Bright white light emission from lanthanide oxide LaGdO3 for LED lighting by Bi3+ to Eu3+ energy transfer.

Phosphors with intrinsic white light emission are of great potential in constructing high-quality white LEDs (WLEDs). In this work, we propose the use of energy transfer from Bi3+ to Eu3+ ions for white light emission. A unique Bi3+-activated phosphor LaGdO3 (LGO):Bi3+ was generated using the conventional high-temperature solid-state process. An energy transfer was established by introducing Eu3+ into the phosphor composition. The emission colour of LGO:Bi3+,Eu3+ phosphors changes from cyan to white to orange-red depending on the Bi3+/Eu3+ doping proportion. The energy transfer between the Bi3+ and Eu3+ ions results from the dipole-dipole interaction. The LGO:Bi3+,Eu3+ phosphors were combined with a near-ultraviolet chip to successfully create a single-component WLED device with a colour-rendering index of 92.4. Our work demonstrates the energy transfer as a route for single-component white light emission and makes LGO:Bi3+,Eu3+ phosphors one of the candidate materials for near-ultraviolet lighting.

Hydrothermal synthesis of ZnGa2O4 nanophosphors with high internal quantum efficiency for near-infrared pc-LEDs.

NIR luminescent materials have garnered widespread attention because of their exceptional properties, with high tissue penetration, low absorption and high signal-to-noise ratio in the field of optical imaging. However, producing nanophosphors with high quantum yields of emitting infrared light with wavelengths above 1000 nm remains a significant challenge. Here, we prepared a nanoscale ZnGa2O4:xCr3+,yNi2+ phosphor with good luminescence performance in near-infrared emission, which was synthesized via a hydrothermal method and subsequent calcination process. By co-doping with Cr3+ and Ni2+, the ZnGa2O4 phosphor shows a strong broadband emission of 1100-1600 nm in the second near-infrared (NIR-II) region, owing to the energy transfer from Cr3+ to Ni2+ with an efficiency up to 90%. Meanwhile, a near-infrared phosphor-conversion LED (NIR pc-LED) device is fabricated based on the ZnGa2O4:0.8%Cr3+,0.4%Ni2+ nanophosphor, which has under 100 mA input current, an output power of 23.99 mW, and a photoelectric conversion efficiency of 7.53%, and can be effectively applied in imaging and non-destructive testing. Additionally, the intensity ratio of INi/ICr of ZnGa2O4:0.8% Cr3+,0.4%Ni2+ with its high sensitivity value of 4.21% K-1 at 453 K under 410 nm excitation, indicates its potential for thermometry application.

Well-Performed Green Phosphor BaY4Si5O17:Ce3+,Tb3+ with High Quantum Efficiency and Thermal Stability.

For Tb3+-doped green phosphors, the energy transfer from Ce3+ to Tb3+ can largely enhance the absorption of excitation; however, obtaining phosphors that exhibit both high quantum efficiency and thermal stability continues to pose a significant challenge. Herein, we established a paradigm to achieve novel silicate BaY4Si5O17 (BYSO):Ce3+,Tb3+. The near-ultraviolet light efficiently excites the BYSO:Ce3+ material, causing it to emit light at a wavelength of 408 nm. The photoluminescence of BYSO:0.12Ce3+ exhibits a relatively small Stokes shift and a thermal stability of 89.8% of the 303 K emission intensity at 423 K (89.8%@423 K). The energy transfer (ET) from Ce3+ to Tb3+ ions can be readily constructed in BYSO:Ce3+,Tb3+ utilizing the overlap between the Ce3+ emission and the Tb3+ excitation. The ET efficiency from the Ce3+ to Tb3+ ions reached 83.8% at y = 1.2 and a maximum of 94.6%. Finally, the optimized phosphor BYSO:0.12Ce3+,1.2Tb3+ had an internal quantum efficiency of 94.4% and had excellent thermal stability (96.1%@423 K). Our work pointed out the avenue to novel green phosphors with high efficiency and thermal stability by choosing appropriate host and construct efficient ET.

Remote Control and Noninvasive Detection Enabled by a High-performance NIR pc-LED.

