Current limitations in the understanding and control of antimicrobial resistance (AMR) in Canada are described through a comprehensive review focusing on: (1) treatment optimization; (2) surveillance of antimicrobial use and AMR; and (3) prevention of transmission of AMR. Without addressing gaps in identified areas, sustained progress in AMR mitigation is unlikely. Expert opinions and perspectives contributed to prioritizing identified gaps. Using Canada as an example, this review emphasizes the importance and necessity of a One Health approach for understanding and mitigating AMR. Specifically, antimicrobial use in human, animal, crop, and environmental sectors cannot be regarded as independent; therefore, a One Health approach is needed in AMR research and understanding, current surveillance efforts, and policy. Discussions regarding addressing described knowledge gaps are separated into four categories: (1) further research; (2) increased capacity/resources; (3) increased prescriber/end-user knowledge; and (4) policy development/enforcement. This review highlights the research and increased capacity and resources to generate new knowledge and implement recommendations needed to address all identified gaps, including economic, social, and environmental considerations. More prescriber/end-user knowledge and policy development/enforcement are needed, but must be informed by realistic recommendations, with input from all relevant stakeholders. For most knowledge gaps, important next steps are uncertain. In conclusion, identified knowledge gaps underlined the need for AMR policy decisions to be considered in a One Health framework, while highlighting critical needs to achieve realistic and meaningful progress. Since antimicrobial use (AMU) became widespread in healthcare, antimicrobial resistance (AMR) is increasing worldwide –3. AntimDue to a limited variety of efficacious antimicrobials, the same products or those within the same class are used in humans, animals,  agricultThe extent of selection of resistant bacteria often reflects the degree of AMU, the type of antimicrobials used, and the effectiveness of infection prevention and control . The COVCurrent and projected AMR impacts require immediate and sustained action across human, animal, and environmental sectors using a true One Health approach, with multiple sectors communicating and collaborating to improve health outcomes while designing and implementing research, initiatives, policies, and legislation , 20. Liv- decreases in social trust, social capital, quality of life, and equality among socio-demographic groups;- weakened social connectivity;- discrimination against those deemed at risk for or with AMR infections;- unequal impacts of AMR, with higher risk for marginalized groups who experience poverty, homelessness, substance use disorder, overcrowding/poor housing/poor sanitation, and First Nations/Inuit/Metis populations); and- a Canadian society that may become less open and trusting .There is substantial support regarding intricate connectivity of AMR in human, animal, and environmental sectors , 23–25, A One Health framework was used to identify three review areas to describe current knowledge gaps in Canada that need to be addressed before realistic, practice-oriented AMR mitigation strategies can be developed and implemented. These areas include: (1) treatment optimization; (2) surveillance of AMU and AMR; and (3) prevention of transmission of AMR. Herein, we have reviewed scientific literature and reports to identify the most pressing gaps in knowledge that currently hamper AMR prevention and control programs ; and- patient compliance.Development of AMS best practices does not ensure their uptake by various stakeholders, for societal, cultural  and econTo increase social science inclusion in AMR research and policy, focus groups with physicians, veterinarians, agricultural crop managers, livestock producers, and other relevant stakeholders should be utilized to identify factors hampering behavioral change and then to develop AMS interventions that ensure uptake. Integration with social science domains could identify considerations essential to each sector for support of AMU reduction strategies, in addition to described economic considerations. Close collaboration with social scientists is needed to successfully implement AMS programs.Stewardship efforts can be supported by further development and availability of rapid diagnostic technology, to decrease empirical prescribing and increase appropriate antimicrobial treatment response times . An impeA key factor in reducing AMU is reducing disease prevalence/burden. Non-antimicrobial alternatives for infection prevention, e.g., vaccines and alternative therapies  are being explored to prevent or treat infections . These aStreptococcus pneumoniae infections increased by 26% from 2013 to 2017  and only 10.2% used in hospitals . In CanaMost unnecessary AMU in humans is not related to gaps in prescriber knowledge, but instead to other factors at the provider and/or patient-level, interplaying with various contextual factors . FurtherThere is limited public knowledge regarding the harms of inappropriate AMU and AMR implications . ReceiviExtensive AMU for treatment and prevention of infectious diseases in livestock has supported development of current animal production systems . In 2016As of December 1, 2018, all “medically important antimicrobials”  for veteThere are opportunities for further AMU reduction in Canadian livestock. For example, the majority of AMU on Canadian dairy farms is for mastitis treatment and prevention , 57. BlaThis example highlights the importance of context when evaluating AMS initiatives. Research is required to develop best management practices to reduce livestock-associated AMU but maintain animal health and production . In addiStaphylococcus pseudintermedius (MRSP), causes common and sometimes untreatable skin and surgical site infections in dogs  and foodborne pathogens   . Additiola spp.) . There ir humans , 87. Ther humans , 89.Direct impacts of human or animal AMU or antimicrobial residues in the environment and impact of AMR in the environment and subsequent impacts on humans and animals are not well-characterized . It is dAMU is a major risk factor for development of AMR bacteria and their environmental presence. Although broad exposure may occur via pathways such as drinking water, there are limited data to quantify direct human health effects from environmental AMR, another major knowledge gap  18, 91), 9118, 9Surveillance is essential to demonstrate trends and monitor emerging and re-emerging AMR pathogens and AMU across all health sectors and provide data to support stewardship to address AMR . SurveilSurveillance for AMU/AMR in Canada has increased, but not all sectors or species affected by AMR are in a holistic system, which remains a compilation of multiple programs . There a- Canadian Antimicrobial Resistance Surveillance System (CARSS): Incorporates epidemiological and laboratory AMR/AMU data from the Public Health Agency of Canada's surveillance systems (listed immediately below), from human, production animal, and food sources.- Canadian Integrated Program for Antimicrobial Resistance Surveillance (CIPARS): Monitors trends in AMR/AMU for select bacteria mainly from humans, animals, and the food supply chain.- Canadian Nosocomial Infection Surveillance Program (CNISP): Collects information on AMR/AMU for nosocomial infections in hospitalized human patients.- Canadian Tuberculosis Laboratory Surveillance System: All tuberculosis cases diagnosed in Canada are reported (with/without treatment started) for: citizens, permanent residents, refugees, refugee claimants, and protected people. For temporary residents, only cases where treatment was started in Canada are reported.- The Gonococcal Antimicrobial Surveillance Program (GASP-Canada): Laboratory surveillance data for Neisseria gonorrhoeae isolated by provincial microbiology laboratories to the National Microbiology Laboratory (NML).- Pest Management Regulatory Agency : Provides AMU data for crop production to CIPARS.S. pneumoniae and Streptococcus pyogenes surveillance, with some provinces only submitting a subset of isolates.- The National Laboratory Surveillance of Invasive Streptococcal Disease (eSTREP): Passive and voluntary collaboration with provincial public health laboratories for Regrettably, these systems do not encompass the full scope of Canadian AMR and AMU. Data on environmental AMR are typically outside their mandates and therefore missing, and information is frequently not linked across systems . CIPARS Without full integration and comparability of collected data, understanding is limited regarding local drivers of AMR and ensuing impacts. For example, CIPARS represents a national surveillance system with a One Health approach but consists only of active AMR surveillance for select bacteria in chickens, turkeys, pigs, dairy and recently, feedlot cattle, and passive reporting in humans and other animal species  51). Fu. Fu51). Up-to-date AMR prevalence estimates for other species/sectors, e.g., prevalence in the general human population, on-farm data for multiple livestock species, and wildlife are lacking. This represents an urgent knowledge gap ; withoutAccording to the Council of Canadian Academies, weaknesses in current Canadian AMR/AMU surveillance include limited data on: (1) infections of priority pathogens in community settings ; (2) AMU in many regions of Canada; (3) AMR in pathogens of domestic animals and wildlife; (4) lack of an established federal/provincial/territorial surveillance system; and (5) lack of access to collected data . FurtherTo fully utilize and integrate data generated by CARSS and other programs and agencies globally, international standards for AMR and AMU data collection and reporting among human health, veterinary, and agricultural sectors are required, but absent , 94. WitHuman health care is primarily provincially funded and regulated in Canada, whereas veterinary and environmental sectors have substantial federal and provincial/territorial components, requiring cooperation/collaboration among governments and engagement of all sectors and relevant stakeholders. In summary, due to the interconnectedness of AMR development, Canada could benefit from integration and standardization of human, animal, and environmental AMU/AMR data collection. This requires coordination of existing surveillance systems and addition of broader environmental considerations to capture local drivers of AMR.Treatment optimization and AMS are important in preventing AMR transmission, as they reduce the overall burden of resistance on the microbiome, limiting risk of transmission. AMS efforts in human hospitals have improved AMU quality , and theAntimicrobials are important to treat, prevent, and control infectious diseases and maintain animal health and welfare in intensive livestock production , 49. By Additionally, infection prevention and control procedures are invaluable to prevent transmission of AMR bacteria. Improved adjacent infection control efforts could further limit AMU. While this refers to sterility and hygienic practices for humans and animals , it alsoEvery infection prevented is one that needs no treatment.”