm in PDAC cells,facilitating tumor cell uptake and mitochondrial enrichment ofΔψm-sensitive agents.MitoQ triggered caspase-dependent apoptosis in PDAC cells in culture if used at high doses,while erlotinib pretreatment potentiated low doses of MitoQ.SynergyFinder suggested that these drugs synergistically induced tumor cell lethality.Consistent with in vitro data,erlotinib and MitoQ combination suppressed human PDAC cell line xenografts in mice more effectively than single treatments of each agent.CONCLUSION Our findings suggest that a combination of erlotinib and MitoQ has the potential to suppress pancreatic tumor cell viability effectively.