Clinical researches of stem cell‐based therapies are highly active in China, while it was arduous to determine the most effective way of clinical translation of those advanced therapies.This article briefly introduced the regulatory framework development, the progress in stem cell clinical researches and clinical trials of commercially developed stem cell‐based products, as well as the clinical review concerns of stem cell‐based products in China.The current regulatory framework of stem cell clinical researches in China was launched in 2015, when regulatory authorities issued “Administrative Measures on Stem Cell Clinical Research” (AMSCCR) detailing the rules of stem cell clinical research. Thereafter, the rapidly growing stem cell clinical researches were rigorously managed and clinical use of stem cell therapy was halted. Meanwhile, commercially developed stem cell‐based products are supervised by Drug Administration Law (DAL).The regulatory framework of stem cell‐based therapy in China has progressed in the last few decades, which is currently regulated according to AMSCCR and DAL. Well‐designed and patient‐focused clinical trial is required for commercially developed stem cell‐based products, and definite clinical benefit evidence is crucial to obtain marketing authorization. This article briefly introduced the regulatory framework development of stem cell‐based therapy, progress in stem cell‐based clinical studies and clinical review concerns in China. The measures, as the first official document focusing on the administration of stem cell clinical research in China, abolished the certification and clinical use of stem cell‐based ‘class III’ medical technologies, and specified that hospital‐prepared stem cell clinical research could only be performed in competent class 3A medical institutions  which have drug clinical trial qualification as well as legal and sufficient funding support for stem cell research. Medical institutions, which are responsible for stem cell preparations and clinical research, should establish quality control system for stem cells, and organize competent academic and ethics committees suitable for reviewing and supervising stem cell clinical research projects.According to AMSCCR, investigators initiating stem cell clinical researches should file materials about the medical institutions and clinical research projects to NHFPC and CFDA, and register the clinical researches online at the Chinese Medicine Registry and Management System.3By the end of 2020, more than 100 medical institutions and stem cell clinical research projects have successfully registered according to AMSCCR. These clinical researches are carried out in more than half of the provinces in China, and most abundant in east China including Shanghai, Guangdong, Beijing and Hubei, etc. Figure  MSCs areOn the other way, the R&D of stem cell‐based products is burgeoning in China. NMPA has initiated regulatory science action on stem cell and gene therapy products since 2019 to improve the regulatory framework for such advanced therapeutic products, thereafter several guidance concerning the development of stem cell‐based products has been releasedAlthough the information originated from these registered stem cell‐based clinical studies is not indubitably accepted as evidence for pharmaceutical evaluation as specified by AMSCCR, CDE has generally acknowledged the value of such information in preliminarily understanding the clinical benefit‐risk profile of tested products and developing marketing‐oriented clinical trial program.4Definite clinical benefit is the prerequisite for marketing authorization of stem cell‐based products in China. Cellular and gene therapy products and other drug products generally share common rationales and purposes in different phases of clinical trials, that is, to explore the dose escalation, safety and tolerance of investigational products in early phase clinical trials, afterwards regimen and benefit‐risk profile in intended populations in late confirmatory clinical trials.4.1The ethical consensus on human biomedical research have been established,4.2Pre‐clinical proof‐of‐concept study is critical to understand the biological characteristics of stem cell‐based products, such as action mechanism, proliferation, differentiation and migration, as well as safety concerns like tumorigenicity, and is of great significance to determine the delivery scheme of clinical research and predict the distribution and action in human body, although cross‐species physiological difference and immunological incompatibility might be obstacles to accurately infer the cell behaviour in vivo. The creation of a more informative set of animal models for stem cell‐based therapies might contribute to overcome such shortcomings.First‐in‐human clinical trial should begin cautiously with dose‐escalation protocols and interval administration to avoid simultaneous exposure of subjects to unreasonable complications. For stem cell‐based products which should be delivered to the lesion area instead of systemic administration, the feasibility and biocompatibility of delivery system, for example, intravascular catheterization or surgical injection for heart and central nervous system disorders, should also be evaluated jointly with the cells. Furthermore, clinical tracking of living cells is proposed