“World Health Organization, 2015Despite new knowledge regarding the role of the environment in preventing AMR, much remains unknown; however, the environment is likely an important reservoir of resistance genes –29, 85. As much of the world's population, including Canadians , obtain Without considering all drivers and pathways of AMR introduction into the environment, any strategy to reduce resistance across all sectors risks failure . To mitiThere are numerous knowledge gaps in understanding AMR in Canada. AMR is complex, with many contributing factors, numerous antimicrobial end users, countless microbial interactions, and varying policies and regulatory capacities around the world. Substantial progress will require much investment in AMR research, surveillance, and capacity building, coupled with effective policies at national, provincial/territorial and local levels.Various knowledge gap assessments , 109 andResearch and increased capacity/resources are required to fully address all knowledge gaps. Required research is similar across the human, animal, and environmental sectors  and willIncreased capacity/resources should accompany further research, as increased funding, research activity design/development, laboratory capacity, data analysis and publishing/knowledge transfer are required for research to be effective and to inform decisions in policy and influence end-user decision-making. However, capacity and financial support for required research may be inadequate. For example, Canada's research and development support for new antimicrobials is severely lacking . TherefoAn emphasis on “further research” and “increased capacity/resources” does not imply that other requirements are less important. Rather, it highlights a lack of required knowledge and understanding to develop effective policy/recommendations. The lack of best management practices for AMU and AMS programs, serve as an example.Salmonella isolates from sick people, and Salmonella and E. coli isolates from chickens at slaughter and retail meat had lower 3rd generation cephalosporin resistance . Although, in general, AMR understanding and mitigation attempts should follow the following roadmap: (1) detailed understanding of missing data required to inform realistic policies and best management practices, (2) implementation and ongoing evaluation of policies and recommendations at the community, provincial/territorial, and national levels, (3) sustainable implementation with ongoing evaluation to account for new innovations and AMU/AMR surveillance findings . AdditioPrudent AMU can still allow development of AMR; however, rigorous management can limit the risks . The vicThis manuscript has been prepared by KDMcC, with supervision from HB and RMA. EdJ, JI, DN, JK, JC, MG, TM, KO, IL, LJ, GP, H-JW, KMcC, ML, JR, LH, AH, NA, SC, GT, AB, ER-M, EG, and SO contributed significantly to the intellectual content related to their respective fields. All authors contributed to manuscript revision, as well as read, and approved the submitted version.This research was part of the Antimicrobial Resistance–One Health Consortium, which is predominantly financed by the Ministry of Jobs, Economy and Innovation, Alberta, Canada. KDMcC was supported by Canadian Dairy Commission Workplace Development Initiative Scholarship, NSERC CREATE in Milk Quality Program Scholarship and the NSERC Alexander Graham Bell Canada Graduate Scholarship.Staphylococcus aureus and Alberta Innovates Health Solutions on use of probiotics as primary prophylaxis for Clostridium difficile colitis. JC has also received financial support from Pfizer for the STRIVE S. aureus vaccine randomized clinical trial in vertebral spinal surgery with instrumentation and CIHR for creation of an AMS app to improve antimicrobial prescribing. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.JC has received peer-reviewed research grants from the Canadian Institutes for Health Research (CIHR) on development of a rapid assay for detection of methicillin-resistant All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The effects of oxidative aging on the static and dynamic properties of nitrile rubber at the molecular scale were investigated by molecular dynamics simulation. The aged nitrile rubber models were constructed by introducing hydroxyl groups and carbonyl groups into rubber molecular chains to mimic oxidative aging. The static and dynamic properties of the unaged and aged nitrile rubber under different conditions were evaluated by mean square displacement, self-diffusion coefficients, hydrogen bond, fractional free volume, radial distribution function, cohesive energy density and solubility parameter. The results show that the elevated temperature intensified significantly the mobility of rubber molecular chains and fractional free volume, while the compressive strain displayed the opposite effect resulting in packing and rearrangement of rubber chains. The introduction of hydroxyl groups and carbonyl groups enhanced the polarity, intermolecular interactions, the volume and rigidity of molecular chains, implying weaker mobility of molecular chains as compared to unaged models. The compressive strain and oxidative aging both decreased the fractional free volume, which inhibited gaseous and liquid diffusion into the rubber materials, and slowed down the oxidative aging rate. This study provides insights to better understand the effect of molecular changes due to oxidative aging on the structural and dynamic properties of rubber materials at the molecular level. Nitrile rubber (NBR) has been widely used as seals in sealing structures of hydraulic systems , due to The degradation mechanism of NBR under high temperature, chemical medium, radiation and stress has been widely studied for decades ,12,13,14In recent years, molecular dynamics (MD) simulation has been employed as an effective theoretical tool to comprehend quantitatively the structure–performance relationships of polymer materials at the molecular scale, especially in modification of polymers and diffusion of small molecules in polymers ,29. AlthIn our previous studies, degradation behavior and the mechanism of rubber seals under actual service conditions such as elevated temperature, hydraulic oil and compressive strain were systematically investigated by accelerated tests ,34. It wTo study the effects of oxidative aging on nitrile rubber properties at the molecular level, unaged and aged nitrile rubber models were constructed by using the Forcite and Amorphous cell modules of Materials Studio 8.0 softwares, respectively. The COMPASS  force field was used for describing molecule interactions and intermolecular potential. The COMPASS force field is widely suitable for most common organics, small inorganic molecules and polymers, and can accurately predict the structural and thermophysical condensed phase properties of the related materials under a wide range of temperature and pressure conditions. The electrostatic and van der Waals forces were calculated by using the atom-based summation method. The Maxwell−Boltzmann profiles were used to set the initial velocities. Firstly, the repeating units of butadiene and acrylonitrile were constructed, respectively, shown in Nchain, the total number of atoms, Natom, and cell lengths, for the constructed models are given in Previous studies indicated that the oxidation of rubber chains was mainly responsible for the performance degradation, accompanied by the formation of oxygen-containing functional groups ,35,36,37In our previous publications ,35, the −5 Kcal mol−1 Å−1 was reached. Then, the cells were annealed at 0.1 MPa from 600 K to 300 k for 200 ps (picosecond). After that, 200 ps of NPT  simulation was conducted at 300 K and 2 GPa, 1 GPa, 0.5 GPa to further relax the rubber chains, respectively. Then, 500 ps of NVT  simulation was carried out at 300 K. Subsequently, 500 ps of NPT simulation was conducted at 300 K and 101 KPa to obtain the stable structure. The simulated densities of the unaged NBR models were obtained and are given in 3), which proved the reliability of models [For the unaged and aged NBR models, the smart minimizer algorithm was applied to minimize the amorphous cells at 298.15 K for 1,000,000 steps, until a convergence value of 1.0 × 10f models . The temf models  and Beref models , respectf models . Then, tTo find out the effects of temperature, compression deformation and oxidative aging on the mobility of nitrile rubber molecule chains, the MSDs of rubber molecule chains in unaged and aged NBR models under different conditions were calculated, as shown in N is the number of molecules, D is the diffusion coefficient of rubber molecule chains, t0, t0 + t, andTo further analyze the influence of hydroxyl groups and carbonyl groups on motion ability of rubber chains, the MSD was used to estimate self-diffusion coefficients by using the Einstein equation ,39,43,44Due to the addition of hydroxyl groups and carbonyl groups to the molecular chains, the energy and volume space required for the movement of the molecular chains is greater than that of the unaged rubber molecular chains, leading to the decrease in mobility. The decrease in MSD and self-diffusion coefficient of rubber molecular chains caused by oxidation aging were mainly due to the increase in volume and rigidity of rubber molecular chains.Furthermore, the MSDs and self-diffusion coefficients of rubber molecular chains under the compression state displayed lower value compared to those in the uncompressed state. However, the MSDs of the compressed rubber molecular chains showed no obvious changes at low and high temperature, implying that the application of compressive strain resulted in the packing and rearrangement of molecular chains, and significantly limited the mobility of rubber molecular chains.During the oxidative aging process, the oxidation functional groups that have strong polarity were formed in the rubber molecular chains. In this study, the hydroxyl groups and carbonyl groups were introduced in the rubber molecular chain to represent the oxidative aging of rubber molecular chain. The introduction of the polar groups contributed to the formation of strong polar interaction including non-bonded interaction and hydrogen bonds among the oxidized rubber chains, which affected the chain dynamics and structure properties of the rubber . Therefo(A) or O–H...N ((B) or O–H...O ((C) or O–H...O ((A) in the uncompressed OH-NBR model and OH-CO-NBR model decreased with increasing temperature, but presented the opposite trend in the compressed state. Additionally, the number of H-bonds (B) in the OH-NBR model and OH-CO-NBR model displayed no obvious changes with temperature. The H-bond (C) only existed in OH-CO-NBR model. Moreover, the number of H-bonds (C) in the uncompressed OH-CO-NBR model showed a slight increase with temperature. These phenomena illustrate that the elevated temperature destroyed the H-bond (A) and H-bond (B) in the uncompressed state. This is mainly because the elevated temperature promoted the mobility of molecular chains and increased the chain space, until the intermolecular distance could no longer meet the conditions to form the hydrogen bond. However, the high temperature promoted the formation of the H-bond (A) under the compression state due to the sufficient energy supplied by elevated temperature. However, at 298.15 K, the number of H-bonds (A) in the compressed state was less than that in the uncompressed state. The results demonstrate that compressive strain destroyed the hydrogen bonds and limited the formation of new hydrogen bond, due to the lower mobility of rubber molecular chains under the coupled effect of lower temperature and compressive strain, which was explained by the results of the MSD and self-diffusion coefficient of rubber molecular chains. However, at 383.15 K, the changes in the number of H-bonds (A) showed an adverse trend, implying that the coupled influence of compressive strain and elevated temperature facilitates the formation of H-bond (A). Nevertheless, the results of the MSD and self-diffusion coefficient of rubber molecular chains at 383.15 K in the compressed state displayed a lower mobility of rubber molecular chains. Thus, the increase in the number of H-bonds (A) was attributed to the fast motion of local segments and side groups caused by the high temperature. The formation of H-bonds strengthened the interaction force between molecular chains, and further restricted the movement of rubber molecular chains. O–H...N a, was fo O–H...O b, was fo O–H...O c, was foV0 = 1.3 Vw, Vw is the van der Waals’s volume, and vs. is the specific volume.Fractional free volume (FFV) can be defined as the fraction of the volume not occupied by the polymer, which is often used to estimate the available space for free movement of rubber chain and the efficiency of rubber chain packing. The FFV can be calculated by the following equation:OH-NBR > FFVCO-NBR > FFVOH-CO-NBR.The volume of rubber models is mainly composed of the volume of the rubber chain and the free volume caused by thermal movement of rubber chain. With increase of temperature, the conformational entropy increased and chain segments motioned significantly, leading to an increase of FFV . Additior is the distance, ijr is the coordinate of the atom; AN and BN are the numbers of atom A and B; Bρ is the average density of the atom B at a given distance r as a center of atom A.The radial distribution function (RDF) is defined as the probability of finding another atom at a distance from a specific atom, which can be used to estimate the interactions between the components and static properties of a rubber model. The RDF can be calculated by the following equation :(4)g(r)=As defined by Hildebrand and Scott , cohesivThe MSD and RDF results show that elevated temperature promoted significantly the mobility of rubber chains, while the compressive strain displayed the opposite effect. The introduction of hydroxyl groups and carbonyl groups weakened the mobility of rubber molecular chains due to increases in polarity, intermolecular force, volume and rigidity of rubber chains.(A) or O–H...N. The increase in cohesive energy density of the aged NBR models also reflected the formation of interaction forces.Hydrogen bonding analysis results demonstrate that the interaction forces including the strong polar interaction and hydrogen bond among chains were intensified due to the introduction of hydroxyl groups and carbonyl groups. In the uncompressed state, high temperature destroyed the formation of H-bonds The fractional free volume results indicate that the fractional free volume increased with increasing temperature, whereas the compressive strain and the introduction of oxidation functional groups decreased the fractional free volume.Aged NBR models were constructed by the introduction of hydroxyl groups and carbonyl groups in rubber molecular chains to investigate the influence of oxidative aging on the static and dynamic characteristics of nitrile rubber using MD simulation. The following conclusions can be drawn:


Orchidaceae is mainly concentrated in the subfamily Epidendroideae, and the self-incompatibility phenotypes are diverse, even in the same genus, and hormones (auxin and ethylene), and new male and female determinants might be involved in SI response. This work provides a good foundation for future studies of the evolution and molecular mechanisms of self-incompatibility. We review recent research progress on self-incompatibility in orchids at the morphological, physiological, and molecular levels, provide a general overview of self-incompatibility in orchids, and propose future research directions.Self-incompatibility affects not only the formation of seeds, but also the evolution of species diversity. A robust understanding of the molecular mechanisms of self-incompatibility is essential for breeding efforts, as well as conservation biology research. In recent years, phenotypic and multiple omics studies have revealed that self-incompatibility in  Self-incompatibility (SI) refers to the inability of hermaphroditic angiosperms to self-pollinate, which promotes outcrossing or hybridization . Self-poS-loci with a variety of S-haplotypes. The specific interactions between both male and female specificity determinants (S-determinants), which are tightly linked at the SI loci, induce SI responses. The key determinants and molecular mechanisms of SI in dicotyledons are well studied. Most studies have focused on Brassicaceae (SRK-based SSI systems), Solanaceae, Rosaceae, Plantaginaceae (S-RNase-based GSI systems), and Papaveraceae (S-glycoprotein-based GSI systems) [Generally, SI is divided into two categories based on genetic characteristics: gametophytic self-incompatibility (GSI) and sporophytic self-incompatibility (SSI). SI is controlled by a single or multiple systems) ,7,8,9,10systems) . By contsystems) ,11.Orchidaceae, the largest monocotyledons family [SI has been reported in more than 100 families and 39% of angiosperm species , there as family ,15, indiDendrobium) [Pleurothallidinae [Oncidiinae [Malaxidinae [Laeliinae [Aeridinae [Angraecinae [Neottieae  [Epidendroideae  , Pleurotllidinae , Oncidiicidiinae ,20, Malaaxidinae ,22,23, Laeliinae ,24, Aerieridinae , Angraecraecinae , and Neoipactis) , which adroideae . Here, wDendrobium. Dendrobium is the second largest genus in Orchidaceae (second only to Bulophyllum) [Studies of the SI of the subtribe have focused on phyllum) , with apphyllum) .Dendrobium [D. fameri (SI) suggested that it was consistent with the GSI phenotype given that the pollen tubes enter the style  in oRestrepia, belonging to clade B [Pleurothallidinae, revealed that 45% of the species are self-incompatible, and seed abortion is lower for cross-pollinated plants (both intraspecific and interspecific cross-pollination) than for self-pollinated plants. Pollen tubes fill the entire ovary after three weeks of cross-pollination, but the number of self-pollinated pollen tubes decreases significantly and stops growing in the upper third of the ovary, as is the case in the R.brachypus  concentration data in D. chrysanthum revealed that there are some genes whose expression patterns are closely related to SI responses, such as genes encoding E3 ubiquitin-protein ligase, RING finger and CHY zinc finger domain-containing protein, NAC domain-containing protein, key enzymes in auxin and ethylene biosynthesis pathways, Ca2+-transporting ATPase, and the rapid alkalinization factors (RALF) [RALF genes and CrRLK1L genes [Studies show that there are diverse SI phenotypes in orchids, even within the same genus, suggesting the high diversity and complex nature of the molecular mechanisms of SI that may exist in orchids. Since  species , includi orchids ,49. The s (RALF) . Meanwhis (RALF) . Then, b1L genes , which iDendrobium, there is more than one SI phenotypes, which is rarely reported in other angiosperm families in which SI molecular mechanisms are known. Furthermore, as one of the most diverse groups of angiosperms, SI is most common in the subfamily Epidendroideae of Orchidaceae, including Dendrobium, Oncidiinae, and Pleurothaldinae, which are groups containing large numbers of species, suggesting SI might be one of the main factors for promoting orchid species diversity. Physiological studies have suggested that auxin-induced ethylene production leads to premature flower abscission, which might be involved in the SI response. The molecular mechanisms of SI in orchids are complex and diverse and might differ from molecular mechanisms known in other angiosperm families. All these research levels are shown in Several morphological, physiological, and molecular features of SI in orchids have been studied. There are several pollen tube growth phenotypes in orchids, including the failure of pollinia to germinate, the cessation of pollen tube growth in the style, and the cessation of pollen tube growth in the ovary. Even within the same genus, such as in Orchidaceae is in an incipient stage. Several types of studies are needed to reveal the molecular mechanisms and the evolutionary process of SI in Orchidaceae. First, artificial pollination studies need to be conducted to facilitate the identification of phenotypes and haplotypes of SI in more orchids, especially by observing self- and cross-pollen tube germination and growth. Such work would enhance our understanding of the SI phenotype of orchids, and aid research examining the molecular mechanisms of SI. Second, SI-related loci and SI candidate genes need to be identified through genomic data analyses, such as genome and transcriptome sequencing, coupled with functional verification experiments; such work would not only enhance our understanding of the complex molecular mechanisms of SI in orchids but also aid hybrid breeding through the identification of advantagous haplotypes with high quality, especially for orchids with high market value, such as Dendrobium and Phalaenopsis. Third, transformation of corn poppy SI genes into Arabidopsis thaliana [The study of SI in thaliana ,51 has bthaliana  suggestiOrchidaceae plants is widely known, and SI is common in large groups of orchids, such as, Dendrobium, and Pleurothallidinae. Therefore, the relationships among SI type, species number, flower morphology, and pollination strategy in the Orchidaceae phylogeny require clarification, as all of these characteristics contribute to the formation and maintenance of orchid species diversity. Most wild orchids are listed as endangered species, and all wild orchid species are included in the CITES  appendix, which accounts for more than 90% of the plants protected by the Convention [In addition, the pollination strategy of nvention . Studies