In an increasing manner, near-infrared phosphor-converted light-emitting diodes (NIR pc-LEDs) are considered to be exemplary light sources owing to their notable attributes of elevated output power, economical nature, and exceptional portability. NIR phosphors are critical components of NIR pc-LEDs. Herein, we report a novel blue light excitable NIR phosphor CaLu2ZrScAl3O12:Cr3+ (CLZSA:Cr3+) as a crucial and efficient broadband NIR emitter. The CLZSA:Cr3+ phosphor displays an intense NIR broadband emission peaking at 776 nm and with a full width at half-maximum (fwhm) of 140 nm. The designed material also exhibits superior resistance to thermal quenching, as the intensity of emission at 423 K remains at 80% of that at room temperature. The constructed NIR pc-LED device based on CLZSA:Cr3+ demonstrates a high total output power of 68.4 mW at a drive current of 100 mA, along with a high photoelectric conversion efficiency of 23.0%. Impressively, the high-power NIR pc-LEDs are utilized as light sources for remote control and non-invasive detection, resulting in the excellent performance and remarkable achievement.

Crystal Field Engineering Yields New 3D Layered Solid Solution Phosphors (Ca/Sr)4MgAl2Si3O14:Eu2+ for White-Light-Emitting Diode Full-Spectrum Lighting.

The cation-equivalent substitution strategy has the ability to manipulate the luminescence color of phosphors and enhance their overall luminescence performance. A series of novel yellow feldspar-type 3D layered phosphors (Ca1-ySry)4MgAl2Si3O14:xEu2+ were synthesized using a high-temperature solid-state reaction. The solid solution phosphors belong to a tetragonal crystal system with a space group of P4̅21m and cell parameters of a = b = 7.75407-7.91794 Å, c = 5.04299-5.22543 Å, and V = 303.166-327.602 Å3. Under near-ultraviolet (n-UV) excitation, the luminescence color of the phosphor undergoes modulation from yellow-green (530 nm) to blue (467 nm) as the Sr2+ ion substitution ratio increases. This modulation is attributed to the gradual decrease in crystal field splitting energy. Additionally, both the Stokes shift and the full width of the luminescence spectra decrease. Furthermore, there is an increase in the quantum yield (QY) from 45.50 to 60.73%. Finally, the fabricated white-light-emitting diode devices emitted warm white light and achieved high Ra (Ra = 94, 96.6, 92.7) and low correlated color temperature (CCT = 3486, 3430, 3788 K), indicating that the prepared solid solution phosphors can be used as candidate materials for WLED lighting.

Energy transfer and tunable emission in BaSrGd4O8:Bi3+,Eu3+ phosphors for warm WLED.

In this work, a series of BaSrGd4O8:xBi3+ blue phosphors was synthesized employing the high-temperature solid-state method. Phase purity of the samples was verified by X-ray diffraction and Rietveld refinement. Time-resolved photoluminescence spectra revealed the existence of two distinct Bi sites. Subsequent optimization of dopant types and doping levels in the batch led to an almost twofold increase in quantum efficiency. The introduction of Eu3+ into the phosphors facilitated the construction of an energy transfer pathway. As the concentration of Eu3+ was increased, the emission color changed from blue to purple and finally to red. In addition, the thermal stability and potential applications of the phosphors were extensively investigated. Finally, two WLED devices were successfully fabricated with color rendering indices of 96.27 and 92.18, and correlated color temperatures of 5198 and 2475 K. This underscores the prospective application of these phosphors in the field of high-quality warm WLEDs.

An efficient blue-excitable broadband Y3ScAl4O12:Ce3+ garnet phosphor for WLEDs.

Most commercial phosphor-converted white light-emitting diodes (pc-WLEDs) are manufactured with blue LED chips and yellow-emitting Y3Al5O12:Ce3+ (YAG:Ce3+) garnet phosphor, but the lack of blue-green light in the spectrum results in a low color rendering index (CRI). In this paper, we synthesized Y3ScAl4O12:Ce3+ (YSAG:Ce3+) by replacing Al3+ in YAG:Ce3+ with Sc3+. The introduction of Sc3+ with a larger ionic radius through a cation substitution strategy causes lattice expansion, elongation of the Y-O bond, and ultimately a decrease in Ce3+ 5d level crystal field splitting. As a consequence, the emission spectrum undergoes a blue-shift of 10 nm. Furthermore, the YSAG:Ce3+ phosphor exhibits good thermal stability, and its emission intensity at 423 K is about 58% of that at 303 K. Moreover, the analysis of Eu3+ emission spectra demonstrates that the introduction of Sc3+ resulted in a slight reduction of the dodecahedral lattice symmetry. YSAG:Ce3+ effectively compensates for the lack of the blue-green region, and WLEDs with high color rendering index (90.1), low color temperature (4566 K) and high luminous efficiency (133.59 lm W-1) were prepared using the combination of YSAG:0.08Ce3+, CaAlSiN3:Eu2+ and 450 nm blue chips. These findings indicate that YSAG:Ce3+ garnet phosphor has potential to be used in high quality WLEDs.

