Directional Crystal Jumping Controlled by Chirality.

Jumping crystals of racemic mixtures of asparagine monohydrate have been presented in this contribution to emphasize the key role of molecular chirality in governing the direction of macroscopic motions. When heated at the specific faces of the single crystals, a pair of enantiomorphs jump in opposite directions, which are further utilized for chiral resolution. The hydrogen-bonded networks between asparagine molecules in a specific direction provide oriented channels for the escape of water molecules during the dehydration, serving as a foundation for the directional crystal jumping. Our findings not only lay the foundation for the future creation of directed actuation systems based on dynamic crystals but shall also guide the efforts to reveal the correlation between chirality and motion across diverse realms of knowledge.

Phase 1 study of safety and preliminary efficacy of intranasal transplantation of human neural stem cells (ANGE-S003) in Parkinson's disease.

BACKGROUND: Intranasal transplantation of ANGE-S003 human neural stem cells showed therapeutic effects and were safe in preclinical models of Parkinson's disease (PD). We investigated the safety and tolerability of this treatment in patients with PD and whether these effects would be apparent in a clinical trial. METHODS: This was a 12-month, single-centre, open-label, dose-escalation phase 1 study of 18 patients with advanced PD assigned to four-time intranasal transplantation of 1 of 3 doses: 1.5 million, 5 million or 15 million of ANGE-S003 human neural stem cells to evaluate their safety and efficacy. RESULTS: 7 patients experienced a total of 14 adverse events in the 12 months of follow-up after treatment. There were no serious adverse events related to ANGE-S003. Safety testing disclosed no safety concerns. Brain MRI revealed no mass formation. In 16 patients who had 12-month Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) data, significant improvement of MDS-UPDRS total score was observed at all time points (p<0.001), starting with month 3 and sustained till month 12. The most substantial improvement was seen at month 6 with a mean reduction of 19.9 points (95% CI, 9.6 to 30.3; p<0.001). There was no association between improvement in clinical outcome measures and cell dose levels. CONCLUSIONS: Treatment with ANGE-S003 is feasible, generally safe and well tolerated, associated with functional improvement in clinical outcomes with peak efficacy achieved at month 6. Intranasal transplantation of neural stem cells represents a new avenue for the treatment of PD, and a larger, longer-term, randomised, controlled phase 2 trial is warranted for further investigation.

Stereoselective Crystallization of Chiral Pharmaceuticals Aided by Cellulose Derivatives through Helical Pattern Matching.

Stereoselective inhibition aided by "tailor-made" polymeric additives is an efficient approach to obtain enantiopure compounds through conglomerate crystallization. The chemical and configurational match between the side groups of polymers and the molecules of undesired enantiomer is considered to be a necessary condition for successful stereoseparation. Whereas in this contribution, we present an effective resolution of chiral pharmaceuticals by using cellulose acetates as the additives, which stereoselectively reside on the specific crystal faces of one enantiomer and inhibit its crystal nucleation and growth through helical pattern and supramolecular interaction complementarity. An investigation of nimodipine serves as a case study to highlight the novelty of this strategy wherein R-crystals exhibiting an impressive enantiomeric excess value of 97% can be attained by employing a mere 0.01 wt% cellulose acetate. Guaifenesin and phenyl lactic acid are also well-resolved by utilizing this methodology. Our work not only brings about a brand-new design strategy for "tailor-made" additives, but will also promote the further exploration of the endless potential for utilizing natural biomolecules in chiral recognition and resolution.

Fast Visualized Conformational Transition of Polyphenylacetylenes with Stepwise Tunable Circularly Polarized Luminescence.