Binge eating, a core diagnostic symptom in binge eating disorder and bulimia nervosa, increases the risk of multiple physiological and psychiatric disorders. The neurotransmitter dopamine is involved in food craving, decision making, executive functioning, and impulsivity personality trait; all of which contribute to the development and maintenance of binge eating. The objective of this paper is to review the associations of dopamine levels/activities, dopamine regulator  levels/activities, and dopamine receptor availability/affinity with binge eating.A literature search was conducted in PubMed and PsycINFO to obtain human and animal studies published since 2010.A total of 31 studies  were included. Among the human studies, there were 12 case–control studies, eight randomized controlled trials, and five cross-sectional studies. Studies used neuroimaging , genetic, and pharmacological  techniques to describe or compare dopamine levels/activities, dopamine transporter levels/activities, dopamine degrading enzyme  levels/activities, and dopamine receptor  availability/affinity among participants with and without binge eating. Most human and animal studies supported an altered dopaminergic state in binge eating ; however, results were divergent regarding whether the altered state was hyperdopaminergic  or hypodopaminergic . The mixed findings may be partially explained by the variability in sample characteristics, study design, diagnosis criteria, and neuroimaging/genetic/pharmacological techniques used. However, it is possible that instead of being mutually exclusive, the hyperdopaminergic and hypodopaminergic state may co-exist, but in different stages of binge eating or in different individual genotypes.For future studies to clarify the inconsistent findings, a homogenous sample that controls for confounders that may influence dopamine levels  is preferable. Longitudinal studies are needed to evaluate whether the hyper- and hypo-dopaminergic states co-exist in different stages of binge eating or co-exist in individual phenotypes.Binge eating is characterized by eating a large amount of food in a short time and a feeling of difficulty to stop while eating. Binge eating is the defining symptom of binge eating disorder and bulimia nervosa, both of which are associated with serious health consequences. Studies have identified several psychological risk factors of binge eating, including a strong desire for food, impaired cognitive skills, and distinct personality traits . However, the physiological markers of binge eating remain unclear. Dopamine is a neurotransmitter that is heavily involved in feeding behavior, human motivation, cognitive ability, and personality. Therefore, dopamine is believed to play a critical role in binge eating. This review synthesized study findings related to the levels and activities of dopamine, dopamine regulators, and dopamine receptors in the context of binge eating. The primary finding is that most studies that used neuroimaging, genetic, or drug techniques found an altered dopaminergic state related to binge eating. However, the literature is inconsistent concerning the direction of the alteration. Considering the mixed findings and the limitations in study design, future studies, especially those that include repeated measurements, are needed to clarify the role of dopamine in binge eating. Binge eating, a core diagnostic symptom in binge eating disorder (BED) and bulimia nervosa (BN), is characterized by eating a large amount of food in a short time and a sense of loss of control while eating . Binge eEnhanced food craving, impaired decision making, diminished executive function, and impulsivity personality traits are among the main risk factors that drive or perpetuate binge eating. Food craving is an intense desire or motivation to consume food, and it has been consistently associated with more frequent or more severe binge eating behaviors in cross-sectional and prospective studies , 9. DeciFood craving, decision making, executive function, and impulsivity are regulated by distinguishable, although somewhat overlapping, brain regions and neurocircuitry. For example, a large brain network including the ventral tegmental area, ventral striatum (nucleus accumbens), lateral hypothalamus, orbitofrontal cortex, and amygdala is involved in the excursion of food craving. In contrast, the dorsal striatum, which can be further divided into dorsomedial striatum (caudate) and dorsolateral striatum (putamen), is essential for orchestrating goal-directed and habitual decision making , 18. FurThe neurotransmitter dopamine has attracted growing attention in the field of binge eating due to its widely distributed receptors in the brain regions and neurocircuitry implicated in food craving, decision making, executive function, and impulsivity, as well as its functional associations with these risk factors.Dopamine is synthesized and released by dopamine neurons located in three main areas in the midbrain: the ventral tegmental area, the substantia nigra, and the retrorubral field . DopaminAfter being synthesized in the dopamine neurons and released into the synapse cleft, dopamine functions through binding to its receptors, generally distinct in two main subclasses: D1-like (D1 and D5 receptors) and D2-like  . D1 and The termination of dopamine function largely relies on dopamine clearance by the dopamine transporter, which drives the reuptake of extracellular dopamine into presynaptic neurons and consequently decreases the synaptic dopamine levels. Additionally, dopamine is degraded by enzymes such as monoamine oxidase and catechol-O-methyltransferase (COMT). COMT is most abundant in the prefrontal cortex and accounts for over 60% of the metabolic degradation of released dopamine in the prefrontal cortex . While aThe role of dopamine in binge eating has been previously reviewed; however, these reviews were predominantly published between 2010 and 2015 –45. ImpoDuring the past decade, there have been increasing efforts to delineate the role of dopamine in binge eating both in humans and animals. Therefore, the goal of this review is to provide an updated assessment of the literature on binge eating and dopamine, including dopamine levels , dopamine activities, dopamine regulator  levels/activities, and dopamine receptor availability/affinity, in both humans and animals.Animal studies were included if (1) they examined binge eating in relation to dopamine levels/activities, dopamine regulator levels/activities, or dopamine receptor availability/affinity, and (2) the binge eating was induced by one of the three standard paradigms: food restriction , food restriction and stress (periods of food restriction followed by stress exposure), and intermittent access .Human studies were included in this review if they (1) compared dopamine levels/activities, dopamine regulator levels/activities, or dopamine receptor availability/affinity between adults with binge eating, BED, or BN and healthy controls; or (2) described the associations of dopamine levels/activities, dopamine regulator levels/activities, or dopamine receptor availability/affinity with binge eating symptoms among healthy or community-based adults, or adults with binge eating, BED, or BN.Qualitative studies, abstracts, editorials, case studies, book chapters, dissertation work, and review papers were excluded.The literature search was conducted in July 2020 with two databases (PubMed and PsycINFO) to obtain relevant studies published since 2010. The search included the combination of the following keywords: “dopamine”, “binge eating”, and “bulimia”. The database search was complemented by a hand search of the reference lists obtained from the identified articles. The study selection flow is presented in Fig. This review included 25 human studies and six animal studies. Among the 25 human studies, participants had BED (n = 6), BN (n = 7), remitted BN (n = 3), both BED and BN (n = 3), and binge eating symptoms (n = 3), and the remaining three studies were comprised of healthy adults or community-based adults. Most of the human studies used case–control design (n = 12), and the others were randomized controlled trials , cross-sectional studies (n = 5), and randomized crossover study (n = 1). For the six animal studies, four used male adult rats, and two used female adult rats. The intermittent access paradigm was consistently used to induce binge eating.11C]raclopride has a high selectivity and affinity to the D2 receptor; thus, it competes with endogenous dopamine binding to the D2 receptor—when endogenous dopamine increases, the radioligand signal decreases [18F]fluorodopa, is an analog of a dopamine precursor, which is uptaken by the presynapse and consequently promotes dopamine synthesis. Therefore, PET can accomplish three primary goals: measuring dopamine receptor availability/affinity, measuring the extracellular dopamine release, and measuring the dopamine synthesis capacity. Three studies used PET in this review: two used [11C]raclopride in conjunction with methylphenidate to measure dopamine D2 receptor availability/affinity and dopamine release (after methylphenidate) [18F]fluorodopa to measure dopamine synthesis capacity [PET relies on the administration and subsequent detection of positron-emitting radiotracers. The radiotracer [ecreases . Furtherenidate) , 48, andcapacity .fMRI measures the hemodynamic and metabolic consequences of brain neuronal activity known as blood-oxygen-level-dependent (BOLD) signal. Although the BOLD signal reflects a mix of neurotransmitter dynamics , many studies have reported a significant relationship between dopamine levels/activities and BOLD signal variability in dopamine-relevant brain regions  , 51, thuThe two primary genetic approaches have been to measure gene expression levels and to look for naturally occurring genetic polymorphisms in dopaminergic genes. Three studies –57 analySeveral polymorphisms of the D2 receptor gene have been studied: (1) Taq1A C/T: the T (A1) allele is associated with lower levels of D2 receptor availability and binding affinity relative to the C (A2) allele , 68; (2)There are also polymorphisms in the lesser studied D3 and D4 receptors. The Ser9Gly variant is a functional polymorphic site in the D3 receptor gene, which increases the D3 receptor binding affinity for dopamine . The D4 The dopamine transporter gene also has a region with a variable number of tandem repeats, and it is the most studied dopamine transporter polymorphism. Relative to the 10-repeat allele, the 9-repeat allele is associated with lower dopamine transporter expression, resulting in increased synaptic dopamine levels for 9-repeat allele carriers .The gene encoding the dopamine degrading enzyme, COMT, contains a well-studied polymorphism  that influences the protein’s ability to degrade extracellular dopamine. The Val allele has a 40% higher enzymatic activity than the Met allele; therefore, carriers of the Val/Val genotype degrade dopamine in the prefrontal cortex more efficiently, resulting in lower synaptic dopamine levels, compared to those with Met/Met or Val/Met genotype .In pharmacological studies, several drugs including the immediate dopamine precursor L-DOPA , dopaminThe hyperdopaminergic state (n = 9) is characterized by 1) two human case–control studies that reported increased dopamine levels and higher dopamine receptor availability/affinity in patients with binge