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Abstract Background Light is a critical factor in plant growth and development, particularly in controlled environments. Light-emitting diodes (LEDs) have become a reliable alternative to conventional high pressure sodium (HSP) lamps because they are more efficient and versatile in light sources. In contrast to well-known specialized LED light spectra for vegetables, the appropriate LED lights for crops such as cotton remain unknown. Results In this growth chamber study, we selected and compared four LED lights with varying percentages (26.44%–68.68%) of red light (R, 600–700 nm), combined with other lights, for their effects on growth, leaf anatomy, and photosynthesis of cotton seedlings, using HSP lamp as a control. The total photosynthetic photon flux density (PPFD) was (215 ± 2) μmol·m−2·s−1 for all LEDs and HSP lamp. The results showed significant differences in all tested parameters among lights, and the percentage of far red (FR, 701–780 nm) within the range of 3.03%–11.86% was positively correlated with plant growth (characterized by leaf number and area, plant height, stem diameter, and total biomass), palisade layer thickness, photosynthesis rate (P n), and stomatal conductance (G s). The ratio of R/FR (4.445–11.497) negatively influenced the growth of cotton seedlings, and blue light (B) suppressed stem elongation but increased palisade cell length, chlorophyll content, and P n. Conclusion The LED 2 was superior to other LED lights and HSP lamp. It had the highest ratio of FR within the total PPFD (11.86%) and the lowest ratio of R/FR (4.445). LED 2 may therefore be used to replace HPS lamp under controlled environments for the study of cotton at the seedling stage.

Xinjiang cotton is characterized by high-density planting, which easily leads to competition between the source and sink, the shading of leaves and reproductive organs, and yield reduction. Balancing the relationship between source and sink can promote high and stable cotton yield. In this study, field experiments were conducted by combining the exogenous application of brassinosteroid with a reduction in leaf source to study their effects on the physiological and yield attributes of cotton. The results indicate that brassinosteroid application increased the yield, with a maximum yield increase of 6.3%. The number of bolls per plant increased by 1.3 nos. The photosynthetic rate and dry matter accumulation were enhanced, and the proportion of reproductive organs in the dry matter increased by >4%. Under the reduced leaf source, brassinosteroid application increased the number of new leaves by 20%, delayed the shedding of reproductive organs by 5–10 days, and reduced the average shedding rate by 8.9%. Additionally, the number of bolls increased in the middle and upper parts and at the edge of the plant. The number of bolls increased by 19.4% on the 4th–8th fruiting branches and 60.7% at the edge. Under leaf reduction treatment, brassinosteroid application could generally increase yield. After brassinosteroid application and removing half the leaves of fruiting branches and all leaves of the vegetive branches, the yield was higher than that of the control. Thus, brassinosteroid application could improve the efficiency of the leaf source and promote dry matter accumulation in sinks. Moreover, it could optimize boll distribution and increase yield by reducing reproductive organ shedding. Under the high-density planting of cotton in Xinjiang, leaf source is a slight surplus, and a moderate reduction in plant density is conducive to increasing yield.

Abstract Background The global burden of invasive fungal infections (IFIs) has shown an upsurge in recent years due to the higher load of immunocompromised patients suffering from various diseases. The role of early and accurate diagnosis in the aggressive containment of the fungal infection at the initial stages becomes crucial thus, preventing the development of a life-threatening situation. With the changing demands of clinical mycology, the field of fungal diagnostics has evolved and come a long way from traditional methods of microscopy and culturing to more advanced non-culture-based tools. With the advent of more powerful approaches such as novel PCR assays, T2 Candida, microfluidic chip technology, next generation sequencing, new generation biosensors, nanotechnology-based tools, artificial intelligence-based models, the face of fungal diagnostics is constantly changing for the better. All these advances have been reviewed here giving the latest update to our readers in the most orderly flow. Main text A detailed literature survey was conducted by the team followed by data collection, pertinent data extraction, in-depth analysis, and composing the various sub-sections and the final review. The review is unique in its kind as it discusses the advances in molecular methods; advances in serology-based methods; advances in biosensor technology; and advances in machine learning-based models, all under one roof. To the best of our knowledge, there has been no review covering all of these fields (especially biosensor technology and machine learning using artificial intelligence) with relevance to invasive fungal infections. Conclusion The review will undoubtedly assist in updating the scientific community’s understanding of the most recent advancements that are on the horizon and that may be implemented as adjuncts to the traditional diagnostic algorithms.

