Complexes of tubulin oligomers and tau form a viscoelastic intervening network cross-bridging microtubules into bundles.

The axon-initial-segment (AIS) of mature neurons contains microtubule (MT) fascicles (linear bundles) implicated as retrograde diffusion barriers in the retention of MT-associated protein (MAP) tau inside axons. Tau dysfunction and leakage outside of the axon is associated with neurodegeneration. We report on the structure of steady-state MT bundles in varying concentrations of Mg2+ or Ca2+ divalent cations in mixtures containing αß-tubulin, full-length tau, and GTP at 37 °C in a physiological buffer. A concentration-time kinetic phase diagram generated by synchrotron SAXS reveals a wide-spacing MT bundle phase (Bws), a transient intermediate MT bundle phase (Bint), and a tubulin ring phase. SAXS with TEM of plastic-embedded samples provides evidence of a viscoelastic intervening network (IN) of complexes of tubulin oligomers and tau stabilizing MT bundles. In this model, αß-tubulin oligomers in the IN are crosslinked by tau's MT binding repeats, which also link αß-tubulin oligomers to αß-tubulin within the MT lattice. The model challenges whether the cross-bridging of MTs is attributed entirely to MAPs. Tubulin-tau complexes in the IN or bound to isolated MTs are potential sites for enzymatic modification of tau, promoting nucleation and growth of tau fibrils in tauopathies.

Effects of irrigation scheduling on the yield and irrigation water productivity of cucumber in coconut coir culture.

Optimum irrigation scheduling is important for ensuring high yield and water productivity in substrate-cultivated vegetables and is determined based on information such as substrate water content, meteorological parameters, and crop growth. The aim of this study was to determine a precise irrigation schedule for coconut coir culture in a solar greenhouse by comparing the irrigation, evapotranspiration (ET), substrate water content (VWC), as well as the crop growth indices and yield of cucumber, and irrigation water productivity (IWP) under three irrigation schedules: the soil moisture sensor-based method (T-VWC), the accumulated radiation combined with soil moisture sensor-based method (Rn-VWC), and the crop evapotranspiration estimated method using the hourly PM-ETo equation with an improved calculation of Kc (T-ETc). The results showed that the daily irrigation and evapotranspiration amount were the highest under T-VWC treatment, while the lowest under T-ETc treatment. In different meteorological environments, the change in irrigation amount was more consistent with the ET,and the VWC was relatively stable in T-ETc treatment compared with that under T-VWC or Rn-VWC treatments. The plant height, leaves number, leaf area, and stem diameter of T-VWC and Rn-VWC treatments were higher than those of the T-ETc treatments, but there was no significant difference in cucumber yield. Compared with the T-VWC treatment, total irrigation amount under Rn-VWC and T-ETc treatments significantly decreased by 25.75% and 34.04%, respectively ([Formula: see text]). The highest IWP values of 25.07 kg m[Formula: see text] was achieved from T-ETc treatment with significantly increasing by 44.33% compared to the T-VWC treatment (17.37 kg m[Formula: see text]). In summary, the T-ETc treatment allowed more reasonable irrigation management and was appropriate for growing cucumber in coconut coir culture.

Lipids with negative spontaneous curvature decrease the solubility of the cancer drug paclitaxel in liposomes.

Paclitaxel (PTX) is a hydrophobic small-molecule cancer drug that loads into the membrane (tail) region of lipid carriers such as liposomes and micelles. The development of improved lipid-based carriers of PTX is an important objective to generate chemotherapeutics with fewer side effects. The lipids 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and glyceryl monooleate (GMO) show propensity for fusion with other lipid membranes, which has led to their use in lipid vectors of nucleic acids. We hypothesized that DOPE and GMO could enhance PTX delivery to cells through a similar membrane fusion mechanism. As an important measure of drug carrier performance, we evaluated PTX solubility in cationic liposomes containing GMO or DOPE. Solubility was determined by time-dependent kinetic phase diagrams generated from direct observations of PTX crystal formation using differential-interference-contrast optical microscopy. Remarkably, PTX was much less soluble in these liposomes than in control cationic liposomes containing univalent cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC), which are not fusogenic. In particular, PTX was not substantially soluble in GMO-based cationic liposomes. The fusogenicity of DOPE and GMO is related to the negative spontaneous curvature of membranes containing these lipids, which drives formation of nonlamellar self-assembled phases (inverted hexagonal or gyroid cubic). To determine whether PTX solubility is governed by lipid membrane structure or by local intermolecular interactions, we used synchrotron small-angle X-ray scattering. To increase the signal/noise ratio, we used DNA to condense the lipid formulations into lipoplex pellets. The results suggest that local intermolecular interactions are of greater importance and that the negative spontaneous curvature-inducing lipids DOPE and GMO are not suitable components of liposomal carriers for PTX delivery.

