Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder, for which available pharmacotherapies have limited efficacy. The authors' previous proof-of-concept randomized controlled ...trial of single-dose intravenous ketamine infusion in individuals with PTSD showed significant and rapid PTSD symptom reduction 24 hours postinfusion. The present study is the first randomized controlled trial to test the efficacy and safety of repeated intravenous ketamine infusions for the treatment of chronic PTSD.
Individuals with chronic PTSD (N=30) were randomly assigned (1:1) to receive six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psychoactive placebo control) over 2 consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). Secondary outcome measures included the Impact of Event Scale-Revised, the Montgomery-Åsberg Depression Rating Scale (MADRS), and side effect measures.
The ketamine group showed a significantly greater improvement in CAPS-5 and MADRS total scores than the midazolam group from baseline to week 2. At week 2, the mean CAPS-5 total score was 11.88 points (SE=3.96) lower in the ketamine group than in the midazolam group (d=1.13, 95% CI=0.36, 1.91). Sixty-seven percent of participants in the ketamine group were treatment responders, compared with 20% in the midazolam group. Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions. Ketamine infusions were well tolerated overall, without serious adverse events.
This randomized controlled trial provides the first evidence of efficacy of repeated ketamine infusions in reducing symptom severity in individuals with chronic PTSD. Further studies are warranted to understand ketamine's full potential as a treatment for chronic PTSD.
A model of murine IgG function is presented in which the co‐expression of the IgG subclasses is a central feature, class switching occurs before the commencement of somatic hypermutation, and there ...is little switching between subclasses. It is named the quartet model to emphasize the harmony that comes from the simultaneous presence of the four subclasses. In this model, IgG3 and IgG2b antibodies are particularly important early in the response, when T‐cell help may be limiting. IgG3 initiates inflammation through complement fixation, whereas IgG2b provides early FcγR‐mediated effector functions. As T‐cell help strengthens, IgG2a antibodies increase the power of the response, whereas IgG1 production helps limit the inflammatory drive and limits immunopathology. The model highlights the fact that murine IgG subclasses function quite differently to human IgG subclasses. This allows them to serve the special immunological needs of a species that is vulnerable because of its small size.
The nuclear pore complex (NPC) controls the transport of macromolecules between the nucleus and cytoplasm, but its molecular architecture has thus far remained poorly defined. We biochemically ...reconstituted NPC core protomers and elucidated the underlying protein-protein interaction network. Flexible linker sequences, rather than interactions between the structured core scaffold nucleoporins, mediate the assembly of the inner ring complex and its attachment to the NPC coat. X-ray crystallographic analysis of these scaffold nucleoporins revealed the molecular details of their interactions with the flexible linker sequences and enabled construction of full-length atomic structures. By docking these structures into the cryoelectron tomographic reconstruction of the intact human NPC and validating their placement with our nucleoporin interactome, we built a composite structure of the NPC symmetric core that contains ~320,000 residues and accounts for ~56 megadaltons of the NPC's structured mass. Our approach provides a paradigm for the structure determination of similarly complex macromolecular assemblies.
Genome editing via CRISPR/Cas9 has rapidly become the tool of choice by virtue of its efficacy and ease of use. However, CRISPR/Cas9-mediated genome editing in clinically relevant human somatic cells ...remains untested. Here, we report CRISPR/Cas9 targeting of two clinically relevant genes, B2M and CCR5, in primary human CD4+ T cells and CD34+ hematopoietic stem and progenitor cells (HSPCs). Use of single RNA guides led to highly efficient mutagenesis in HSPCs but not in T cells. A dual guide approach improved gene deletion efficacy in both cell types. HSPCs that had undergone genome editing with CRISPR/Cas9 retained multilineage potential. We examined predicted on- and off-target mutations via target capture sequencing in HSPCs and observed low levels of off-target mutagenesis at only one site. These results demonstrate that CRISPR/Cas9 can efficiently ablate genes in HSPCs with minimal off-target mutagenesis, which could have broad applicability for hematopoietic cell-based therapy.
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•Efficient ablation of B2M and CCR5 in human hematopoietic cells using CRISPR/Cas9•CRISPR/Cas9 CCR5-deleted CD34+ HSPCs retain multilineage engraftment potential•Minimal off-target mutational events in CD34+ HSPCs after CRISPR/Cas9 treatment
Genome editing has the potential to revolutionize cell-based gene therapy. In this study, Mandal et al. developed approaches for using CRISPR/Cas9 in human CD34+ HSPCs that yielded high on-target with minimal off-target mutagenesis. These results indicate that CRISPR/Cas9 could broadly enable gene and cell-based therapies of blood.
The advantageous performance of hybrid organic–inorganic perovskite halide semiconductors in optoelectronic applications motivates studies of their fundamental crystal chemistry. In particular, ...recent studies have sought to understand how dipolar, dynamic, and organic cations such as methylammonium (CH3NH3 +) and formamidinium (CH(NH2)2 +) affect physical properties such as light absorption and charge transport. To probe the influence of organic–inorganic coupling on charge transport, we prepared the series of vacancy-ordered double perovskite derivatives A 2SnI6, where A = Cs+, CH3NH3 +, and CH(NH2)2 +. Despite nearly identical cubic structures by powder X-ray diffraction, replacement of Cs+ with CH3NH3 + or CH(NH2)2 + reduces conductivity through a reduction in both carrier concentration and carrier mobility. We attribute the trends in electronic behavior to anharmonic lattice dynamics from the formation of hydrogen bonds that yield coupled organic–inorganic dynamics. This anharmonicity manifests as asymmetry of the interoctahedral I–I pair correlations in the X-ray pair distribution function of the hybrid compounds, which can be modeled by large atomistic ensembles with random rotations of rigid SnI6 octahedral units. The presence of soft, anharmonic lattice dynamics holds implications for electron–phonon interactions, as supported by calculation of electron–phonon coupling strength that indicates the formation of more tightly bound polarons and reduced electron mobilities with increasing cation size. By exploiting the relatively decoupled nature of the octahedral units in these defect-ordered perovskite variants, we interrogated the impact of organic–inorganic coupling and lattice anharmonicity on the charge transport behavior of hybrid perovskite halide semiconductors.