eating than those without binge eating; (2) five cross-sectional studies that showed positive associations of dopamine levels, activities, and receptor availability/affinity with binge eating symptoms among healthy adults, community-based adults, or adults with binge eating; and (3) two animal studies that demonstrated dopamine receptor-blocked or dopamine-depleted rats reduced or failed to develop binge eating symptoms . Results revealed that under the condition of food stimuli and methylphenidate, binge eaters showed significantly more dopamine release in the caudate compared to non-binge eaters, and the increased dopamine release was significantly correlated with higher binge eating severity.One study  applied Davis et al.  comparedA research group from Spain analyzed the associations of three polymorphisms in the dopamine genes  with binge eating symptoms in patients with BED (n = 34) or BN (n = 80) . ResultsIn a study with 74 BN patients , the autIn a study of 1003 community-based adults , the autDavis et al.  examinedA small-scale study  of eightAn animal study  used malAnother animal study  used femThe hypodopaminergic state (n = 17) is characterized by 1) six case–control studies that reported decreased dopamine levels, reduced dopamine activities, and lower dopamine receptor availability/affinity in patients with binge eating compared to those without binge eating; 2) two cross-sectional studies that showed negative associations between dopamine levels and binge eating symptoms in patients with BN or BED; 3) six RCTs and one randomized crossover study that reported using dopamine synthesis inhibitor triggered binge eating, or using dopamine transported inhibitor reduced binge eating; and 4) two animal studies that demonstrated lower dopamine receptor levels/affinity in binge rats  is characterized by 1) three case–control studies that reported no difference of dopamine receptor availability/affinity in patients with binge eating compared to those without binge eating; 2) an RCT that showed no effect of dopamine receptor antagonist on binge behaviors; and 3) an animal study that demonstrated no effect of dopamine receptor agonist or antagonist on binge behaviors  documented an altered dopaminergic state related to binge eating. However, the literature is inconsistent concerning the direction of the alteration, supporting either a hyperdopaminergic  or a hypodopaminergic  state in binge eating.The dissonance may be partially due to the complexity of the dopamine system   and the Another reason that can possibly explain the inconsistency is that this review included two distinct types of eating disorders: BED and BN. Although both BED and BN are marked by binge eating symptoms, BN additionally requires using compensatory behaviors after binge episodes . Notably, the few studies that have compared the etiology and neural underpinnings of BED and BN revealed that despite a large magnitude of overlap , differeAlthough there are possible explanations for the inconsistent findings, two hypotheses that could potentially reconcile the inconsistency should be considered in future studies. The first hypothesis is that instead of being mutually exclusive, the hyperdopaminergic and hypodopaminergic states may co-exist, but in different stages of binge eating. This hypothesis is supported by the observations in this review as well as similar conjectures proposed in other disease conditions that are highly correlated with binge eating, such as obesity and substance use disorder.Among studies included in this review, although not all of them reported the stage or severity of binge eating, the two studies , 78 condThe hypothesis of hyper- then hypodopaminergic state in binge eating is also consistent with the reward-related models or theories in obesity (dynamic vulnerability model), drug addiction (dopamine desensitization theory), and alcohol use disorder (three-stage model). In obesity literature, two opposing dopamine-related theories are debated—the reward surfeit and reward deficit theories . The forBinge eating is also highly correlated with substance use disorder as the two disease conditions have a high comorbidity  , 99 and The dopamine desensitization theory of drug addiction proposes that dopamine elevations occur in the initial stages of addiction but not after repeated excessive intake of drugs. Instead, the later stage of drug use is possibly associated with a decreased dopamine release, reduced dopamine D2 receptor availability, and downregulated dopaminergic responses to drug cues –103. LikAn alternate hypothesis to reconcile the inconsistent findings is that the hyper- and hypodopaminergic states represent two distinct pathways to binge eating, and individual genotypes determine whether it is the hyper- or hypodopaminergic state that confers a risk of binge eating . This hyAs previously mentioned, both reward surfeit and reward deficit theories exist to explain the development of obesity. Despite that evidence overwhelmingly supported the reward surfeit theory, Stice et al.  tested wIn this review, two studies have compared the Taq1A A1 and A2 allele between BED patients and healthy controls, with one study reporting overrepresentation of Taq1A A1  and the This review has several limitations. First, results were organized based on different dopaminergic states in binge eating behaviors. While this structure makes the opposing viewpoints stand out and emphasizes the possibility of the co-existence of hyper- and hypodopaminergic states in binge eating, it may complicate the direct comparisons between studies that used the same technique  or adopted a similar study design . Additional limitations are mostly limitations that are inherent in the included studies, including small sample size, lack of control for confounding variables in some studies, and the absence of longitudinal studies that cover different stages of binge eating . Moreover, it should be noticed that only a few studies reported the specific brain areas where dopamine alterations occur, and no study functionally correlated the alterations to corresponding risk factors of binge eating. This limitation precludes a clear understanding of what aberrant dopamine functions contribute to the initiation or maintenance of binge eating. Studies from substance use disorder have provided useful clues for the delineation of specific brain areas and dopamine functions in different disease stages. For example, the three-stage model of alcohol dependence elaborates that the three stages—binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation—map onto disturbances in three major neurocircuits , which correspond to three functional domains characterized by excessive incentive salience/habit formation, negative emotional states, and dysregulation of executive function –109. GivIn conclusion, although most studies have supported altered dopamine levels, dopamine activities, dopamine regulator levels/activities, or dopamine receptor availability/affinity related to binge eating, the direction of the alteration is unclear. Future studies may benefit from a careful control of confounding variables that may influence dopamine functioning (e.g. psychiatric diseases). Furthermore, longitudinal studies are needed to test whether there is a shift from hyperdopaminergic to hypodopaminergic state as binge eating progresses and whether individual genotypes modulate the relationship between dopamine and binge eating, which are two hypotheses that may potentially reconcile the inconsistent findings.


The antimicrobial-resistance (AMR) in bacteria represents a major challenge for public health. The misuse and or overuse of antibiotics in livestock is known to have contributed to the emergence of AMR. To date, there is growing concern over the possibility of AMR transmission via the food chain . AMR fooThis Special Issue includes full research articles and one review focused on the emergence of AMR in food chain.Escherichia coli viability in lettuce with flow cytometry. The authors showed that this technique is a powerful tool for rapidly evaluating the effect of disinfection on Escherichia coli viability in lettuce. Additionally, the detection of VBNC cells is possible within a few minutes, which avoids their persistence, spread and, consequently, food-borne outbreaks [A critical problem is the existence of bacteria in a state of latency induced by stressful conditions called “viable but nonculturable (VBNC) cells”. The main aim of the study carried out by Texeira and co-workers was to conduct a thorough analysis of the efficacy of chemical disinfectants by assessing utbreaks .Staphylococcus aureus from milk was the focus of the contribution by Agbortabot Bissong and co-workers. The high frequency of AMR Staphylococcus aureus strains in milk intended for human consumption demonstrates the importance of this multi-drug resistant bacteria in terms of public health in the North West Province of South Africa [Salmonella serovars isolated from foods in Italy was investigated by Peruzy and co-workers. A high prevalence of AMR and multi-drug resistant Salmonella strains was found [Salmonella Rissen isolates from humans, animals, animal-derived products and the environment in China. A high incidence of AMR among Salmonella Rissen isolates recovered from various sources was observed [Salmonella Infantis antimicrobial susceptibility pattern and the prevalence of Salmonella Infantis Extended Spectrum β-Lattamase (ESBL) isolated from the broiler food chain and humans in Italy. The authors showed the great diffusion of ESBL multi-drug resistant Salmonella Infantis strains [Staphylococcus aureus from healthy pigs, diseased pigs and environment. The multidrug resistance observed among various isolates showed that pigs and pork may have an important role in AMR dissemination [Escherichia coli isolates form ready-to-eat meats in Ghana. They showed that the antibiotics used by farmers have a strong link with the resistance pattern of bacteria isolated from animals. With regard to this, ready to eat meats may be a source of AMR Escherichia coli isolates [The genotypic and phenotypic characteristics of biofilm producing and AMR in h Africa . The occas found . The conobserved . In thei strains . Zhou anmination . The stuisolates . The maiEnterobacteriaceae in the pork production chain. Overall, an increasing trend in the prevalence of presumptive ESBL producing Escherichia coli in pigs in the EU has been observed in the last decade. Although the prevalence of ESBL producing Escherichia coli is lower in pork meat than in pigs, pork meat can act as a transmission route for this group of critically important AMR bacteria [Anyway, further investigations focusing on the selective pressure applied by antimicrobial treatments on the expression of AMR genes in gut microbiota need to be carried out . Finallybacteria .This Special Issue collects multidisciplinary researches related to the possible emergence, spread and transfer of AMR in the food chain. The contributions here collected constitute a valuable knowledge reservoir for scientists working in the field of AMR.