Lipids with negative spontaneous curvature decrease the solubility of the cancer drug paclitaxel in liposomes.

Paclitaxel (PTX) is a hydrophobic small-molecule cancer drug that loads into the membrane (tail) region of lipid carriers such as liposomes and micelles. The development of improved lipid-based carriers of PTX is an important objective to generate chemotherapeutics with fewer side effects. The lipids 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and glyceryl monooleate (GMO) show propensity for fusion with other lipid membranes, which has led to their use in lipid vectors of nucleic acids. We hypothesized that DOPE and GMO could enhance PTX delivery to cells through a similar membrane fusion mechanism. As an important measure of drug carrier performance, we evaluated PTX solubility in cationic liposomes containing GMO or DOPE. Solubility was determined by time-dependent kinetic phase diagrams generated from direct observations of PTX crystal formation using differential-interference-contrast optical microscopy. Remarkably, PTX was much less soluble in these liposomes than in control cationic liposomes containing univalent cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC), which are not fusogenic. In particular, PTX was not substantially soluble in GMO-based cationic liposomes. The fusogenicity of DOPE and GMO is related to the negative spontaneous curvature of membranes containing these lipids, which drives formation of nonlamellar self-assembled phases (inverted hexagonal or gyroid cubic). We used synchrotron small-angle x-ray scattering to determine whether PTX solubility is governed by lipid membrane structure (condensed with DNA in pellet form) or by local intermolecular interactions. The results suggest that local intermolecular interactions are of greater importance and that the negative spontaneous curvature-inducing lipids DOPE and GMO are not suitable components of lipid carriers for PTX delivery regardless of carrier structure.

Synchrotron X-ray study of intrinsically disordered and polyampholytic Tau 4RS and 4RL under controlled ionic strength.

Aggregated and hyperphosphorylated Tau is one of the pathological hallmarks of Alzheimer's disease. Tau is a polyampholytic and intrinsically disordered protein (IDP). In this paper, we present for the first time experimental results on the ionic strength dependence of the radius of gyration (Rg) of human Tau 4RS and 4RL isoforms. Synchrotron X-ray scattering revealed that 4RS Rg is regulated from 65.4 to 58.5 Å and 4RL Rg is regulated from 70.9 to 57.9 Å by varying ionic strength from 0.01 to 0.592 M. The Rg of 4RL Tau is larger than 4RS at lower ionic strength. This result provides an insight into the ion-responsive nature of intrinsically disordered and polyampholytic Tau, and can be implicated to the further study of Tau-Tau and Tau-tubulin intermolecular structure in ionic environments.

Performance analysis of two typical greenhouse lettuce production systems: commercial hydroponic production and traditional soil cultivation.