as it is conducive to exhibit the biodistribution, transplantation and clearance of stem cells in vivo.4.3Stem cell‐based products have been investigated in a wide range of indications in China. Endpoints consistent with clinical practice guidelines or consensus are recommended in clinical benefit evaluation. Unverified or alternative endpoints, for example, changes in cytokines or biomarkers, reduction or cessation of concomitant treatments, are generally not accepted as the primary efficacy evaluation criteria in confirmatory clinical trials, unless the correlation between such endpoints with patients' clinical benefits has been confirmed.As a living medicine, stem cell‐based products usually survive for extended time periods in vivo; and repeated administration of allogeneic stem cell‐based products might induce immune response, thereby reducing their effectiveness and/or increasing safety risk. Therefore, the duration of efficacy is concerned in benefit‐risk evaluation of stem cell‐based products, and continuous monitoring and prolonged follow‐up are necessary to avoid the possibility of delayed reactions, for example, tumour formation after treatments.5In recent years, stem cell‐based therapy has become a very promising biomedical research topic in China. The regulatory framework in China has been evolving in the past few decades, along with a deepening understanding of the scientific, social and ethical aspects of stem cell research. Although what is the most effective way to supervise and promote the development of stem cell therapy is still far from perfect in China and many other countries, patient‐focused assessment is critical for patient protection and clinical benefit‐risk evaluation in a well‐designed regulatory system.Both authors conceived the presented idea; G.J.C collected the data and wrote the paper; G.C.Y designed the analysis and modified the manuscript.


Drought is intensifying globally with climate change, creating an urgency to understand ecosystem response to drought both during and after these events end to limit loss of ecosystem functioning. The literature is replete with studies of how ecosystems respond during drought, yet there are far fewer studies focused on ecosystem dynamics after drought ends. Furthermore, while the terms used to describe drought can be variable and inconsistent, so can those that describe ecosystem responses following drought. With this review, we sought to evaluate and create clear definitions of the terms that ecologists use to describe post‐drought responses. We found that legacy effects, resilience and recovery were used most commonly with respect to post‐drought ecosystem responses, but the definitions used to describe these terms were variable. Based on our review of the literature, we propose a framework for generalizing ecosystem responses after drought ends, which we refer to as ‘the post‐drought period’. We suggest that future papers need to clearly describe characteristics of the imposed drought, and we encourage authors to use the term post‐drought period as a general term that encompasses responses after drought ends and use other terms as more specific descriptors of responses during the post‐drought period. Based on an initial review of the literature, we identified the following terms for our search: ‘drought AND legacy effect*’; ‘drought AND memory effect*’; ‘drought AND lag effect*’; ‘drought resilience’; ‘drought recovery’; and ‘compound drought OR compounded drought’. We did not filter by year or subject area so as to not miss any possible papers. This February 2021 search yielded 1415 results, of which we deemed 94 papers relevant Appendix . A largeThe 94 papers included in our review most commonly used the term legacy effect(s) 41%), followed by recovery (27%), resilience (19%), lag effect (4%), compound(ed) drought (4%), memory (4%) and rewetting (2%) , we counted the paper separately for each category they fell into. The drought characteristics examined were the reduction in precipitation that occurred; the length of drought; and whether there were one or two droughts. We found that studies were mostly from grassland and forest ecosystems, were mostly tree ring and plant growth measurements, consisted of mostly aboveground measurements and were mostly field experiments Fig. a. We alsc. 1 yr after the event ended when using the terms recovery, legacy effects and lagged effects. If a legacy effect or lagged effect is still occurring, this is probably closer in duration to when the drought ended. Lastly, drought memory studied the effects after drought on average after 0.5 yr. Although the terms differed in on how long on average investigators measured the effects post‐drought, the time frame in which post‐drought responses/effects were measured averaged around 1 yr after drought (range 0–20 yr), which could be too short‐term, since most papers observed lingering effects from the drought.One such study attribute was the average time after drought that studies measured post‐drought responses Fig. . When thet al., Another study attribute that provides important context for the post‐drought terms usage was the direction  of post‐drought responses measured Box . We founBox 2P‐value  would indicate that our results were not due to chance and there is a bias involved. The test produced a significant P‐value (< 