Two novel poly(3,5-diamide substituted phenylacetylene)s bearing L- or D-alanine residues with a long alkyl chain were synthesized. In low polar or apolar solvents, the polymers adopted contracted cis-cisoid helix showing strong yellow fluorescence, which was transferred to stretched cis-transoid helix by adding polar solvents or decreasing temperature, accompanied with the disappearance of fluorescence. The critical conformational transition temperature could be readily tuned in a wide range by altering the content of polar solvent, and the conformational variation at molecular level could be directly read out via the change in fluorescent property. The synergistical participation of amide and ester groups in the formation of intramolecular hydrogen bonds accelerated the conformational transition rate, resulting in remarkable reduction of hysteresis. Moreover, the polymers displayed switchable CPL performance and the luminescent dissymmetry factor could be stepwise amplified by forming chiral aggregates or liquid crystalline structure. This study may open a new avenue for the development of controllable helical structure-based smart CPL materials.

A cascade Fermat spiral microfluidic mixer chip for accurate detection and logic discrimination of cancer cells.

Since cancer has emerged as one of the most serious threats to human health, the highly sensitive determination of cancer cells is of significant importance to improve the accuracy of early clinical diagnosis. In our investigation, a novel cascade Fermat spiral microfluidic mixer chip (CFSMMC) combined with fluorescence sensors as a point-of-care (POC) testing system is successfully fabricated to detect and differentiate cancer cells (MCF-7) from normal cells with excellent sensitivity and selectivity. Here, copper ions (Cu2+) with peroxidase properties can catalyze the oxidation of the non-fluorescent substrate Amplex Red (AR) to the highly fluorescent resorufin (ox-AR) in the presence of hydrogen peroxide (H2O2). Subsequently, thanks to the quenching response of AS1411-AuNPs to ox-AR in the microchannel and the binding of AS1411 to nucleolin on the surface of cancer cells, a CFSMMC-based POC system is established for the highly sensitive detection and identification of human breast cancer cells in a "turn on" manner. The change in fluorescence intensity is linearly related to the concentration of MCF-7, ranging from 102 to 107 cells per mL with a limit of detection (LOD) as low as 17 cells per mL. Interestingly, the cascaded AND logic gate is integrated with CFSMMC for the first time to distinguish cancer cells from normal cells under the control of logic functions, which exhibits great potential in the development of one-step rapid and intelligent detection and logic discrimination.

Accelerating supramolecular aggregation by molecular sliding.

Diffusion-based translocation along DNA or RNA molecules is essential for genome regulatory proteins to execute their biological functions. The reduced dimensionality of the searching process makes the proteins bind specific target sites at a "faster-than-diffusion-controlled rate". We herein report a photoresponsive slider-track diffusion system capable of self-assembly rate acceleration, which consists of (-)-camphorsulfonic acid, 4-(4'-n-octoxylphenylazo)benzenesulfonic acid, and isotactic poly(2-vinylpyridine). The protonated pyridine rings act as the footholds for anionic azo sliders to diffusively bind and slide along polycationic tracks via electrostatic interactions. Ultraviolet light triggers the trans to cis isomerization and aggregation of azo sliders, which can be monitored by multiple spectroscopic methods without labeling. The presence of vinyl polymer track increases the aggregation rate of cis azobenzene up to ∼20 times, depending on the stereoregularity of the polymer chain, the acid/base ratio and the addition of salt. This system has a feature of simplicity, monitorability, controllability, and could find applications in designing molecular machines with desired functionalities.

Effect of pendant stereostructure on backbone conformation and enantioseparation ability of helical polyacetylene-based chiral stationary phases.