Introduction: Due to the shortage of land and water resource, optimization of systems for production in commercial greenhouses is essential for sustainable vegetable supply. The performance of lettuce productivity and the economic benefit in greenhouses using a soil-based system (SBS) and a hydroponic production system (HPS) were compared in this study. Methods: Experiments were conducted in two identical greenhouses over two growth cycles (G1 and G2). Three treatments of irrigation volumes (S1, S2, and S3) were evaluated for SBS while three treatments of nutrient solution concentration (H1, H2, and H3) were evaluated for HPS; the optimal levels from each system were then compared. Results and discussion: HPS was more sensitive to the effects of environmental temperature than SBS because of higher soil buffer capacity. Compared with SBS, higher yield (more than 134%) and higher water productivity (more than 50%) were observed in HPS. We detected significant increases in ascorbic acid by 28.31% and 16.67% and in soluble sugar by 57.84% and 32.23% during G1 and G2, respectively, compared with SBS. However, nitrate accumulated in HPS-grown lettuce. When the nutrient solution was replaced with fresh water 3 days before harvest, the excess nitrate content of harvested lettuce in HPS was removed. The initial investment and total operating cost in HPS were 21.76 times and 47.09% higher than those in SBS, respectively. Consideration of agronomic, quality, and economic indicators showed an overall optimal performance of the H2 treatment. These findings indicated that, in spite of its higher initial investment and requirement of advanced technology and management, HPS was more profitable than SBS for commercial lettuce production.

Sequencing and analysis of the complete mitochondrial genomes of Toona sinensis and Toona ciliata reveal evolutionary features of Toona.

BACKGROUND: Toona is a critical genus in the Meliaceae, and the plants of this group are an asset for both restorative and restorative purposes, the most flexible of which are Toona sinensis and Toona ciliata. To concentrate on the advancement of mitochondrial(Mt) genome variety in T.sinensis and T.ciliata, the Mt genomes of the two species were sequenced in high throughput independently, after de novo assembly and annotation to construct a Mt genome map for comparison in genome structure. Find their repetitive sequences and analyze them in comparison with the chloroplast genome, along with Maximum-likelihood(ML) phylogenetic analysis with 16 other relatives. RESULTS: (1) T. sinensis and T.ciliata are both circular structures with lengths of 683482 bp and 68300 bp, respectively. They share a high degree of similarity in encoding genes and have AT preferences. All of them have the largest Phe concentration and are the most frequently used codons. (2) Both of their Mt genome are highly preserved in terms of structural and functional genes, while the main variability is reflected in the length of tRNA, the number of genes, and the value of RSCU. (3) T. siniensis and T. ciliata were detected to have 94 and 87 SSRs, respectively, of which mononucleotides accounted for the absolute proportion. Besides, the vast majority of their SSRs were found to be poly-A or poly-T. (4)10 and 11 migrating fragments were identified in the comparison with the chloroplast genome, respectively. (5) In the ML evolutionary tree, T.sinensis and T.ciliata clustered individually into a small branch with 100% support, reflecting two species of Toona are very similarly related to each other. CONCLUSIONS: This research provides a basis for the exploitation of T.sinensis and T.ciliata in terms of medicinal, edible, and timber resources to avoid confusion; at the same time, it can explore the evolutionary relationship between the Toona and related species, which does not only have an important practical value, but also provides a theoretical basis for future hybrid breeding of forest trees, molecular markers, and evolutionary aspects of plants, which has great scientific significance.

Efficient In Vitro Sterilization and Propagation from Stem Segment Explants of Cnidoscolus aconitifolius (Mill.) I.M. Johnst, a Multipurpose Woody Plant.

Cnidoscolus aconitifolius (Mill.) I.M. Johnst is a multipurpose woody plant. In this study, an in vitro efficient propagation system of stem segment explants derived from field-grown C. aconitifolius plants was established for the first time. The sterilization effect, axillary bud initiation, and proliferation efficiency of stem segments were evaluated. The results showed that the sterilization time of 0.1% mercuric chloride, the concentration of Plant Preservative Mixture (PPM), the pretreatment method, and the sampling season had significant effects on the sterilization of stem segments (p < 0.05). The type of medium and plant growth regulators (PGRs) affected the initiation of axillary buds, and the proliferation efficiency was significantly affected by PGRs. The results showed that the best sterilization method for stem segment explants was as follows: a pretreatment by rinsing with running water for 120 min, soaking in 75% ethanol for 50 s, soaking in 0.1% mercuric chloride for 10 min, and medium supplemented with 3 mL/L PPM. When inoculated on the medium in spring, the contamination rate was as low as 25.56%. The optimal initiation medium for axillary buds in stem segments was half-strength Murashige and Skoog (1/2 MS) medium supplemented with 0.5 mg/L 6-benzyladenine (6-BA). The induction rate was as high as 93.33%, and the mean length of axillary buds was 2.47 cm. The optimal proliferation medium was 1/2 MS medium supplemented with 4.0 mg/L 6-BA and 0.2 mg/L indole-3-butyric acid (IBA). The induction rate was up to 80.00%, the total proliferation coefficient was 4.56, and the net proliferation coefficient was 5.69. The 1/2 MS medium supplemented with 0.1 mg/L 6-BA and 1.5 mg/L indole-3-acetic acid (IAA) was most conducive to the elongation of the adventitious shoot, and the adventitious shoot of approximately 1 cm reached 1.93 cm after culturing for 14 days. The best medium for adventitious shoot rooting was 1/2 MS medium supplemented with 0.1 mg/L α-naphthalene acetic acid (NAA), the highest rooting rate was 82.00%, and the survival rate of transplanting was over 90%.