0.001), which supports that reported results were biased toward those that are negative. We checked if this bias applies to just legacy effects papers, which was the category with the largest number of papers. There were nine studies with positive effects, 26 with negative effects and six with neutral effects. We found a significant P‐value in this test as well (P = 0.002), indicating that these differences were not due to chance.We identified papers as positive if the response after drought was positive (e.g. increased plant growth or increases in soil nutrients), negative if the response was negative (e.g. losses in plant growth or loss of soil nutrients) or neutral if there was no significant response found (e.g. plant growth was the same as the control or predisturbance). We counted the number of studies that by our definition had a positive, negative or neutral response. When papers had both neutral and negative effects or neutral and positive effects, we counted each effect as a separate entry. We conducted a chi‐square test for the number of papers that had positive, negative or neutral responses post‐drought to determine if the difference observed was by chance. Overall, 19 studies had positive effects, 55 had negative effects and 17 had neutral (or no) effects. To assess if there was bias in the publications, we used R statistical software and the base R function ‘chitest’ to obtain our Our review illuminated the variety of terms used to describe ecosystem responses after drought ends and the variability in definitions of these terms and the contexts in which they are used. To provide a cohesive framework, we propose using the term ‘post‐drought period’ to describe ecosystem responses that are observed after a drought ends Fig.  and usinet al., et al., The first most commonly used term in the papers we reviewed was legacy effects. Legacy effects and lag effects have similar definitions and thus can be used interchangeably. However, the term legacy effect(s) is more commonly used over lag effects, and we suggest it is the more appropriate term to use for describing responses during the post‐drought period. Furthermore, we propose that legacy effects be used to describe responses observed in the post‐drought period, whether they are positive or negative. These effects can last for an undefined period of time or could be indefinite. Sometimes the changes may be irreversible, indicating a state change, which would also be an example of a legacy effect. The term legacy effect(s) is most appropriate for describing the directionality of effects but would not be appropriate for describing a neutral effect. Legacy effects would also not be appropriate for describing the post‐drought period generally, since it is a descriptor of what occurred not a temporal description of the period after drought. As we observed across the papers used in this study, not all responses were positive or negative. Indeed, 19% of the papers had a neutral response, which would make legacy effects inappropriate for describing such responses, since our framework argues that legacy effects must have a directional response Fig. . AdditioThe second and third most commonly used terms were recovery and resilience. Both terms are different from legacy effects because they describe a trend towards pre‐drought conditions, but they are generally quantified in different ways  if they are observed. Compounded drought depicts the sequential occurrence of drought events within a certain period and is not related to the characteristics of ecosystem responses. We suggest calling the period after a compounded drought the post‐drought period and using the terms legacy effects, resilience and resistance in the same way as after a single drought event to describe the nature of the response. It is important to note that compounded drought has also been defined as another perturbation such as a heat wave occurring at the same time as drought  as the only mechanism responsible for the effect in the study Fig. . AdditioBox 3Mechanisms were grouped into categories (below) and then the numbers of papers that fit into these categories were counted. Mechanisms were determined by each paper’s reasoning for the response post‐drought typically highlighted in the discussion section. These mechanisms were then grouped and compiled as in Supporting Information Table Overall, our review suggests that we have limited understanding of the period after drought due to a dearth of studies and an undue emphasis on aboveground ecosystem responses, with potential publication biases making it difficult to parse out what happens after drought. Indeed, 71% of the studies examined aboveground ecosystem responses alone, which leaves a large gap in the knowledge of belowground responses after drought Fig. a. There et al., Furthermore, as a body of research in ecology matures, metaanalyses become an important way in which results from numerous studies can be synthesized to find generality  drought, double‐stressed or drought memory to describe the effect of a second drought after a previous drought has occurred in the system. This could be important for future understanding of a drying climate because subsequent drought events may occur before the system has recovered from a previous drought  should be directed to the Click here for additional data file.