Six proline-derived acetylene monomers bearing either two stereocenters (S-mR, S-mS, R-mS, Rac-mS and S-mRac) or one stereocenter (S-mBn) were obtained from commercially available N-(tert-butoxycarbonyl)-prolinal. Under the catalysis of Rh-diene complex, they were converted to the corresponding optically active helical polymers, S-pR, S-pS, R-pS, Rac-pS, S-pRac, and S-pBn. The correlations between configuration and position of stereocenters in pendants with the polymer conformation as well as chiral resolution performance were systematically explored by a combination of nuclear magnetic resonance (NMR), Raman, UV-Vis absorption, electronic/vibration circular dichroism spectroscopies, high-performance liquid chromatography (HPLC), and computational simulation. The configuration of the stereocenter adjacent to polymer mainchain determined the sense of helical conformation and the elution order of analytes, while that of the remote one affected the arrangement of pendants and the scope of analytes that could be discriminated. Among 18 aromatic analytes selected, S-pR could discriminate 10, while S-pS recognized 12. The racemization of adjacent or remote stereocenters greatly reduced the scope of analytes that could be resolved. Based on computer simulations, S-pS had larger recognition space than S-pR, favoring the steric fit with the racemates containing axial chirality. The strength and number of intermolecular hydrogen bondings between enantiomers and CSPs predominantly determined the chiral discrimination.

Self-Reporting Activated Ester-Amine Reaction for Enantioselective Multi-Channel Visual Detection of Chiral Amines.

Chiral recognition is of importance not only in living systems but also in estimating the optical purity of enantiomeric drugs and fabricating advanced materials. Herein we report a novel self-reporting activated ester-amine reaction that can provide multi-channel visual detection of organic amines. It relies on the reaction extent dependent cis-transoid to cis-cisoid helical transition of the polyphenylacetylene backbone and the thus triggered fluorescence. Owing to the high selectivity, this visual process can recognize structurally diverse achiral amines and quantitatively check the impurity content. It also shows an outstanding enantioselectivity towards various chiral amines and can be applied to determine enantiomeric composition. The multiple responses in absorption, circular dichroism, photoluminescence, and circularly polarized luminescence make the helical transition of the polymer backbone a potential detection mode for high-throughput screening of chiral chemicals.

2D Hexagonal Assemblies of Amphiphilic Double-Helical Poly(phenylacetylene) Homopolymers with Enhanced Circularly Polarized Luminescence and Chiral Self-Sorting.

Two-dimensional (2D) chiral materials have been attracting immense attentions owing to their unique properties. Herein, we successfully developed a unique assembly strategy of amphiphilic homopolymers to construct stable free-standing 2D chiral nanosheets in solution. The amphiphilic poly(phenylacetylene) (PPA) homopolymers bearing the hydrophobic and hydrophilic dendritic side chains adopt a DNA-like double-helical conformation. The regular hexagonal nanosheets were formed in THF/EtOH through nucleation and epitaxial growth. The sizes of the nanosheets can be modulated from nanometers to submillimeters upon varying the ratio of binary solvents, while the thickness is linearly correlated with the molecular weights. The 2D architecture can significantly enhance the CPL of polymers with a high dissymmetry factor ≈0.1. Driven by a discrimination of helical conformation, the PPAs can self-sort into homochiral 2D nanosheets, as directly visualized by using fluorescent microscopy.

Consensus guidelines for botulinum toxin therapy: general algorithms and dosing tables for dystonia and spasticity.

Botulinum toxin (BT) therapy is a complex and highly individualised therapy defined by treatment algorithms and injection schemes describing its target muscles and their dosing. Various consensus guidelines have tried to standardise and to improve BT therapy. We wanted to update and improve consensus guidelines by: (1) Acknowledging recent advances of treatment algorithms. (2) Basing dosing tables on statistical analyses of real-life treatment data of 1831 BT injections in 36 different target muscles in 420 dystonia patients and 1593 BT injections in 31 different target muscles in 240 spasticity patients. (3) Providing more detailed dosing data including typical doses, dose variabilities, and dosing limits. (4) Including total doses and target muscle selections for typical clinical entities thus adapting dosing to different aetiologies and pathophysiologies. (5) In addition, providing a brief and concise review of the clinical entity treated together with general principles of its BT therapy. For this, we collaborated with IAB-Interdisciplinary Working Group for Movement Disorders which invited an international panel of experts for the support.