An Efficient Propagation System through Root Cuttings of an Ecological and Economic Value Plant-Broussonetia papyrifera (L.) L'Hér. ex Vent.

Broussonetia papyrifera (L.) L'Hér. ex Vent. has considerable economic and ecological value and a long history of use in China. In this paper, root cuttings were used as the material to establish an efficient vegetative propagation of B. papyrifera. The results revealed that root segments with a diameter of 1.5~2.0 cm and a length of 20~30 cm were most suitable for shoot regeneration, as these segments had the highest adventitious shoot induction rates (93.3%), strongest adventitious shoots, and highest multiplication coefficients (7.07). With regard to the methods used for root burial, a horizontal burial at a depth of 1~3 cm yielded the best results, in this case, the adventitious shoot induction rate can reach 86.7%. The best substrate combination was perlite: peat: coconut chaff = 1:1:1 (v/v/v), wherein the adventitious shoot induction rate can reach 75.6%. The best sterilization method was mixing soil with carbendazim and soaking the root sections in carbendazim for 30 min, wherein the adventitious shoot induction rate can reach 77.8%. Adding 0.2 mg/L naphthaleneacetic acid (NAA) to 1/4 Hoagland nutrient solution significantly improved the rooting rate of adventitious shoots to 82.2%, and the survival rate of the acclimatized plants was more than 90.0%.

Responses of butter leaf lettuce to mixed red and blue light with extended light/dark cycle period.

To investigate the effects of extended light/dark (L/D) cycle period (relative to the diurnal L/D cycle) on lettuce and explore potential advantages of abnormal L/D cycles, butter leaf lettuce were grown in a plant factory with artificial light (PFAL) and exposed to mixed red (R) and blue (B) LED light with different L/D cycles that were respectively 16 h light/8 h dark (L16/D8, as control), L24/D12, L48/D24, L96/D48 and L120/D60. The results showed that, all the abnormal L/D cycles increased shoot dry weight (DW) of lettuce (by 34-83%) compared with the control, and lettuce DW increased with the L/D cycle period prolonged. The contents of soluble sugar and crude fiber in lettuce showed an overall upward trend with the length of L/D cycle extended, and the highest vitamin C content as well as low nitrate content were both detected in lettuce treated with L120/D60. The light use efficiency (LUE) and electric use efficiency (EUE) of lettuce reached the maximum (respectively 5.37% and 1.76%) under L120/D60 treatment and so were DW, Assimilation rate (A), RC/CS, ABS/CS, TRo/CS and DIo/CS, indicating that longer L/D cycle period was beneficial for the assimilation efficiency and dry matter accumulation in lettuce leaves. The highest shoot fresh weight (FW) and nitrate content detected in lettuce subjected to L24/D12 may be related to the vigorous growth of root, specific L/D cycle seemed to strengthen root growth and water absorption of lettuce. The openness level of RC in PSII (Ψo), ETo/CS, and PIabs were all the highest in lettuce treated with L24/D12, implying that slightly extending the L/D cycle period might promote the energy flowing to the final electron transfer chain. In general, irradiation modes with extended L/D cycle period had the potential to improve energy use efficiency and biomass of lettuce in PFAL. No obvious stress or injury was detected in lettuce subjected to prolonged L/D cycles in terms of plant growth and production. From the perspective of shoot FW, the optimal treatment in this study was L24/D12, while L120/D60 was the recommended treatment as regards of the energy use efficiency and nutritional quality.