C‐methylerythritol‐d‐erythritol 4‐phosphate (MEP) pathway  are responsible for the synthesis of universal precursors of the large and structurally diverse family of isoprenoids. This pathway is absent in humans, but present in many pathogenic organisms and plants, making it an attractive source of drug targets. Here, we present a high‐throughput screening approach that led to the discovery of a novel fragment hit active against the third enzyme of the MEP pathway, PfIspD. A systematic SAR investigation afforded a novel chemical structure with a balanced activity–stability profile (16). Using a homology model of PfIspD, we proposed a putative binding mode for our newly identified inhibitors that sets the stage for structure‐guided optimization.The enzymes of the 2‐ Screening of a part of the BASF library against the PfIspD enzyme led to the identification of a pyrrole as an underexplored chemical scaffold that is able to target the third enzyme in the MEP pathway. A detailed structure–activity relationship (SAR) study around the fragment hit compound helped us to successfully improve the potency as well as the physicochemical properties. C‐methylerythritol‐d‐erythritol 4‐phosphate (MEP) pathway, consists of seven enzymes, and is an essential biosynthetic pathway for the production of isopentenyl diphosphate (IDP) and its isomer dimethylallyl diphosphate (DMADP) both of which are universal building blocks of isoprenoids, a large and structurally diverse group of natural products with crucial physiological functions.Mycobacterium tuberculosis and Plasmodium falciparum, the parasite responsible for malaria, it is an attractive source of anti‐infective drug targets.C‐methylerythritol (CDP‐ME) from MEP and cytidine triphosphate CTP in the presence of Mg2+, with the release of inorganic diphosphate (PPi)  Figure .[7]Plasmodium IspD (PfIspD), we performed a high‐throughput screening (HTS), using the proprietary BASF library of about 100,000 diverse selected compounds. The search for novel antimalarial compounds endowed with a novel mechanism of action has a continuous and long history of research. Although novel approved treatments and preventions helped to save many lives, malaria is still responsible for more than 400,000 deaths worldwide, mostly young children.Looking at the IspD inhibitors, to date only a few compounds have been reported.16) able to inhibit PfIspD in vitro in the micromolar range and with a suitable physicochemical profile  study, as we could not rely on any structural information about the protein. High‐resolution structures are only available for Escherichia coli IspD,i) find a replacer for the pyrrole ring as it is known to be a structural alert,ii) validate the fragment hit by improving the potency and the physicochemical profile for further optimization. With these goals in mind, we initially started our exploration by keeping the core molecule constant and varying only the terminal nitro group (1–8); while, the second subset of molecules (9–18) includes modifications around the pyrrole ring.The screening performed against 50) values against purified PfIspD are reported in Table Half‐maximal inhibitory concentration .Compounds 3–5. In fact, while for the azolopyrimidine scaffold only activity against the plant Arabidopsis thaliana (AtIspD) is reported, the pseudilin‐type inhibitors showed potency against the malaria parasite too, in vitro and in cell‐based assays. Specifically, in our series of compounds, the best halogen turned out to be bromine (4) that is slightly more potent than hit 1 and about two‐fold more potent than its iodo derivative 5. By contrast, activity is completely lost upon introduction of an electron‐donating group (6–8) and also a short elongation with an acetamide group 8 is not tolerated. The drop in activity observed for compound 2 suggests the influence played by a substituent in position 5 of the phenyl ring within this subset of derivatives.Based on our previously reported discovery of azolopyrimidinesNext, we moved our attention to the pyrrole core. For consistency, we maintained the initial 5‐nitrobenzoic acid scaffold, having the 2‐position occupied by a small but diverse library of aliphatic and substituted aromatic rings  as a template and docked our compounds into the substrate binding pocket  parameter is not ideal. Most probably, the better IC50 value is due to the higher cLogP value. Conversely, with compound 16 we have a good balance in all the ligand efficiency scores evaluated. Of note, having an aromatic core with a nitrile substituent as in 16, has several advantages compared to the pyrrole liability.Finally, as the affinity for the target is not the only aspect to be considered during fragment‐based drug discovery, we also focused our attention on the physicochemical properties of our compounds  should be addressed to the authors.Supporting InformationClick here for additional data file.