Lanthanide-doped Na2MgScF7 exhibiting downshifting and upconversion emissions for multicolor anti-counterfeiting.

Na2MgScF7 (NMSF) was experimentally obtained for the first time by combining hydrothermal and high-temperature solid-state reactions. X-ray powder diffraction (XRD) combined with Rietveld refinement confirms that NMSF is crystallized in the space group Imma with the cell parameters a = 10.40860(18), b = 7.32804(12) and c = 7.52879(11) Å, α = ß = γ = 90° and V = 574.256(24) Å3. Through doping with Tb3+ or Eu3+ ions, downshifting yellow-green or red emission could be achieved in NMSF-based phosphors, respectively. Upconversion emission could also be designed by doping with Yb3+-Er3+, Yb3+-Tm3+, Yb3+-Ho3+ or Er3+. Moreover, the NMSF:Er3+ phosphor exhibited green upconversion emission upon excitation at 980 nm, and it exhibited red emission upon excitation at 1532 nm. Finally, recognizable patterns were obtained under excitation at 254, 365 and 980 nm, indicating that the as-prepared phosphors can be applied to multicolor anti-counterfeiting. Moreover, our synthesis strategy opens up new avenues for the synthesis of novel fluorides.

Structural and Mechanistic Basis for the Inactivation of Human Ornithine Aminotransferase by (3S,4S)-3-Amino-4-fluorocyclopentenecarboxylic Acid.

Ornithine aminotransferase (OAT) is overexpressed in hepatocellular carcinoma (HCC), and we previously showed that inactivation of OAT inhibits the growth of HCC. Recently, we found that (3S,4S)-3-amino-4-fluorocyclopentenecarboxylic acid (5) was a potent inactivator of γ-aminobutyric acid aminotransferase (GABA-AT), proceeding by an enamine mechanism. Here we describe our investigations into the activity and mechanism of 5 as an inactivator of human OAT. We have found that 5 exhibits 10-fold less inactivation efficiency (kinact/KI) against hOAT than GABA-AT. A comprehensive mechanistic study was carried out to understand its inactivation mechanism with hOAT. pKa and electrostatic potential calculations were performed to further support the notion that the α,ß-unsaturated alkene of 5 is critical for enhancing acidity and nucleophilicity of the corresponding intermediates and ultimately responsible for the improved inactivation efficiency of 5 over the corresponding saturated analogue (4). Intact protein mass spectrometry and the crystal structure complex with hOAT provide evidence to conclude that 5 mainly inactivates hOAT through noncovalent interactions, and that, unlike with GABA-AT, covalent binding with hOAT is a minor component of the total inhibition which is unique relative to other monofluoro-substituted derivatives. Furthermore, based on the results of transient-state measurements and free energy calculations, it is suggested that the α,ß-unsaturated carboxylate group of PLP-bound 5 may be directly involved in the inactivation cascade by forming an enolate intermediate. Overall, compound 5 exhibits unusual structural conversions which are catalyzed by specific residues within hOAT, ultimately leading to an enamine mechanism-based inactivation of hOAT through noncovalent interactions and covalent modification.

Double Perovskite Mn4+-Doped La2CaSnO6/La2MgSnO6 Phosphor for Near-Ultraviolet Light Excited W-LEDs and Plant Growth.