CB-LPD, MGUS, T-LGLL, and PRCA: A rare case report of 4 concomitant hematological disorders.

RATIONALE: Monoclonal gammopathy of undetermined significance (MGUS) is a clinically asymptomatic clonal plasma cell or lymphoplasmacytic proliferative disorder. Recently, some case reports have described the association of pure red cell aplasia (PRCA) with MGUS, even with a relatively low monoclonal immunoglobulin burden. T large granular lymphocyte leukemia (T-LGLL) is a chronic lymphoproliferative disorder characterized by clonal expansion of T large granular lymphocytes, which is rare in China. There are some reports about T-LGL leukemia in patients with B-cell lymphoma; however, it is very rare that T-LGLL coexists with MGUS and clonal B-cell lymphoproliferative disorders (CB-LPD). PATIENT CONCERNS: A 77-year-old man was hospitalized because of anemia. He was diagnosed with MGUS, CB-LPD, and PRCA. During the development of the disease, a group of abnormal T lymphocytes was detected by flow cytometry of peripheral blood. DIAGNOSIS: Combining clinical manifestations with the result of T cell receptor gene rearrangement and immunophenotype, it was consistent with the diagnosis of T large granular lymphocyte leukemia. INTERVENTIONS: The patient was treat with bortezomib and dexamethasone regimen, Rituximab and sirolimus. OUTCOMES: The patient was transfusion independent after therapies. LESSONS: We report a patient with 4 concomitant hematological disorders: T-LGLL, MGUS, CB-LPD, and PRCA, aiming to represent the clinical and flow cytometry characteristics of these concomitant diseases, analyze the mechanism between diseases, and provide a clinical reference.

Development and validation of a nomogram for steroid-resistance prediction in immune thrombocytopenia patients.

OBJECTIVES: Corticosteroid is first-line therapy in immune thrombocytopenia. However, nearly 30% of patients appear in steroid-resistance. Our research analyses the relevant indicators of patients and develops a risk prediction model to predict the poor response to steroid-therapy in ITP patients. METHODS: We collected data from 111 ITP patients admitted to Xiamen University Zhongshan Hospital from 2013 to 2019 as the training cohort and 65 ITP patients during 2019-2020 as the external validation cohort. Screening significant factors(P < 0.05) in univariate analysis, and further identified to be independent variables in multivariable logistic regression analysis. Incorporated the significant risk factors in and presented them with a nomogram based on independent risk predictors. The nomogram was assessed by receiver operating characteristics curves and decision curve analysis. RESULTS: We constructed a steroid-resistance prediction model based on the potential predictors including age, serum ferritin and expression of HBsAg. As a result, based on the area under the ROC curves, the training cohort (AUC: 0.718, 95% CI: 0.615-0.821) and the external validation cohort (AUC:0.799,95%CI:0.692-0.905), which displayed good discrimination. The decision curve showed that predicting the steroid-refractory risk in ITP patients using this nomogram with a range of the threshold probability between >16% and <70%. The nomogram appears good performance in predicting steroid-refractory ITP patients. CONCLUSION: Prediction model shows that elder patients with a high level of ferritin and positive expression of HBsAg may appear a high possibility of steroid-resistance. For these patients, TPO-RAs can be considered to help patients to get better treatment effects and develop a better health-related quality of life.

Cardiac dysfunction associated with consumptive hypothyroidism in a case of hepatic haemangioma.

Not required for Clinical Vignette.

Red and blue wavelengths affect the morphology, energy use efficiency and nutritional content of lettuce (Lactuca sativa L.).