Noncovalently Functionalized Commodity Polymers as Tailor-Made Additives for Stereoselective Crystallization.

Stereoselective inhibition of the nucleation and crystal growth of one enantiomer aided by "tailor-made" polymeric additives is an efficient method to obtain enantiopure compounds. However, the conventional preparation of polymeric additives from chiral monomers are laborious and limited in structures, which impedes their rapid optimization and applicability. Herein, we report a "plug-and-play" strategy to facilitate synthesis by using commercially available achiral polymers as the platform to attach various chiral small molecules as the recognition side-chains through non-covalent interactions. A library of supramolecular polymers made up of two vinyl polymers and six small molecules were applied with seeds in the selective crystallization of seven racemates in different solvents. They showed good to excellent stereoselectivity in yielding crystals with high enantiomeric purities in conglomerates and racemic compound forming systems. This convenient, low-cost modular synthesis strategy of polymeric additives will allow for high-efficient, economical resolution of various racemates on different scales.

Allostery-Mimicking Self-assembly of Helical Poly(phenylacetylene) Block Copolymers and the Chirality Transfer.

Allostery can regulate protein self-assembly which further affects biological activities, and achieving precise control over the chiral suprastructures during self-assembly remains challenging. Herein, to mimic the allosterical nature of proteins, the poly(phenylacetylene) block copolymers PPA-b-PsmNap with the dynamic helical backbone were synthesized to investigate their conformational-transition-induced self-assembly. As the helical conformation of the block PsmNap spontaneously transforms from cis-transiod to cis-cisoid, the decreasing solubility of PsmNap blocks in THF induced self-assembly of PPA-b-PsmNap. The self-assembly structures of copolymers can sequentially evolve from vesicles to nanobelts to helical strands during the process of conformation transformation. The screw sense of final helical strands was strictly correlated to the helicity of the block PsmNap. This is helpful to understand the mechanism of allostery-modulated self-assembly.

Brightening up Circularly Polarized Luminescence of Monosubstituted Polyacetylene by Conformation Control: Mechanism, Switching, and Sensing.

The first example of luminescent monosubstituted polyacetylenes (mono-PAs) is presented, based on a contracted cis-cisoid polyene backbone. It has an excellent circularly polarized luminescence (CPL) performance with a high dissymmetric factor (up to the order of 10-1 ). The luminescence stems from the helical cis-cisoid PA backbone, which is tightly fixed by the strong intramolecular hydrogen bonds, thereby reversing the energy order of excited states and enabling an emissive energy dissipation. CPL switches are facilely achieved by the solvent and temperature through reversible conformational transition. By taking advantages of fast response and high sensitivity, the thin film of mono-PAs could be used as a CPL-based probe for quantitative detection of trifluoroacetic acid with a wider linear dynamic range than those of photoluminescence and circular dichroism. This work opens a new avenue to develop novel smart CPL materials through modulating conformational transition.

Modulation of thermodynamic and kinetic inverted phase behavior of block copolymers by inorganic polyoxometalates.

The Keggin polyoxometalates (POM) H3PW12O40 (PW) electrostatically complexed with poly(styrene-block-2-vinyl pyridine) (PS-b-P2VP) in DMF, and ordered microphase separation occurred through solvent evaporation. The phase behaviors of PS-b-P2VP/PW in bulk were systematically investigated by using SAXS and TEM to discover the effect of POM content and molecular weight of the block copolymers. Computational simulation was also performed to reveal the same phase transition sequence as the experimental results. As the POM content increases, the PS-b-P2VP/PW complex with a low molecular weight changed from lamellar phase (LAM) to hexagonal cylindrical phase (HEX), and finally transited into spherical phase (SPH). Unexpectedly, PS-b-P2VP/PW complexes with a high molecular weight were inclined to form a kinetic-trapped intermediate phase (inverted HEX). The mechanism of formation of inverted phases was proposed based on simulation that asymmetric swelling in the concentrated DMF solution would result in the ultimate kinetic-trapped nanostructure in the bulk.