Non-rare earth doped oxide phosphors with far-red emission have become one of the hot spots of current research due to their low price and excellent physicochemical stability as the red component in white light-emitting diodes (W-LEDs) and plant growth. Herein, we report novel Mn4+-doped La2CaSnO6 and La2MgSnO6 phosphors by high-temperature solid-phase synthesis and analyzed their crystal structures by XRD and Rietveld refinement. Their excitation spectra consist of two distinct excitation bands with the dominant excitation range from 250 to 450 nm, indicating that they possess strong absorption of near-ultraviolet light. Their emission is located around 693 and 708 nm, respectively, and can be absorbed by the photosensitive pigments Pr and Pfr, proving their great potential for plant growth. Finally, the prepared samples were coated with 365 nm UV chips to fabricate far-red LEDs and W-LEDs with low correlation color temperature (CCT = 4958 K/5275 K) and high color rendering index (Ra = 96.4/96.6). Our results indicate that La2CaSnO6:Mn4+ and La2MgSnO6:Mn4+ red phosphors could be used as candidate materials for W-LED lighting and plant growth.

A Color-tunable Nitride Phosphor for Near-Ultraviolet Excitation of White Light-emitting Diodes.

Due to the diversity of structure and composition and the unique coordination environment, nitride materials enable the doped activator ions to possess compelling luminescence characteristics, such as rich emission colors, favorable stability and tunable emission spectra. Here, novel SrLuSi4 N7 :Ce3+ ,Tb3+ nitride phosphors were successfully synthesized by a modified carbothermal reduction and nitridation method at atmospheric pressure. SrLuSi4 N7 (SLSN) belongs to hexagonal symmetry, with space group P63 mc, and its crystal structure is composed of the basic building block with corner-sharing [SiN4 ] tetrahedron. Under 365 nm excitation, SLSN:Ce3+ exhibits a broad emission band peaking at 450 nm with a full width at half-maximum (FWHM) of 92 nm and the most forceful intensity obtained at the Ce3+ concentration amount of 0.04. On the basis of the efficient energy transfer, SLSN:Ce3+ ,Tb3+ exhibits color-tunable emission from blue (450 nm) to green (545 nm). Our results indicate that SLSN nitride phosphor is a promising candidate for near-ultraviolet (n-UV) based white LEDs.

Turnover and Inactivation Mechanisms for (S)-3-Amino-4,4-difluorocyclopent-1-enecarboxylic Acid, a Selective Mechanism-Based Inactivator of Human Ornithine Aminotransferase.

The inhibition of human ornithine δ-aminotransferase (hOAT) is a potential therapeutic approach to treat hepatocellular carcinoma. In this work, (S)-3-amino-4,4-difluorocyclopent-1-enecarboxylic acid (SS-1-148, 6) was identified as a potent mechanism-based inactivator of hOAT while showing excellent selectivity over other related aminotransferases (e.g., GABA-AT). An integrated mechanistic study was performed to investigate the turnover and inactivation mechanisms of 6. A monofluorinated ketone (M10) was identified as the primary metabolite of 6 in hOAT. By soaking hOAT holoenzyme crystals with 6, a precursor to M10 was successfully captured. This gem-diamine intermediate, covalently bound to Lys292, observed for the first time in hOAT/ligand crystals, validates the turnover mechanism proposed for 6. Co-crystallization yielded hOAT in complex with 6 and revealed a novel noncovalent inactivation mechanism in hOAT. Native protein mass spectrometry was utilized for the first time in a study of an aminotransferase inactivator to validate the noncovalent interactions between the ligand and the enzyme; a covalently bonded complex was also identified as a minor form observed in the denaturing intact protein mass spectrum. Spectral and stopped-flow kinetic experiments supported a lysine-assisted E2 fluoride ion elimination, which has never been observed experimentally in other studies of related aminotransferase inactivators. This elimination generated the second external aldimine directly from the initial external aldimine, rather than the typical E1cB elimination mechanism, forming a quinonoid transient state between the two external aldimines. The use of native protein mass spectrometry, X-ray crystallography employing both soaking and co-crystallization methods, and stopped-flow kinetics allowed for the detailed elucidation of unusual turnover and inactivation pathways.

Tetrahydroquinoline-Capped Histone Deacetylase 6 Inhibitor SW-101 Ameliorates Pathological Phenotypes in a Charcot-Marie-Tooth Type 2A Mouse Model.