Defoliation and accelerating ripening are important measures for cotton mechanization, and judging the time of defoliation and accelerating the ripening and harvest of cotton relies heavily on the boll opening rate, making it a crucial factor to consider. The traditional methods of cotton opening rate determination are time-consuming, labor-intensive, destructive, and not suitable for a wide range of applications. In this study, the relationship between the change rate of the vegetation index obtained by the unmanned aerial vehicle multi-spectrum and the ground boll opening rate was established to realize rapid non-destructive testing of the boll opening rate. The normalized difference vegetation index (NDVI) and green normalized difference vegetation index (GNDVI) had good prediction ability for the boll opening rate. NDVI in the training set had an R2 of 0.912 and rRMSE of 15.387%, and the validation set performance had an R2 of 0.929 and rRMSE of 13.414%. GNDVI in the training set had an R2 of 0.901 and rRMSE of 16.318%, and the validation set performance had an R2 of 0.909 and rRMSE of 15.225%. The accuracies of the models based on GNDVI and NDVI were within the acceptable range. In terms of predictive models, random forests achieve the highest accuracy in predictions. Accurately predicting the cotton boll opening rate can support decision-making for harvest and harvest aid spray timing, as well as provide technical support for crop growth monitoring and precision agriculture.

Abstract Background Cotton production in China is challenged by high labor input including manual topping (MT). Recently, to replace MT in the Xinjiang cotton region of China, mepiquat chloride (MC) was applied once more than the traditional multiple-application; this was designated as chemical topping (CT), but it is unclear whether the amount of irrigation needs to be adjusted to accommodate CT. Results The main plots were assigned to three drip irrigation amounts [300 (I1), 480 (I2), and 660 (I3) mm], and the subplots were assigned to the CT treatments [450 (MC1), 750 (MC2), and 1 050 (MC3) mL·hm−2 25% MC] with MT as a control that was performed after early bloom. The optimum drip irrigation amount for CT was explored based on leaf photosynthesis, chlorophyll fluorescence, biomass accumulation, and yield. There were significant influences of drip irrigation, topping treatments and their interaction on chlorophyll fluorescence characteristics, gas exchange parameters and biomass accumulation characteristics as well as yield. The combination of I2 and MC2 (I2MC2) performed best. Compared with I2MT, the net photosynthetic rate (Pn), stomatal conductance (Gs), transpiration rate (Tr), and photochemical quenching coefficient (qP) of I2MC2 significantly increased by 4.0%∼7.2%, 6.8%∼17.1%, 5.2%∼17.6%, and 4.8%∼9.6%, respectively, from the peak flowering to boll opening stages. Moreover, I2MC2 showed fast reproductive organ biomass accumulation and the highest seed cotton yield; the latter was 6.6%∼12.8% higher than that of I2MT. Further analysis revealed that a 25% MC emulsion in water (MCEW) application resulted in yield improvement by increasing Pn, φPSII, and qP to promote biomass accumulation and transport to reproductive organs. Conclusion The results showed that the 480 mm drip irrigation combined with 750 mL·hm−2 MC increased the rate of dry matter accumulation in reproductive organs by increasing Pn, φPSII, and qP to improve photosynthetic performance, thus achieving higher yield.

Invasive Aspergillus fumigatus infection poses a serious threat to global human health, especially to immunocompromised individuals. Currently, triazole drugs are the most commonly used antifungals for aspergillosis. However, owing to the emergence of drug-resistant strains, the effect of triazole drugs is greatly restricted, resulting in a mortality rate as high as 80%. Succinylation, a novel post-translational modification, is attracting increasing interest, although its biological function in triazole resistance remains unclear. In this study, we initiated the screening of lysine succinylation in A. fumigatus. We discovered that some of the succinylation sites differed significantly among strains with unequal itraconazole (ITR) resistance. Bioinformatics analysis showed that the succinylated proteins are involved in a broad range of cellular functions with diverse subcellular localizations, the most notable of which is cell metabolism. Further antifungal sensitivity tests confirmed the synergistic fungicidal effects of dessuccinylase inhibitor nicotinamide (NAM) on ITR-resistant A. fumigatus. In vivo experiments revealed that treatment with NAM alone or in combination with ITR significantly increased the survival of neutropenic mice infected with A. fumigatus. In vitro experiments showed that NAM enhanced the killing effect of THP-1 macrophages on A. fumigatus conidia. Our results suggest that lysine succinylation plays an indispensable role in ITR resistance of A. fumigatus. Dessuccinylase inhibitor NAM alone or in combination with ITR exerted good effects against A. fumigatus infection in terms of synergistic fungicidal effect and enhancing macrophage killing effect. These results provide mechanistic insights that will aid in the treatment of ITR-resistant fungal infections.