L‐MoS2 or 1L‐WSe2). The molecular dipole moment direction determines the direction of the band bending of the 2D semiconductors, affecting the dominant transport pathways upon voltage application. Notably, in the molecular heterostructure with 1L‐WSe2, the opposite rectification direction is observed depending on the molecular dipole moment direction, which does not hold for the case with 1L‐MoS2. In addition, the nonlinearity of the molecular heterojunction selector can be significantly affected by the molecular dipole moment direction, type of 2D semiconductor, and metal work function. According to the choice of these heterojunction constituents, the nonlinearity is widely tuned from 1.0 × 101 to 3.6 × 104 for the read voltage scheme and from 0.4 × 101 to 2.0 × 105 for the half‐read voltage scheme, which can be scaled up to an ≈482 Gbit crossbar array.Understanding and designing interfacial band alignment in a molecular heterojunction provides a foundation for realizing its desirable electronic functionality. In this study, a tailored molecular heterojunction selector is implemented by controlling its interfacial band offset between the molecular self‐assembled monolayer with opposite dipole orientations and the 2D semiconductor (1 By tailoring the interfacial band offset with the molecular dipole orientation, molecular heterojunction selector is presented. Based on diverse interfacial band offsets achieved by changing the heterojunction constituents, such as the molecular dipole moment direction, types of two‐dimensional transition metal dichalcogenide, and work function of the electrodes, the nonlinearity is widely tuned, scaling up to an ≈482 Gbit crossbar array. Therefore, using a specific designed molecular species is a general and rational way to realize a functional molecular device. For example, molecular self‐assembled monolayers (SAMs) composed of aliphatic groups  only act as simple insulators. In contrast, molecules with an aliphatic backbone but an altered anchoring group of electroactive moieties  can rectify the current. In addition, diarylethene and azobenzene molecules can exhibit photoswitching behavior depending on the wavelength of light. Molecular resistive random‐access memory was also reported based on alkyl molecular SAMs containing functional MV2+ (where MV is methylviologen) redox units, which can adjust the molecular energy level via the various oxidation states.Implementing a functional molecular‐scale device is an essential step toward realizing the ultimate electronic device scaling beyond the complementary metal‐oxide‐semiconductor scaling limit without increasing the thermal budget.1 Gene For example, Vezzoli et al. demonstrated enhancement of the photocurrent in a metal‐molecule‐semiconductor nanodevice by adjusting the doping density of GaAs and the frontier molecular orbital levels. They insisted that the interfacial energy gap between the molecular energy level and the Fermi level (EF) of the metal is a significant factor determining the magnitude of the photocurrent. Margapoti et al. reported an abrupt change in the electrical characteristics of an Au/photochromic azobenzene molecular SAM/single‐layer MoS2 junction depending on the trans and cis molecular configuration modulated by light. Lastly, we reported molecular heterojunctions with nonfunctional molecules and different types of 2D transition metal dichalcogenide (TMD) semiconductors (MoS2 and WSe2), which exhibit different transport pathways upon the application of different voltage polarities, realizing a molecular‐scale diode. These methods can all provide a novel strategy for designing functional molecular junctions distinguished from the traditional forms in which a specifically designed molecular system has been an absolute necessity to provide electronic functionality.In contrast to this conventional strategy, which uses the functionality of the molecule itself, by exploiting a combination of molecules and various nanomaterials, a variety of functional molecular heterojunctions have been recently developed and suggested.20 For In addition, orientation of the molecular dipole moment along an external electric field can significantly affect the transport conduction through the molecular junction. For example, Baghbanzadeh et al. designed a specific molecular SAM with functional dipolar groups, exhibiting a rectification feature up to ≈20. Kovalchuk et al. ascribed the dipole‐induced asymmetric tunneling conduction in eutectic Ga‐In/pyrimidyl‐based molecules/Au. Moreover, many studies on organic thin‐film transistors (OTFTs) with various molecular dipole moments have also been performed. Molecular dipoles can create an electrostatic potential that withdraws or injects charge carriers from/into the semiconductor channel according to the molecular dipole moment direction. This leads to a change in the threshold and the turn‐on voltage of the OTFT device. Despite this crucial role of the molecular dipole moment in the electronic transport in junctions, molecular heterojunctions with different molecular dipoles and orientations have rarely been studied. In addition, a comprehensive understanding of how the charge transport can be affected by the direction of the molecular dipole moment in the molecular heterojunction and what electronic functionality can be designed and applied is not yet systematically established.Apart from the functionalities of molecular building blocks, the molecular dipole moment can also be considered an essential variable determining the charge transport. It can adjust the direction of the interfacial band bending and local electric field induced in the junction. In general, the magnitude of the molecular dipole moment of the SAM attached to the metal substrate can determine the degree of change in its work function by shifting the relative vacuum levels.26 In L‐MoS2 or 1L‐WSe2) based on a conducting atomic force microscopy (CAFM) technique. According to the choice of constituents in the molecular heterojunction, such as the direction of the molecular dipole moment, the type of 2D TMD, and the metal work function, diverse interfacial band offsets can be established, tuning the rectification features and direction. Notably, this interfacial band engineering can also be used to widely adjust the degree of current increase and the nonlinearity of the rectification characteristics upon voltage application. This characteristic suggests the potential for a tailored molecular‐scale heterojunction selector that can prevent sneak current flow in a crossbar array structure. Based on the readout margin estimated by conventional one bit‐line pull‐up simulation for different reading voltage schemes, a switching array integrated with this molecular selector could be scaled up to ≈482 Gbit. This result could pave a novel way to extend the application region of the molecular junction.In this study, we investigate the charge transport according to the interfacial band offsets in various molecular heterojunctions consisting of molecular SAMs with opposite dipole orientations and different types of monolayer‐thick 2D TMD  stacked on an Au/SiO2/Si substrate, for which the CAFM technique is used to investigate the electrical properties. Two different molecular species are selected: 1‐octanethiol (CH3(CH2)7SH, denoted C8) and tridecafluoro‐1‐octanethiol (CF3(CF2)5(CH2)2SH, denoted F6H2) have opposite charge distributions driven by the different terminal/backbone groups of —CHn and —CFn, exhibiting opposite dipole moment directions with respect to the Au metal  to the Au metal. In contrast, the dipole moment of C8 is oriented from the Au metal to the molecular terminal (—CH3). As shown in Figure Evac) by the interfacial potential drop (Δϕ), changing the work function of the underlying Au metal. The dipole moment direction determines the sign of Δϕ with respect to the Fermi level of the Au metal, enabling an increase or a decrease in the work function. The F6H2 molecules are expected to shift Evac up , while the C8 molecules on Au are expected to shift Evac down . To confirm the change in Δϕ with the molecular dipole moment direction, we performed scanning Kelvin probe microscopy (SKPM) on F6H2/Au, bare Au, and C8/Au substrates. SAMs of F6H2 have a positive Δϕ of 0.78 ± 0.02 eV, while SAMs of C8 have a negative Δϕ of −0.60 ± 0.02 eV, which are both in good agreement with the theoretical expectations and previous studies for similar molecular species, as shown in Figure l Figure .[19, 2) and p‐type (WSe2)) on Au/SiO2/Si substrates were prepared by using the typical mechanical exfoliation and transfer method . The prepared MoS2 and WSe2 and their layer numbers were investigated by Raman spectroscopy, photoluminescence (PL) spectroscopy, and topological line profiling using AFM  based on the scanned topological profile. In the Raman spectra, both TMDs exhibit vibration modes corresponding to monolayer‐thick MoS2 and WSe2 (denoted 1L‐MoS2 and 1L‐WSe2). The spacing between E12g = 377 cm−1 and A1g = 396 cm−1 is δ = 18.9 cm−1 for 1L‐MoS2, and overlapped spectra of E12g and A1g at 242 cm−1 are observed for 1L‐WSe2. After the dense formation of SAMs of both C8 and F6H2 on Au (or Pt) tips, each tip brought to the 2D TMD with the loading force FL = 1 nN, and five different types of molecular heterojunctions were made: 1) Au‐tip/C8/1L‐MoS2/Au, 2) Au‐tip/F6H2/1L‐MoS2/Au, 3) Au‐tip/C8/1L‐WSe2/Au, 4) Au‐tip/F6H2/1L‐WSe2/Au, and 5) Pt‐tip/F6H2/1L‐MoS2/Au. For the electrical measurement, a voltage was applied to the bottom Au electrode, and the metal tip was grounded. Note that the change of molecular effective dipole moments according to contact curvature of the tip can be negligible. The details of the molecular effective dipole moment according to the contact curvature are described in Note Two different types of 2D TMD monolayers  baFigure I–V) characteristics for four different molecular heterojunctions: a) Au‐tip/C8/1L‐MoS2/Au, b) Au‐tip/F6H2/1L‐MoS2/Au, c) Au‐tip/C8/1L‐WSe2/Au, and d) Au‐tip/F6H2/1L‐WSe2/Au. Each I–V characteristic was measured at several positions (≈20 positions) in different junction samples. The black lines in Figure I–V characteristics for the four different molecular heterojunctions. All I–V curves exhibit reproducible and reliable rectification behavior with a certain rectification ratio (RR), defined as RR = |I (V = 1.5 V)/I (V = −1.5 V)|. With this definition, if RR > 1, then the rectification direction is positive, while if 0 < RR < 1, then it is negative. Note that for the junctions composed of only the molecules junctions or only the 2D TMDs vertical junctions, the I–V characteristics exhibit a symmetric‐like behavior due to the single transport barrier between two Au electrodes  × 102 and (5.9 ± 0.7) × 102, respectively. Both junctions have positive rectification directions regardless of the molecular dipole direction . This rectification characteristic can be understood based on the different transport conductions driven by the change in interfacial energy band alignments depending on the voltage polarity. In this type of molecular heterostructure with 1L‐MoS2 , for example, the energy band alignment of the molecular SAM and 1L‐MoS2 can be independently varied according to the applied voltage polarity due to the different coupling strengths at the Au‐tip/molecule, molecule/1L‐MoS2, and 1L‐MoS2/Au interfaces. This interfacial band shift can lead to different transport pathways according to the voltage polarity, causing positive rectification characteristics  × 102 and (2.2 ± 0.9) × 10−2, respectively, indicating opposite rectification directions. To systematically understand this opposite direction, the interfacial band alignments for both molecular heterojunctions are established according to the voltage polarities (at V = ± 1.5 V), as shown in Figure EF of the Au tip upon voltage application. However, the EF of the bottom Au electrode can be strongly pinned at the mid‐gap state between the energy levels (conduction band (CB) and valence band (VB)) of 1L‐WSe2 due to the existence of vacancy states in the mechanically transferred TMD. Therefore, the energy band of 1L‐WSe2 can shift along with the EF of the bottom Au electrode according to the applied voltage. In the interfacial energy band alignment schematics, the effect of the molecular dipole moments can be additionally considered. Depending on the sign of Δϕ determined by the molecular dipole moment direction, the energy band edges of C8 and F6H2 are shifted downward or upward, causing the band bending of 1L‐WSe2 at the interface to differ , two different transport pathways may be attributed according to V = ± 1.5 V, where one is the tunneling across both the C8 and 1L‐WSe2 barriers (dT = dM + d2D) at V = −1.5 V, and the other is the combination transport of Schottky emission (dSE = d2D) and the tunneling (dT = dM) across the 1L‐WSe2 and C8 barriers at V = 1.5 V  transfer across dT (= dM+ d2D) from the top Au tip to the bottom Au electrode. During the charge transfer, the C8 barrier height (defined as the difference between the EF of the top Au tip and the HOMO of C8 in this case) remains constant, while the effective tunneling barrier across 1L‐WSe2 is further reduced for a higher negative voltage. In contrast, when V = 1.5 V, the charge transfer direction is the opposite , and the pathway is changed. Under this circumstance, the effective Schottky barrier at 1L‐WSe2/Au remains constant due to the Fermi level pinning effect, while the C8 barrier is further reduced for a higher positive voltage. Therefore, the effective C8 barrier height changes depending on the applied voltage polarity, which might be a major factor determining the asymmetricity of the transport current. In other words, the relatively low C8 tunneling barrier at V = 1.5 V results in a higher transport current than that at V = −1.5 V. In contrast, for the F6H2/1L‐WSe2 junction, the positive Δϕ due to the F6H2 SAMs on Au induces the opposite band bending (upward) of 1L‐WSe2, changing the major transport pathways. Charges mainly transfer across F6H2  only when V = −1.5 V with a high possibility  and tunneling (dT = dM) transport across the 1L‐WSe2 and F6H2 barriers .However, in the type of molecular heterostructure with 1e Figure . For exar Figure . For theFigure I–V characteristics for Au‐tip/F6H2/1L‐MoS2/Au and Pt‐tip/F6H2/1L‐MoS2/Au junctions. Compared with the Au‐tip/F6H2/1L‐MoS2/Au junction, the Pt‐tip/F6H2/1L‐MoS2/Au junction shows a slightly higher RR and a lower transport current , respectively. Note that the degree of the current increase is defined as Δ = (I (V = 1.5 V) − I (V = 1.0 V))/I (V = 1.0 V). The Δ for the Pt‐tip/F6H2/1L‐MoS2/Au junction is ≈47.2, more than twice the Δ for the Au‐tip/F6H2/1L‐MoS2/Au junction (≈19.3). We speculate that the Δ difference is associated with the upward degree (the green arrows) of the band bending of 1L‐MoS2 depending on the work function of the top metal electrode (Au and Pt)  when the molecular species was changed from C8 to F6H2 and the top electrode was changed from Au to Pt metal. However, in the molecular heterojunction with 1L‐WSe2, Δ decreased by more than a few tens of times (from (4.4 ± 0.9) × 102 to (1.2 ± 0.3) × 101) when the molecular species was changed from C8 to F6H2. This opposite behavior of Δ is associated with the change in the type of 2D TMD (change in the majority carrier) that can affect the dominant transport pathway. Notably, Δ is strongly related to the nonlinearity (NL) of the rectification characteristics; hence, it could offer a distinctive design rule that can be suggested as a molecular selector.To investigate the effect of the metal work function on the interfacial band alignment in the molecular heterojunction, we changed the top Au tip to the Pt tip. t  Figure . A largeNL and readout margin for the five different molecular heterojunction systems under two different reading voltage schemes (Vr and Vr/2 schemes)  structure with two different reading voltage schemes (Vr and Vr/2 schemes). The switching behavior with ON and OFF states is assumed to be exhibited only in the positive voltage region, while the current is suppressed in the negative voltage region as a whole. Note that each circle corresponds to the current at V = −Vr, 0, Vr/2, and Vr. The red and blue circles represent the ON and OFF currents at Vr, respectively. With these conditions, two different reading voltage schemes in the 2 × 2 crossbar form are schematized, as shown in the bottom panels of Figure R, R, R, and R), corresponding to the colored circles in Figure R and is either in the ON (red circle) or OFF (blue circle) state, while the remaining unselected cells correspond to R, R, and R. Based on these resistance values, each NL for the Vr and Vr/2 schemes can be calculated from R/R and R /R or R/R, respectively. Here, NL indicates the relative resistance difference between a single selected cell and other unselected cells where the applied voltage drops. Hence, a memory array with a higher NL enables a more accurate reading of the switching state on the selected cell. Considering the RR and the rectification directions for the molecular heterojunctions, Vr is set to 1.5 or −1.5 V (only for the F6H2/1L‐WSe2 junction). Figure NL for the five molecular heterojunctions according to the Vr and Vr/2 schemes. Noticeably, in the case of 1L‐MoS2, the NL in the Vr/2 scheme is largely increased from (1.3 ± 0.3) × 101 to (3.7 ± 0.7) × 102 when the molecular species is changed from C8 to F6H2 and the top electrode is changed from Au to Pt metal, while the NL in the Vr scheme increases slightly  × 103 to (2.3 ± 0.3) × 101 when the molecular species is changed from C8 to F6H2 compared with the Vr scheme  degree of band bending induced by the molecular dipole moment and metal work function and the different dominant transport pathways depending on the type of 2D TMD.Figure structure51 witNL values for the five molecular heterojunctions, we examined the maximum size of the crossbar array (M.S.) according to a 10% readout margin based on conventional one bit‐line pull‐up (one BLPU) simulation for the Vr and Vr/2 schemes  for ≈2 h in a glove box filled with nitrogen gas with less than 10 ppm O2. The nonassembled molecules on the Au tip were removed by carefully rinsing it with ethanol droplets followed by gentle blow drying with N2 gas. After mechanical exfoliation of the 2D TMDs (1L‐MoS2 and 1L‐WSe2), they were carefully picked up and transferred onto each Au/SiO2/Si substrate by using a polydimethylsiloxane stamp coated with polypropylene carbonate. The number of 2D TMD layers was confirmed by the AFM technique  through noncontact mode. The Raman and PL spectra of the 1L‐2D TMDs were measured using a home‐built spectrometer equipped with a monochromator  and a 532 nm excitation laser with a spot diameter of 0.5 µm. The signal was collected by an objective lens (100 × NA = 0.9) and dispersed by 1200 and 300 line per mm gratings for the Raman and PL measurements  were densely packed on the Au tip (or Pt tip) by immersing the tip in the prepared molecular solutions (C8 and F6H2 with ≈5 mL‐MoS2 (or 1L‐WSe2)/Au/SiO2/Si substrate with FL = 1 nN. The molecular heterojunction was finally formed when the Au tip with the molecular SAMs contacted the 2D TMD. The Au tip was grounded, and voltage was applied on the bottom Au electrode. The electrical I−V characteristics were measured in stationary mode with FL = 1 nN using a DLPCA‐2000 built‐in current amplifier  at a humidity of <15%. To statistically investigate the electrical characteristics, the Au tip was repeatedly brought to different junction points. It should be noted that, whenever the CAFM measurements were conducted, the location of the 1L‐MoS2 was confirmed based on the Raman spectra, PL, and the optical/AFM scanning images, and then the Au (or Pt) tip that was coated with the molecular SAMs was approached on that point. The current range of the I–V characteristics was limited in the range of around three orders of magnitude due to the limitation of the current experimental set‐up  built‐in with CAFM measurement system, Electro‐Optical Components). All the current levels at the flat region that was limited by the current measurement set‐up were excluded when investigating the electrical transport behavior. For example, the rectification ratio (RR), the degree of the current increase (Δ), the nonlinearity (NL), and the Readout Margin were investigated in relatively high voltage region.For electrical measurement through the CAFM technique, the Au tip (or Pt tip) treated with molecular SAMs (C8 or F6H2) was carefully brought to the 1The authors declare no conflict of interest.Supporting InformationClick here for additional data file.