Histone deacetylase 6 (HDAC6) is a promising therapeutic target for the treatment of neurodegenerative disorders. SW-100 (1a), a phenylhydroxamate-based HDAC6 inhibitor (HDAC6i) bearing a tetrahydroquinoline (THQ) capping group, is a highly potent and selective HDAC6i that was shown to be effective in mouse models of Fragile X syndrome and Charcot-Marie-Tooth disease type 2A (CMT2A). In this study, we report the discovery of a new THQ-capped HDAC6i, termed SW-101 (1s), that possesses excellent HDAC6 potency and selectivity, together with markedly improved metabolic stability and druglike properties compared to SW-100 (1a). X-ray crystallography data reveal the molecular basis of HDAC6 inhibition by SW-101 (1s). Importantly, we demonstrate that SW-101 (1s) treatment elevates the impaired level of acetylated α-tubulin in the distal sciatic nerve, counteracts progressive motor dysfunction, and ameliorates neuropathic symptoms in a CMT2A mouse model bearing mutant MFN2. Taken together, these results bode well for the further development of SW-101 (1s) as a disease-modifying HDAC6i.

Mercaptoacetamide: A promising zinc-binding group for the discovery of selective histone deacetylase 6 inhibitors.

Histone deacetylase 6 (HDAC6) is a zinc-dependent HDAC that mainly modulates the acetylation status of non-histone substrates, such as α-tubulin and heat shock protein 90 (HSP90). The activity of HDAC6 plays a critical role in cell proliferation, protein trafficking and degradation, cell shape, migration, as well as regulation of immunomodulatory factors. For this reason, HDAC6 influences the progress of cancers, neurodegenerative disorders, and autoimmune responses. In the last few years, the discovery of selective HDAC6 inhibitors (HDAC6is) has become an attractive research area as five HDAC6is are being investigated in phase I/II clinical trials. However, the hydroxamic acid functional group still represents the predominant zinc-binding group (ZBG), that often suffers from poor pharmacokinetics and mutagenic potential, thus impairing the application of hydroxamate-based HDAC6is for long-term therapies. On the other hand, mercaptoacetamide (MCA)-based HDAC6is comprise a class of compounds that, in some cases, display nanomolar HDAC6 potency and a thousand-fold selectivity over class I HDAC isozymes. Moreover, MCA-based HDAC6is lack the mutagenicity associated with the hydroxamate function and display pharmacological effects, demonstrating the potential of this particular ZBG to improve upon the drug-like properties of HDAC6is. Herein, we summarize for the first time the structure-activity relationships (SARs) of MCA-based HDAC6is, discuss their HDAC6 selectivity at the molecular level using inhibitor-HDAC co-crystal structures, and further provide our perspective regarding their drug metabolism, pharmacokinetics, and pharmacological properties.

Structural and Kinetic Analyses Reveal the Dual Inhibition Modes of Ornithine Aminotransferase by (1S,3S)-3-Amino-4-(hexafluoropropan-2-ylidenyl)-cyclopentane-1-carboxylic Acid (BCF3).

Hepatocellular carcinoma (HCC) is the most common form of liver cancer and the leading cause of death among people with cirrhosis. HCC is typically diagnosed in advanced stages when tumors are resistant to both radio- and chemotherapy. Human ornithine aminotransferase (hOAT) is a pyridoxal-5'-phosphate (PLP)-dependent enzyme involved in glutamine and proline metabolism. Because hOAT is overexpressed in HCC cells and a contributing factor for the uncontrolled cellular division that propagates malignant tumors (Ueno et al. J. Hepatol. 2014, 61, 1080-1087), it is a potential drug target for the treatment of HCC. (1S,3S)-3-Amino-4-(hexafluoropropan-2-ylidenyl)-cyclopentane-1-carboxylic acid (BCF3) has been shown in animal models to slow the progression of HCC by acting as a selective and potent mechanism-based inactivator of OAT (Zigmond et al. ACS Med. Chem. Lett. 2015, 6, 840-844). Previous studies have shown that the BCF3-hOAT reaction has a bifurcation in which only 8% of the inhibitor inactivates the enzyme while the remaining 92% ultimately acts as a substrate and undergoes hydrolysis to regenerate the active PLP form of the enzyme. In this manuscript, the rate-limiting step of the inactivation mechanism was determined by stopped-flow spectrophotometry and time-dependent 19F NMR experiments to be the decay of a long-lived external aldimine species. A crystal structure of this transient complex revealed both the structural basis for fractional irreversible inhibition and the principal mode of inhibition of hOAT by BCF3, which is to trap the enzyme in this transient but quasi-stable external aldimine form.