Morphology Evolution of Stimuli-Responsive Triblock Copolymer Modulated by Polyoxometalates.

Polyoxometalate (POM) H3PMo12O40 was coassembled with stimuli-responsive triblock copolymer poly(ethylene oxide)- block-polystyrene- block-poly(2-(dimethylamino)ethyl methacrylate) (PEO- b-PS- b-PDMAEMA) by electrostatic interactions. Depending on the POM contents, the hybrid complexes can self-assemble into a series of morphologies: micelles, rods, toroids, and vesicles. Unlike traditional morphology transition of amphiphilic block copolymer derived from a broad range of hydrophobic volume fractions, POM-induced morphology transitions just occurred in a narrow range of volume fractions. The length of rod micelles exponentially decreased with solvent compositions (tetrahydrofuran/H2O). The hybrid assemblies showed acid-base responsibility due to the PDMAEMA block. Rod micelles could further assemble and disassemble reversibly upon adding acid/base. Fluorescent polyoxometalate Na9EuW10O36 was also complexed with PEO- b-PS- b-PDMAEMA to prepare fluorescent vesicles. The vesicles showed off-on switchable fluorescence behavior accompanied with reversible vesicle-to-micelle transformation in response to pH stimuli.

Pallidal Deep Brain Stimulation in Patients With Chorea-Acanthocytosis.

INTRODUCTION: Chorea-acanthocytosis (ChAc) is an autosomal recessive hereditary disorder caused by the mutation of gene VPS13A. Deep brain stimulation of ChAc has made substantial progress in the recent decades. However, the reports were scattered across centers and performed by different neurosurgeons. Here, we report a case series consisting of six patients diagnosed with ChAc, receiving bilateral high-frequency stimulation of globus pallidus internus (GPi) in a single center. METHODS: We report six consecutive patients diagnosed with ChAc and present a review of the literature. All patients received neurological evaluations using the Unified Huntington's Disease Rating Scale (UHDRS) motor score before surgery and during clinical follow-ups. One patient was observed over six months, while five patients were seen over 12 months. RESULTS: All patients underwent high-frequency stimulation ranging from 130 Hz to 175 Hz. In the follow-up period, a general trend was found toward higher amplitude and broader pulse widths, with a mean current range of 2.08 mA to 3.06 mA and a mean pulse width range of 75 µsec to 98 µsec. On preoperative evaluation, the mean UHDRS motor score was 35.7 ± 16.3 and the chorea subscore was 11.3 ± 4.7. At the three-month postoperative follow-up, both UHDRS motor score (13.5 ± 5.8) and chorea subscore (3.0 ± 1.2) reached valley values. Thereafter, the UHDRS motor score and chorea subscore showed a gradual rise, reaching 19.2 ± 5.9 and 4.8 ± 1.7, respectively, at the 12-month follow-up. In addition, adverse events were also seen. Patient 1 developed dysarthria six months after surgery, whereas Patient 6 had a generalized tonic-clonic seizure attack one day after surgery CONCLUSION: High frequency stimulation of the GPi is an effective and safe modality for the treatment of ChAc, with both rapid symptomatic improvements and steady chronic outcomes.

Progress in the Diagnosis and Management of Chorea-acanthocytosis.

Chorea-acanthocytosis (ChAc) is the most common subtype of neuroacanthocytosis syndrome, characterized by the presence of acanthocytes and neurological disorders. It is thought to be caused by VPS13A mutations. Characteristic movement disorders in ChAc is choreiform movements affecting both trunk and extremities and prominent orolingual dyskinesia is pathognomonic. Acanthocytosis in peripheral blood smear, elevated serum creatine kinase and atrophy of heads of caudate nuclei and dilation of the anterior horn of the lateral ventricles in magnetic resonance imaging could assist the diagnosis of ChAc. Botulinum toxin injection is a possible treatment for the typical orofacial dystonia. Deep brain stimulation is a novel surgical treatment modality. Most cases chose globus pallidus internus as target. Patients with dystonia as a major manifestation will benefit more from high-frequency stimulation and those with major findings of chorea and dysarthria are suitable for low-frequency stimulation. More evidence of long-term outcomes is warranted.