Neutropenia is a common complication in the treatment of hematological diseases and the most common predisposing factor for invasion by fungi, such as Candida krusei. Recent studies have shown that C. krusei, a life-threatening pathogen, has developed resistance to amphotericin B (AMB). However, the mechanisms that led to the rapid emergence of this AMB-resistant phenotype are unclear. In this study, we found the sensitivity for AMB could be promoted by inhibiting histone acyltransferase activity and western blot analysis revealed differences in the succinylation levels of C. krusei isolated from immunocompromised patients and of the corresponding AMB-resistant mutant. By comparative succinyl-proteome analysis, we identified a total of 383 differentially expressed succinylated sites in with 344 sites in 134 proteins being upregulated in the AMB-resistant mutant, compared to 39 sites in 23 proteins in the wild-type strain. These differentially succinylated proteins were concentrated in the ribosome and cell wall. The critical pathways associated with these proteins included those involved in glycolysis, gluconeogenesis, the ribosome, and fructose and mannose metabolism. In particular, AMB resistance was found to be associated with enhanced ergosterol synthesis and aberrant amino acid and glucose metabolism. Analysis of whole-cell proteomes, confirmed by parallel reaction monitoring, showed that the key enzyme facilitating lysine acylation was significantly upregulated in the AMB-resistant strain. Our results suggest that lysine succinylation may play an indispensable role in the development of AMB resistance in C. krusei. Our study provides mechanistic insights into the development of drug resistance in fungi and can aid in efforts to stifle the emergence of AMB-resistant pathogenic fungi.

Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections with Candida of the skin, nails, and mucous membranes (e.g., mouth, esophagus, and vagina). Compared with that of other infectious diseases, the immune pathogenic mechanism of CMC is still poorly understood. We identified a signal transducer and activator of transcription 1 gain-of-function (c.Y289C) mutation in a CMC patient. Single-cell transcriptional profiling on peripheral blood mononuclear cells from this patient revealed decreases in immature B cells and monocytes. Further analysis revealed several differentially expressed genes related to immune regulation, including RGS1, TNFAIP3, S100A8/A9, and CTSS. In our review of the literature on signal transducer and activator of transcription 1 gain-of-function (c.Y289C) mutations, we identified seven cases in total. The median age of onset for CMC (n=4, data lacking for three cases) was 10.5 years (range: birth to 11 years), with an average onset age of 8 years. There were no reports linking tumors to the c.Y289C mutation, and the incidence of pre-existing clinical disease in patients with the c.Y289C mutation was similar to previous data.

Manual removal of the main stem tips of cotton (Gossypium hirsutum L.) is a traditional topping approach in China. However, chemical topping has become an inevitable trend. Therefore, it is of great significance to study the effect and appropriate concentration of agents for advancement of cotton whole process mechanization management technology. A two-year field experiment was conducted to evaluate the effects of different methods of topping on cotton yield and plant architecture in Shihezi, Xinjiang, China. Plant topping included manual topping, non-topping as the control, and chemical topping (high, medium, and low concentrations of topping agent) to determine a suitable topping method and topping agent concentration for machine-picked cotton. Chemical topping was performed using fortified mepiquat chloride (DPC+). Chemical topping and manual topping increased seed cotton yield compared with non-topping. Compared with non-topping, high, medium, and low concentrations of topping agent significantly increased the yield by 19.5–27.9%, 24.1–29.4%, and 24.3–28.4%, respectively. Topping treatment mainly regulated yield and total boll number per unit area by affecting the boll number per plant and had a certain positive effect on fiber strength but no significant effect on boll weight. Chemical topping affected both vertical and horizontal plant architecture characteristics of cotton; the plant height of low-, medium-, and high-concentration treatments increased by 7.2–11.4 cm, 4.0–5.7 cm, and 2.3–4.4 cm, respectively, compared with manual topping and decreased by 5.1–7.8 cm, 8.3–13.5 cm, and 9.4–16.9 cm, respectively, compared with non-topping. The number of main stem internodes was significantly different between high- and low-concentration treatments, which showed that the higher the concentration, the lower the number of the main stem internodes. Chemical topping controlled the increase in the length of the upper branches, the higher the concentration, the lower the increase in the length of the upper fruit branch. Compared with non-topping, the medium concentration of topping agent controlled the number of fruit branches, similar to manual topping. The role of upper internode length of cotton cannot be ignored under chemical topping. The peak leaf area index (LAI) of medium- and high-concentration treatments was delayed for 1 week in the late growth period (after topping for 28 d) compared with manual topping. The LAI values were high, and the duration of high values was prolonged. The optimal chemical topping agent was the medium concentration.