Since red (R) and blue (B) LED light has different quantum efficiency and photoelectric conversion efficiency, mixed RB with different proportions of R and B results in varied energy consumption. In order to improve the energy use efficiency of the closed-type plant production systems, the effects of R and B proportions on the electric use efficiency (EUE), light use efficiency (LUE) as well as the quality of butter leaf lettuce were evaluated in this study. Lettuce seedlings were cultivated in a plant factory with artificial lighting (PFAL) and subjected to eleven combinations of R and B (100%R, 90%R, 80%R, 70%R, 60%R, 50%R, 40%R, 30%R, 20%R, 10%R, 0%R; the rest of the photons in each treatment were B) with the same total photosynthetic photon flux density (PPFD) and photoperiod (200 ± 3 µmol·m-2·s-1, 16 h) for 35 days. The results showed that palpable petiole distortion appeared when R proportion was more than 70% and the distortion was aggravated with the increase of R proportion. The highest EUE and LUE were both detected in lettuce under 90%R treatment, which were respectively 3.64% and 1.20%. The least number of photons and the least electricity amount required to produce 1 g dry weight of lettuce was respectively 2.92 mol and 1.67 MJ, which were both detected in lettuce treated with 90%R. The sucrose content in lettuce treated with more than 50%R was significantly higher than those treated with less than 50%R (50%R included). Lettuce treated with 80%R possessed the highest soluble sugar content as well as the lowest crude fiber and nitrate content (not significantly different with the minimum values). R proportion exceeding 50% in mixed RB light was beneficial to the accumulation of hexose and sucrose, as well as the decomposition of nitrate in lettuce. The vitamin C content in lettuce treated with 100%R was significantly higher than that in lettuce under other treatments in the study. On the whole, the study indicated that the proportions of R and B affected the energy use efficiency and quality of lettuce in closed plant factory, however the responses of plants to the proportions of R and B varied according to different indexes. Thus, some indexes of top priority should be determined before choosing the optimal proportions of R and B.

Paclitaxel loading in cationic liposome vectors is enhanced by replacement of oleoyl with linoleoyl tails with distinct lipid shapes.

Lipid carriers of hydrophobic paclitaxel (PTX) are used in clinical trials for cancer chemotherapy. Improving their loading capacity requires enhanced PTX solubilization. We compared the time-dependence of PTX membrane solubility as a function of PTX content in cationic liposomes (CLs) with lipid tails containing one (oleoyl; DOPC/DOTAP) or two (linoleoyl; DLinPC/newly synthesized DLinTAP) cis double bonds by using microscopy to generate kinetic phase diagrams. The DLin lipids displayed significantly increased PTX membrane solubility over DO lipids. Remarkably, 8 mol% PTX in DLinTAP/DLinPC CLs remained soluble for approximately as long as 3 mol% PTX (the solubility limit, which has been the focus of most previous studies and clinical trials) in DOTAP/DOPC CLs. The increase in solubility is likely caused by enhanced molecular affinity between lipid tails and PTX, rather than by the transition in membrane structure from bilayers to inverse cylindrical micelles observed with small-angle X-ray scattering. Importantly, the efficacy of PTX-loaded CLs against prostate cancer cells (their IC50 of PTX cytotoxicity) was unaffected by changing the lipid tails, and toxicity of the CL carrier was negligible. Moreover, efficacy was approximately doubled against melanoma cells for PTX-loaded DLinTAP/DLinPC over DOTAP/DOPC CLs. Our findings demonstrate the potential of chemical modifications of the lipid tails to increase the PTX membrane loading while maintaining (and in some cases even increasing) the efficacy of CLs. The increased PTX solubility will aid the development of liposomal PTX carriers that require significantly less lipid to deliver a given amount of PTX, reducing side effects and costs.

Forced Crowding of Colloids by Thermophoresis and Convection in a Custom Liquid Clusius-Dickel Microdevice.