Mechanism-Based Design of 3-Amino-4-Halocyclopentenecarboxylic Acids as Inactivators of GABA Aminotransferase.

Aminotransferases are pyridoxal 5'-phosphate-dependent enzymes that catalyze reversible transamination reactions between an amino acid and an α-keto acid, playing a critical role in cellular nitrogen metabolism. It is evident that γ-aminobutyric acid aminotransferase (GABA-AT), which balances the levels of inhibitory and excitatory neurotransmitters, has emerged as a promising therapeutic target for epilepsy and cocaine addiction based on mechanism-based inactivators (MBIs). In this work, we established an integrated approach using computational simulation, organic synthesis, biochemical evaluation, and mass spectrometry to facilitate our design and mechanistic studies of MBIs, which led to the identification of a new cyclopentene-based analogue (6a), 25-times more efficient as an inactivator of GABA-AT compared to the parent compound (1R,3S,4S)-3-amino-4-fluorocyclopentane carboxylic acid (FCP, 4).

Rational Design of Suprastat: A Novel Selective Histone Deacetylase 6 Inhibitor with the Ability to Potentiate Immunotherapy in Melanoma Models.

Selective inhibition of histone deacetylase 6 (HDAC6) is being recognized as a therapeutic approach for cancers. In this study, we designed a new HDAC6 inhibitor, named Suprastat, using in silico simulations. X-ray crystallography and molecular dynamics simulations provide strong evidence to support the notion that the aminomethyl and hydroxyl groups in the capping group of Suprastat establish significant hydrogen bond interactions, either direct or water-mediated, with residues D460, N530, and S531, which play a vital role in regulating the deacetylase function of the enzyme and which are absent in other isoforms. In vitro characterization of Suprastat demonstrates subnanomolar HDAC6 inhibitory potency and a hundred- to a thousand-fold HDAC6 selectivity over the other HDAC isoforms. In vivo studies reveal that a combination of Suprastat and anti-PD1 immunotherapy enhances antitumor immune response, mediated by a decrease of protumoral M2 macrophages and increased infiltration of antitumor CD8+ effector and memory T-cells.

Structural and in Vivo Characterization of Tubastatin A, a Widely Used Histone Deacetylase 6 Inhibitor.

Tubastatin A, a tetrahydro-γ-carboline-capped selective HDAC6 inhibitor (HDAC6i), was rationally designed 10 years ago, and has become the best investigated HDAC6i to date. It shows efficacy in various neurological disease animal models, as HDAC6 plays a crucial regulatory role in axonal transport deficits, protein aggregation, as well as oxidative stress. In this work, we provide new insights into this HDAC6i by investigating the molecular basis of its interactions with HDAC6 through X-ray crystallography, determining its functional capability to elevate the levels of acetylated α-tubulin in vitro and in vivo, correlating PK/PD profiles to determine effective doses in plasma and brain, and finally assessing its therapeutic potential toward psychiatric diseases through use of the SmartCube screening platform.

HDAC6 inhibition promotes α-tubulin acetylation and ameliorates CMT2A peripheral neuropathy in mice.

Charcot-Marie-Tooth type 2A (CMT2A) peripheral neuropathy, the most common axonal form of CMT, is caused by dominantly inherited point mutations in the Mitofusin 2 (Mfn2) gene. It is characterized by progressive length-dependent degeneration of motor and sensory nerves with corresponding clinical features of motor and sensory impairment. There is no cure for CMT, and therapeutic approaches are limited to physical therapy, orthopedic devices, surgery, and analgesics. In this study we focus on histone deacetylase 6 (HDAC6) as a therapeutic target in a mouse model of mutant MFN2 (MFN2R94Q)-induced CMT2A. We report that these mice display progressive motor and sensory dysfunction as well as a significant decrease in α-tubulin acetylation in distal segments of long peripheral nerves. Treatment with a new, highly selective HDAC6 inhibitor, SW-100, was able to restore α-tubulin acetylation and ameliorate motor and sensory dysfunction when given either prior to or after the onset of symptoms. To confirm HDAC6 is the target for ameliorating the CMT2A phenotype, we show that genetic deletion of Hdac6 in CMT2A mice prevents the development of motor and sensory dysfunction. Our findings suggest α-tubulin acetylation defects in distal parts of nerves as a pathogenic mechanism and HDAC6 as a therapeutic target for CMT2A.