The use of 1,1-dimethyl-piperidinium chloride (DPC) in Xinjiang is one of the necessary measures for regulating cotton populations and optimizing canopy structure. However, mechanical spraying involves operation and energy consumption, which can alternatively be achieved via drip application. In the present study, to investigate the effect of drip application, two types of hydrophobic nano-released DPCs were used to regulate plant type at different dosages. DPC dripingation reduced plant height by more than 10 cm and plant width by more than 4 cm, and the effect improved with increasing concentration and times. The main effect of height control was at the 6th–10th nodes of the main stem, and the effect of width control was observed at the 1st and 2nd nodes of the fruit branch. The SPAD value was higher than that in the control group during the initial stages. An irregular downward trend was observed in the subsequent stages. The proline content was higher than that of the control and increased with higher concentrations of DPC. There was no significant difference in the soil DPC content at the different sites. The DPC content decreased by more than 30% at the seventh day after dripping, and the content was 2–4 μg·g−1 in each treatment. At 15 days after application, the soil DPC was lower than 1 μg·g−1 in all treatments. The number of harvested plants was more than 150,000 plants·hm−2, and the number of bolls per plant increased at least by one, compared with the control. The final yield of seed cotton increased by at least 300 kg·hm−2, with a maximum increase of 1672.01 kg·hm−2. Considering the different types of DPCs, nano-released types worked better than the conventional type in terms of plant height, plant width, degradation in soil and boll formation. Nano-released DPC can play an even better role than conventional DPC in chemical regulation with drip irrigation.

Thidiazuron (TDZ) is a widely used chemical defoliant in cotton and can stimulate the production of ethylene in leaves, which is believed to be the key factor in inducing leaf abscission. Ethephon (Eth) can also stimulate ethylene production in leaves, but it is less effective in promoting leaf shedding. In this study, the enzyme-linked immunosorbent assays (ELISA) and RNA-seq were used to determine specific changes at hormonal levels as well as transcriptomic mechanisms induced by TDZ compared with Eth. The TDZ significantly reduced the levels of auxin and cytokinin in cotton leaves, but no considerable changes were observed for Eth. In addition, TDZ specifically increased the levels of brassinosteroids and jasmonic acid in the leaves. A total of 13 764 differentially expressed genes that specifically responded to TDZ were identified by RNA-seq. The analysis of KEGG functional categories suggested that the synthesis, metabolism, and signal transduction of auxin, cytokinin, and brassinosteroid were all involved in the TDZ-induced abscission of cotton leaves. Eight auxin transport genes (GhPIN1-c_D, GhPIN3_D, GhPIN8_A, GhABCB19-b_A, GhABCB19-b_D, GhABCB2-b_D, GhLAX6_A, and GhLAX7_D) specifically responded to TDZ. The pro35S::GhPIN3a::YFP transgenic plants showed lower defoliation than the wild type treated with TDZ, and YFP fluorescence in leaves was almost extinguished after treatment with TDZ rather than Eth. This provides direct evidence that GhPIN3a is involved in the leaf abscission induced by TDZ. We found that 959 transcription factors (TFs) specifically responded to TDZ, and a co-expression network analysis (WGCNA) showed five hub TFs (GhNAC72, GhWRKY51, GhWRKY70, GhWRKY50, and GhHSF24) during chemical defoliation with TDZ. Our work sheds light on the molecular basis of TDZ-induced leaf abscission in cotton.