We report a study demonstrating that simultaneous induction of a steady-state convection current and temperature gradient in a confined geometry can be an effective way to force crowding of dissolved particulates. To investigate this thermogravitationally driven concentration of particles in situ, we developed a microdevice capable of sustaining controlled transverse temperature gradients within a 5 cm long, 0.1 mm inner diameter capillary that allowed visualization of particle movement with standard optical microscopy. Experiments were conducted on two material systems representative of nanoscale small molecules and microscale particles. With the small molecules (aromatic dyes, 530-790 g/mol, 1-1.5 nm), thermophoretic and gravitational effects in the microdevice resulted in an asymmetrical 2× concentration change along the capillary height over 3 days. In contrast, the concentration change under similar conditions for 40-micron diameter latex colloids is 50-fold in 30 min. This dramatic difference in separation times is consistent with simulations and models of thermophoresis where the thermophoretic effect scales with particle size. Induced crowding of particulates leads to formation of accumulation and depletion zones at the bottom and top of the capillary, respectively. Both the concentration of dye molecules over time in the depletion zone and the spatial distribution of colloids over the entire capillary length were found to be good fits to simple first-order exponential decay functions. These results suggest potential applications of thermogravitational separation in developing new functional materials via thermophoretic and convective effects.

Relapsed/refractory acute promyelocytic leukemia with RARA-LBD region mutation was salvaged by venetoclax: A case report.

RATIONALE: Acute promyelocytic leukemia (APL) is one of the most curable cancers. However, relapse of the disease is a difficult issue in clinical practice and it remains a great challenge that patients have a poor effect of conventional treatment in the clinic. Therefore, new and more effective therapeutic measures are urgently needed. Herein, we report a case of relapsed and refractory APL harboring a RARA-LBD region mutation successfully treated with venetoclax (VEN). PATIENT CONCERNS: A 37-years-old woman was admitted to our hospital with worsening spontaneous gingival bleeding and skin ecchymosis. Physical examination revealed multiple petechiae and ecchymosis in the extremities. DIAGNOSES: The patient was diagnosed with L-type PML-RARα-positive APL, harboring a RARA-LBD region mutation, low-risk, based on bone marrow cytology, immunophenotypic analysis by flow cytometry, karyotype analysis, and molecular analysis. INTERVENTIONS: Complete remission was achieved after the first induction therapy of all-trans retinoic acid (ATRA) combined with arsenic trioxide, but relapse was observed only after 11 months. Reinduction with ATRA and arsenic trioxide combined with anthracycline failed. Therefore, we tried to provide a new treatment with the Bcl-2 inhibitor VEN orally (100 mg d1, 200 mg d2 to d18, followed by 300 mg daily continuously). OUTCOMES: Clinical symptoms and laboratory indicators improved rapidly with VEN treatment. A complete hematologic response was achieved with VEN-based therapy. LESSONS: Related drug resistance gene monitoring should be performed canonically in relapsed and refractory APL. Some relapsed and refractory APL that failed to respond to conventional treatment were at risk of death. Bcl-2 inhibitors are expected to be an effective salvage therapy for patients with resistance to ATRA, which is worthy of further discussion.

Assembly of Building Blocks by Double-End-Anchored Polymers in the Dilute Regime Mediated by Hydrophobic Interactions at Controlled Distances.

Hierarchical assembly of building blocks via competing, orthogonal interactions is a hallmark of many of nature's composite materials that do not require highly specific ligand-receptor interactions. To mimic this assembly mechanism requires the development of building blocks capable of tunable interactions. In the present work, we explored the interplay between repulsive (steric and electrostatic) and attractive hydrophobic forces. The designed building blocks allow hydrophobic forces to effectively act at controlled, large distances, to create and tune the assembly of membrane-based building blocks under dilute conditions, and to affect their interactions with cellular membranes via physical cross-bridges. Specifically, we employed double-end-anchored poly(ethylene glycol)s (DEA-PEGs)-hydrophilic PEG tethers with hydrophobic tails on both ends. Using differential-interference-contrast optical microscopy, synchrotron small-angle X-ray scattering (SAXS), and cryogenic electron microscopy, we investigated the ability of DEA-PEGs to mediate assembly in the dilute regime on multiple length scales and on practical time scales. The PEG length, anchor hydrophobicity, and molar fraction of DEA-PEG molecules within a membrane strongly affect the assembly properties. Additional tuning of the intermembrane interactions can be achieved by adding repulsive interactions via PEG-lipids (steric) or cationic lipids to the DEA-PEG-mediated attractions. While the optical and electron microscopy imaging methods provided qualitative evidence of the ability of DEA-PEGs to assemble liposomes, the SAXS measurements and quantitative line-shape analysis in dilute preparations demonstrated that the ensemble average of loosely organized liposomal assemblies maintains DEA-PEG concentration-dependent tethering on defined nanometer length scales. For cationic liposome-DNA nanoparticles (CL-DNA NPs), aggregation induced by DEA-PEGs decreased internalization of NPs by cells, but tuning the DEA-PEG-induced attractions by adding repulsive steric interactions via PEG-lipids limited aggregation and increased NP uptake. Furthermore, confocal microscopy imaging together with colocalization studies with Rab11 and LysoTracker as markers of intracellular pathways showed that modifying CL-DNA NPs with DEA-PEGs alters their interactions with the plasma and endosomal membranes.