Self-Reporting Inhibitors: A Single Crystallization Process To Obtain Two Optically Pure Enantiomers.

Collection of two optically pure enantiomers in a single crystallization process can significantly increase the chiral separation efficiency but this is difficult to realize. Now a self-reporting strategy is presented for visualizing the crystallization process by a dyed self-assembled inhibitor made from the copolymers with tri(ethylene glycol)-grafting polymethylsiloxane as the main chain and poly(N6 -methacryloyl-l-lysine) as side chains. When applied with seeds together for the fractional crystallization of conglomerates, the inhibitors can label the formation of the secondary crystals and guide the complete separation process of two enantiomers with colorless crystals as the first product and red crystals as the second. This method leads to high optical purity of d/l-Asn⋅H2 O (99.9 % ee for d-crystals and 99.5 % for l-crystals) in a single crystallization process. It requires a small amount of additives and shows excellent recyclability.

Light Triggered Co-Assembly of Photocleavable Copolymers and Polyoxometalates with Enhanced Photoluminescence.

A novel co-assembly based on the block copolymer bearing photocleavable groups and macroanionic polyoxometalates Na9 [Ln(W5 O18 )2 ] (LnW10 , Ln = Eu, Dy) triggered by UV light is realized in aqueous solution. The copolymer synthesized by atom transfer radical polymerization (ATRP) undergoes irreversible cleavage upon UV irradiation to generate primary amine (pKa ≈ 8-9) residues which are completely protonated under a neutral pH in aqueous solution. Electrostatic attractions between the resulting positively charged copolymers and anionic LnW10 drive the formation of assemblies. In situ small angle X-ray scattering and transmission electron microscopy are used to characterize the morphology of the assemblies. The microenvironments around polyoxometalates in the core of hybrid assemblies become highly hydrophobic, resulting in dramatically enhanced photoluminescence with the obvious intensity enhancement. The solution parameters pH and salt additives show great effects on the formation of assemblies.

Subthalamic Nuclei Stimulation in Patients With Pantothenate Kinase-Associated Neurodegeneration (PKAN).

INTRODUCTION: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive genetic disease that leads to extrapyramidal symptoms, such as dystonia, ataxia, dysarthria, and involuntary movements. Treatment of PKAN with deep brain stimulation (DBS) has been reported, but mainly focuses on targeting the globus pallidus internus (GPi). Subthalamic nuclei (STN) may also be a potential target for treatment of PKAN. METHODS: In this study, we reviewed three patients with PKAN (two with typical PKAN and one with atypical PKAN) treated by bilateral STN stimulation and present a review of the literature. All patients received neurological evaluation using the Burke-Fahn-Marsden Dystonia Rating Scale-movement (BFMDRS) scoring system before and after surgery. Patients were then subject to regular clinical follow-ups (ranging from 22 to 44 months). RESULTS: The mean stimulation amplitude, pulse width and frequency was 2.65 ± 0.45 V, 91.7 ± 21.9 µs, and 146.7 ± 12.5 Hz, respectively. BFMDRS scores were improved in all patients after surgery, ranging from 41.6 to 73.1%. Improvements of appendicular symptoms ranged from 46.2 to 94.1%, and improvements of axial symptoms ranged from 27.3 to 33.3%. No side effects were reported in patients 1 and 2; whereas patient 3 exhibited a mild decline in verbal fluency one year after surgery. CONCLUSION: STN stimulation could serve as a candidate DBS target in the treatment of PKAN, especially for patients with prominent appendicular symptoms.