The balance between vegetative and reproductive growth is the central objective in the cotton production system, which is associated with cotton maturity and yield. In China, manual topping (MT) has been performed many years prior to or during the flowering period to inhibit vegetative growth and enhance reproductive growth. MT is gradually being replaced by chemical topping (CT) with mepiquat chloride (MC, 180 g ha−1, 98% soluble powder) due to labor shortages and increasing labor cost. To determine whether CT influences cotton maturity and yield relative to MT, we carried out field experiments at four locations in the Yellow River Valley of China during 2018–2020. The results showed that CT did not alter the boll age, and although it produced taller and slender spatial boll distribution under several environments, it had little effect on the accumulation of boll fraction (the number of bolls in a given period divided by total boll number) over time at the end of blooming across locations. As a result, there were no significant differences between MT and CT in boll opening percentage in the late season. CT did not influence yield or yield components, except under severe drought. Therefore, CT with MC (180 g/ha, 98% soluble powder) during the flowering period will not compromise the maturity or yield of cotton in the Yellow River Valley of China. Similar outcomes would be achieved in other areas with similar ecological conditions and social conditions that require an alternative to extensive manual labor.

Abstract Background Mepiquat chloride (MC), a plant growth regulator, enhances root growth by promoting lateral root formation in cotton. However, the underlying molecular mechanisms of this phenomenon is still unknown. Methods In this study, we used 10 cotton (Gossypium hirsutum Linn.) cultivars to perform a seed treatment with MC to investigate lateral root formation, and selected a MC sensitive cotton cultivar for dynamic monitor of root growth and transcriptome analysis during lateral root development upon MC seed treatment. Results The results showed that MC treated seeds promotes the lateral root formation in a dosage-depended manner and the effective promotion region is within 5 cm from the base of primary root. MC treated seeds induce endogenous auxin level by altering gene expression of both gibberellin (GA) biosynthesis and signaling and abscisic acid (ABA) signaling. Meanwhile, MC treated seeds differentially express genes involved in indole acetic acid (IAA) synthesis and transport. Furthermore, MC-induced IAA regulates the expression of genes related to cell cycle and division for lateral root development. Conclusions Our data suggest that MC orchestrates GA and ABA metabolism and signaling, which further regulates auxin biosynthesis, transport, and signaling to promote the cell division responsible for lateral root formation.

Cotton constitutes 81% of the world’s natural fibers. Accurate and rapid cotton yield estimation is important for cotton trade and agricultural policy development. Therefore, we developed a remote sensing index that can intuitively represent cotton boll characteristics and support cotton yield estimation by extracting cotton boll pixels. In our study, the Density of open Cotton boll Pixels (DCPs) was extracted by designing different cotton boll indices combined with the threshold segmentation method. The relationship between DCP and field survey datasets, the Density of Total Cotton bolls (DTC), and yield were compared and analyzed. Five common yield estimation models, Linear Regression (LR), Support Vector Regression (SVR), Classification and Regression Trees (CART), Random Forest (RF), and K-Nearest Neighbors (KNN), were implemented and evaluated. The results showed that DCP had a strong correlation with yield, with a Pearson correlation coefficient of 0.84. The RF method exhibited the best yield estimation performance, with average R2 and rRMSE values of 0.77 and 7.5%, respectively (five-fold cross-validation). This study showed that RedGreenBlue (RGB) and Near Infrared Red (NIR) normalized, a normalized form index consisting of the RGB and NIR bands, performed best.

Thidiazuron (TDZ) is widely used as a defoliant to induce leaf abscission in cotton. However, the underlying molecular mechanism is still unclear. In this study, RNA-seq and enzyme-linked immunosorbent assays (ELISA) were performed to reveal the dynamic transcriptome profiling and the change of endogenous phytohormones upon TDZ treatment in leaf, petiole, and abscission zone (AZ). We found that TDZ induced the gene expression of ethylene biosynthesis and signal, and promoted ethylene accumulation earlier in leaf than that in AZ. While TDZ down-regulated indole-3-acetic acid (IAA) biosynthesis genes mainly in leaf and IAA signal and transport genes. Furthermore, the IAA content reduced more sharply in the leaf than that in AZ to change the auxin gradient for abscission. TDZ suppressed CTK biosynthesis genes and induced CTK metabolic genes to reduce the IPA accumulation for the reduction of ethylene sensitivity. Furthermore, TDZ regulated the gene expression of abscisic acid (ABA) biosynthesis and signal and induced ABA accumulation between 12–48 h, which could up-regulate ABA response factor genes and inhibit IAA transporter genes. Our data suggest that TDZ orchestrates metabolism and signal of ethylene, auxin, and cytokinin, and also the transport of auxin in leaf, petiole, and AZ, to control leaf abscission.