Tubulin Double Helix: Lateral and Longitudinal Curvature Changes of Tubulin Protofilament.

By virtue of their native structures, tubulin dimers are protein building blocks that are naturally preprogrammed to assemble into microtubules (MTs), which are cytoskeletal polymers. Here, polycation-directed (i.e., electrostatically tunable) assembly of tubulins is demonstrated by conformational changes to the tubulin protofilament in longitudinal and lateral directions, creating tubulin double helices and various tubular architectures. Synchrotron small-angle X-ray scattering and transmission electron microscopy reveal a remarkable range of nanoscale assembly structures: single- and double-layered double-helix tubulin tubules. The phase transitions from MTs to the new assemblies are dependent on the size and concentration of polycations. Two characteristic scales that determine the number of observed phases are the size of polycation compared to the size of tubulin (≈4 nm) and to MT diameter (≈25 nm). This work suggests the feasibility of using polycations that have scissor- and glue-like properties to achieve "programmable breakdown" of protein nanotubes, tearing MTs into double-stranded tubulins and building up previously undiscovered nanostructures. Importantly, a new role of tubulins is defined as 2D shape-controllable building blocks for supramolecular architectures. These findings provide insight into the design of protein-based functional materials, for example, as metallization templates for nanoscale electronic devices, molecular screws, and drug delivery vehicles.

A Multifunctional Lipid Incorporating Active Targeting and Dual-Control Release Capabilities for Precision Drug Delivery.

Active targeting and precise control of drug release based on nanoparticle therapies are urgently required to precisely treat cancer. We have custom-synthesized a functional lipid (termed Fa-ONB) by introducing a folic acid-targeting group into an o-nitro-benzyl ester lipid. As designed, the liposomes formed by Fa-ONB combine active targeting and dual trigger release capabilities, which help to improve drug efficacy and reduce the toxicity of traditional liposomes. We first verified that both pH-induced hydrolysis and light treatment were able to cleave the Fa-ONB lipid. We then prepared a series of liposomes (termed FOBD liposomes) by compounding the Fa-ONB lipid with DOPC at different ratios. After encapsulation of doxorubicin (DOX), we found that the particle size of DOX-loaded FOBD liposomes (DOX/FOBD) first increased (290 to 700 nm) and then decreased again (to 400 nm) under continuous UV irradiation (120 min). The photocatalytic release efficiency under different pH conditions was investigated by dialysis experiments, and it was found that the release efficiency in an acidic environment was significantly increased relative to neutral pH. This pH-triggered release response helps distinguish pathological tissues such as lysosomal compartments and tumors. The light-induced formation of a DOX precipitate increases in efficiency with increasing UV exposure time as well as with increasing environmental acidity or alkalinity. In addition, confocal imaging and flow cytometry showed that the ability of FOBD lipids to actively target HeLa cells increased with increasing Fa-ONB lipid content. Real-time in vivo fluorescence small animal experiments proved targeting to tumors and pH- and photo-induced release properties. Furthermore, therapeutic experiments using a mouse model found a significant tumor inhibitory effect for DOX/FOBD55 liposomes with UV irradiation, clearly demonstrating the benefit of light treatment: the tumor size of the control (PBS) group was 7.59 times that of the light treatment group. Therefore, this research demonstrates the benefits of combining triggerable release functions and effective active tumor targeting in one small lipid molecule for precise cancer treatment.