P1, carbazole P2, and 3,4-alkoxythiophene P3) or electron-deficient moieties  were synthesized via direct C–H (hetero)arylation polymerization (DHAP) in moderate to excellent yields (60–98%) with medium to high molecular weights . Owing to their various electronic and structural properties, different absorption spectra  as well as different specific capacitances of 70, 68, 75, 51, and 25 F/g with 19, 10, 21, 26, and 69% of capacity retention after 1,000 cycles were observed for P1–P5, respectively. After careful study through multiple experimental measurements and theoretical calculation, appropriate electronic characteristics, small molecular conformation differences between different oxidative states, and well-ordered molecular stacking could improve the electrochemical performance of CPs.Over the past decades, π-conjugated polymers (CPs) have drawn more and more attention and been essential materials for applications in various organic electronic devices. Thereinto, conjugated polymers based on the 3,4-ethylenedioxythiophene (EDOT) backbone are among the high-performance materials. In order to investigate the structure–property relationships of EDOT-based polymers and further improve their electrochemical properties, a series of organic solvent–soluble EDOT-based alternative copolymers consisting of electron-rich fragments (fluorene  Accordingly, the molecular structure types of polymers synthesized by these two methods are relatively limited, which is not conducive to the study of the structure–property relationship. For example, the A–B alternative copolymer cannot be readily synthesized by classical electropolymerization or oxidative chemical polymerization. Moreover, the products of electropolymerization generally have problems in further processing, large-scale preparation, and limited molecular structure diversity, due to their infusibility and poor solubility in common solvents. And the products of oxidative chemical polymerization also have problems in the metal ion residue and low reactivity for electron-deficient monomers. In other words, to design more appropriate synthetic methods is of crucial importance to the development of high-performance CPs.With the rapid development in the field of wearable and flexible electronics during the past decades, π-conjugated polymers (CPs) have drawn more and more attention and been essential materials for applications in organic solar cells (OSCs) , organicvia DHAP have been widely applied in the field of high-performance organic semiconductors and have shown a variety of merits, such as a well-defined structure, a diversified molecular structure, high reproducibility, large-scale throughput, and good solubility  were synthesized effectively via DHAP in moderate to excellent yields (60–98%) with medium to high molecular weights . Although several similar examples of these polymers have been synthesized before, the relationships between the photophysical and electrochemical properties and their structures have not been systematically investigated arylation polymerization (DHAP) of non-preactivated (hetero)arenes with (hetero)aryl halides is one of the most ideal and effective methods to construct conjugated polymers, avoiding tedious reaction steps and formation of stoichiometric toxic organometallic byproducts in the traditional organometallic couplings . Furtherlubility . Based ovia DHAP , we herestigated . The rel2 (5 mol%), K2CO3 (2.5 equiv.), and 1-adamantanecarboxylic acid  in DMAc at 100 C for 24 h was used to synthesize our EDOT-based CPs. As shown in P1, carbazole P2, and 3,4-alkoxythiophene P3) and electron-deficient units  were successfully engaged in the reactions, offering structure-diversified EDOT-based CPs in moderate to excellent yields (60–98%) with medium to high molecular weights . The yield and molecular weight of P2 can be further improved up to 81% and 7,900 Da after 48 h, respectively, indicating its relatively low reactivity of 3,6-dibromocarbazole. The good yields of P1–P5 with comparable or even higher Mn compared to those obtained in previous works indicated the high reactivity of EDOT under this catalytic system and good applicability of DHAP , films for characterization of UV-Vis absorption, electrochemical properties, and microscopic packing properties were fabricated by solution processing, such as drip coating and spray coating.Owing to the wide application of EDOT-based CPs and high reactivity of C–H bonds, the DHAP of EDOT was early and extensively studied by several research groups . Based o of DHAP . It is oterature . Br termP1–P5 were optimized through density functional theory (DFT), as shown in P1–P5, covering the near-UV and blue, green, and red color regions, suggest their distinct electronic and structural properties. The obviously red-shifted absorption of P1–P5 in the thin film in comparison with that in the solution could be generated from the strong intermolecular interaction between the polymer backbones in film states. On comparison with P1 and P2 containing electron-rich units , P4 and P5 with electron-deficient units displayed significantly red-shifted absorption , which should be assigned to the intramolecular charge transfer (ICT) from the EDOT donor to corresponding electron-deficient acceptor units. When connecting 3,4-alkoxythiophene with EDOT, P3 also displayed a red-shifted absorption (λsolution = 547 nm and λfilm = 558 nm), owing to its almost planar backbone  induced by an intramolecular O∙∙∙S interaction (o), P5 exhibited the most red-shifted maximum absorption wavelength among these five polymers, implying its efficient electron delocalization, transport property, and close molecular stacking.The UV-Vis spectra and data of these five EDOT-based CPs in diluted solution and in films are shown in eraction . Thus, c+ wire (silver wire in 0.01 M AgNO3 in acetonitrile) as the reference electrode, and a Pt disk or foam-nickel electrode drop-coated with the polymer as the working electrode and using 0.1 M tetrabutylammonium hexafluorophosphate in dry acetonitrile as the electrolyte solution. Firstly, cyclic voltammetry (CV) measurements of P1–P5 films on a Pt disk electrode were performed to analyze their p-doping/dedoping processes at a scan rate of 100 mV s−1  eV, where Eox,onset is the onset potential of the oxidation peak with respect to the ferrocene/ferrocenium (Fc/Fc+) redox couple. The HOMO energy levels of P1 (−5.17 eV), P2 (−5.06 eV), and P3 (−4.79 eV) are in good agreement with those reported by other groups  (P5 (−5.35 eV) among P1–P5, the coplanar and electron-rich P3 showed the highest HOMO energy level (−4.79 eV), indicating its easiness of losing electrons and the potential development of new polymeric anodes. The arrangement trends of HOMO energy levels of P1–P5 estimated by CV were in accordance with those of HOMO values calculated by DFT, besides slightly overestimated HOMO and LUMO levels by DFT  curves, and electrochemical impedance spectroscopy (EIS) and are summarized in −1 demonstrated their fast redox behaviors and high rate charge/discharge performances (P1–P5 exhibited obvious pseudocapacitive energy storage properties. The measured specific capacitances of the polymers (P1–P5)/foam-nickel electrode were calculated to be 70, 68, 75, 51, and 25 F/g (at 100 mV s−1) with 19, 10, 21, 26, and 69% of capacity retention after 1,000 cycles, respectively. These specific capacitances were higher than those of some other conducting polymer electrodes deposited by solution processing methods  . Compares by DFT . Subsequormances . For theormances , suggestormances . From thormances , it can  methods , probablcy range , indicatcy range .θ = 3.43, 6.79, 9.94, and 25.54°, corresponding to d-spacings of 25.73, 13.01, 8.89, and 3.48 Å, respectively, representing the existence of lamellar stacking and π–π stacking of polymer main chains. With the lowest roughness and best XRD crystallinity of P5 among all polymers, the relatively good cyclic stability could be attributed to the homogeneous surface and well-ordered stacking of molecules in films. All the thermal degradation temperatures (Td) over 300°C of P1–P5 at 5% weight loss manifested their good thermal stability  through direct (hetero)arylation polymerization. Owing to the structural diversity of obtained EDOT-based copolymers, the varied absorption spectra, specific capacitance, and capacity retention were observed, which should be attributed to the electronic characteristics of various units introduced, molecular torsions in the polymer backbone, and thus resultant different surface morphologies and molecular packings. Clear redshifts in absorption of P3, P4, and P5 were observed, due to their good coplanarity and/or ICT property. When using a foam-nickel electrode drop-coated with the polymer as the working electrode in a three-electrode cell, good specific capacitances of 70, 68, 75, 51, and 25 F/g (at 100 mV s−1) with 19, 10, 21, 26, and 69% of capacity retention after 1,000 cycles for P1–P5 were obtained, respectively, owing to the good redox activity of the EDOT unit. The results of our present study confirm that appropriate electronic characteristics, fast charge transfer, good coplanarity, low RMSD between different oxidative states, homogeneous surface, and well-ordered molecular stacking could improve the cycling stability of polymeric capacitive performance which is still one of the main obstacles in further applications of supercapacitors based on π-conjugated polymers. It is anticipated that such study will provide a novel strategy for the molecular design of π-conjugated polymers regarding electrochemical properties.In this work, a series of novel soluble EDOT-based conjugated copolymers consisting of electron-rich or electron-deficient units were synthesized steadily in moderate to excellent yields (60–98%) with medium to high molecular weights (