Abstract Background In order to efficiently determine genotypic differences in rooting patterns of crops, novel hardware and software are needed simultaneously to characterize dynamics of root development. Results We describe a prototype robotic monitoring platform—the RhizoChamber-Monitor for analyzing growth patterns of plant roots automatically. The RhizoChamber-Monitor comprises an automatic imaging system for acquiring sequential images of roots which grow on a cloth substrate in custom rhizoboxes, an automatic irrigation system and a flexible shading arrangement. A customized image processing software was developed to analyze the spatio-temporal dynamics of root growth from time-course images of multiple plants. This software can quantify overall growth of roots and extract detailed growth traits (e.g. dynamics of length and diameter) of primary roots and of individual lateral roots automatically. It can also identify local growth traits of lateral roots (pseudo-mean-length and pseudo-maximum-length) semi-automatically. Two cotton genotypes were used to test both the physical platform and the analysis software. Conclusions The combination of hardware and software is expected to facilitate quantification of root geometry and its spatio-temporal growth patterns, and therefore to provide opportunities for high-throughput root phenotyping in support of crop breeding to optimize root architecture.

Mechanical harvesting has become inevitable for cotton production in China due to the rising labor cost in the country. It usually requires a moderate plant height and compact plant architecture. Correlation and stepwise regression were employed to analyze databases of our 24 field experiments between 2010 and 2017 in Hebei Province. The purpose is to identify the relationships between plant architecture traits and seed cotton yield within natural plant height range (58.6−163.2 cm) or preferred plant height range (80−120 cm) for mechanical harvesting in the Yellow River Valley of China, and define some important factors affecting seed cotton yield. Under natural plant height range across all experiments, there was a significantly negative correlation (r = −0.452) between plant height and yield. On limited plant height range desired for mechanical harvesting, the degree of this negative correlation decreased to r = −0.366. The correlation of plant height with seed cotton yield varied greatly with year, cultivar, plant density and mepiquat chloride (MC) application. Moreover, stepwise regression analysis picked internode length of the 1st (generally including 1st−7th mainstem node from bottom), 2nd (8th−12th node) and 4th (above 17th node) mainstem section and the length of lower fruiting branch (LFB) as significant factors influencing seed cotton yield under plant height range of 80−120 cm. The results have implications for precise control of cotton plant architecture preferred for mechanized harvesting in China.

Defoliants can increase machine harvest efficiency of cotton (Gossypium hirusutum L.), prevent lodging and reduce the time from defoliation to harvest. Coronatine (COR) is a chlorosis-inducing non-host-specific phytotoxin that induces leaf and/or fruit abscission in some crops. The present study investigates how COR might induce cotton leaf abscission by modulating genes involved in cell wall hydrolases and ACC (ethylene precursor) in various cotton tissues. The effects of COR on cotton boll ripening, seedcotton yield, and seed development were also studied. After 14 d of treatment with COR, cells within the leaf abscission zone (AZ) showed marked differentiation. Elevated transcripts of GhCEL1, GhPG and GhACS were observed in the AZs treated with COR and Thidiazuron (TDZ). The relative expression of GhCEL1 and GhACS in TDZ treated plants was approximately twice that in plants treated with COR for 12 h. However, only GhACS expression increased in leaf blade and petiole. There was a continuous increase in the activity of hydrolytic enzymes such as cellulase (CEL) and polygalacturonase (PG), and ACC accumulation in AZs following COR and TDZ treatments, but there was greater increase in ACC activity of COR treated boll crust, indicating that COR had greater ripening effect than TDZ. Coronatine significantly enhanced boll opening without affecting boll weight, lint percentage and seed quality. Therefore, COR can be a potential cotton defoliant with different physiological mechanism of action from the currently used TDZ.