Background Ketamine is reported to have rapid antidepressant effects; however, there is limited understanding of the time-course of ketamine effects beyond a single infusion. A previous report ...including 10 participants with treatment-resistant major depression (TRD) found that six ketamine infusions resulted in a sustained antidepressant effect. In the current report, we examined the pattern and durability of antidepressant effects of repeated ketamine infusions in a larger sample, inclusive of the original. Methods Participants with TRD ( n = 24) underwent a washout of antidepressant medication followed by a series of up to six IV infusions of ketamine (.5 mg/kg) administered open-label three times weekly over a 12-day period. Participants meeting response criteria were monitored for relapse for up to 83 days from the last infusion. Results The overall response rate at study end was 70.8%. There was a large mean decrease in Montgomery–Åsberg Depression Rating Scale score at 2 hours after the first ketamine infusion (18.9 ± 6.6, p < .001), and this decrease was largely sustained for the duration of the infusion period. Response at study end was strongly predicted by response at 4 hours (94% sensitive, 71% specific). Among responders, median time to relapse after the last ketamine infusion was 18 days. Conclusions Ketamine was associated with a rapid antidepressant effect in TRD that was predictive of a sustained effect. Future controlled studies will be required to identify strategies to maintain an antidepressant response among patients who benefit from a course of ketamine.
Discussion of the antibody repertoire usually emphasizes diversity, but a conspicuous feature of the light chain repertoire is its lack of diversity. The diversity of reported allelic variants of ...germline light chain genes is also limited, even in well-studied species. In this review, the implications of this lack of diversity are considered. We explore germline and rearranged light chain genes in a variety of species, with a particular focus on human and mouse genes. The importance of the number, organization and orientation of the genes for the control of repertoire development is discussed, and we consider how primary rearrangements and receptor editing together shape the expressed light chain repertoire. The resulting repertoire is dominated by just a handful of IGKV and IGLV genes. It has been hypothesized that an important function of the light chain is to guard against self-reactivity, and the role of secondary rearrangements in this process could explain the genomic organization of the light chain genes. It could also explain why the light chain repertoire is so limited. Heavy and light chain genes may have co-evolved to ensure that suitable light chain partners are usually available for each heavy chain that forms early in B cell development. We suggest that the co-evolved loci of the house mouse often became separated during the inbreeding of laboratory mice, resulting in new pairings of loci that are derived from different sub-species of the house mouse. A resulting vulnerability to self-reactivity could explain at least some mouse models of autoimmune disease.
Two-dimensional perovskites have emerged as more intrinsically stable materials for solar cells. Chemical tuning of spacer organic cations has attracted great interest due to their additional ...functionalities. However, how the chemical nature of the organic cations affects the properties of two-dimensional perovskites and devices is rarely reported. Here we demonstrate that the selection of spacer cations (i.e., selective fluorination of phenethylammonium) affects the film properties of two-dimensional perovskites, leading to different device performance of two-dimensional perovskite solar cells (average n = 4). Structural analysis reveals that different packing arrangements and orientational disorder of the spacer cations result in orientational degeneracy and different formation energies, largely explaining the difference in film properties. This work provides key missing information on how spacer cations exert influence on desirable electronic properties and device performance of two-dimensional perovskites via the weak and cooperative interactions of these cations in the crystal lattice.
Background A single subanesthetic (intravenous) IV dose of ketamine might have rapid but transient antidepressant effects in patients with treatment-resistant depression (TRD). Here we tested the ...tolerability, safety, and efficacy of repeated-dose open-label IV ketamine (six infusions over 12 days) in 10 medication-free symptomatic patients with TRD who had previously shown a meaningful antidepressant response to a single dose. Methods On day 1, patients received a 40-min IV infusion of ketamine (.5 mg/kg) in an inpatient setting with continuous vital-sign monitoring. Psychotomimetic effects and adverse events were recorded repeatedly. The primary efficacy measure was change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) score. If patients showed a ≥50% reduction in MADRS scores on day 2, they received five additional infusions on an outpatient basis (days 3, 5, 8, 10, and 12). Follow-up visits were conducted twice-weekly for ≥4 weeks or until relapse. Results Ketamine elicited minimal positive psychotic symptoms. Three patients experienced significant but transient dissociative symptoms. Side effects during and after each ketamine infusion were generally mild. The response criterion was met by nine patients after the first infusion as well as after the sixth infusion. The mean (SD) reduction in MADRS scores after the sixth infusion was 85% (12%). Postketamine, eight of nine patients relapsed, on average, 19 days after the sixth infusion (range 6 days–45 days). One patient remained antidepressant-free with minimal depressive symptoms for >3 months. Conclusions These pilot findings suggest feasibility of repeated-dose IV ketamine for the acute treatment of TRD.
Ependymal tumors across age groups are currently classified and graded solely by histopathology. It is, however, commonly accepted that this classification scheme has limited clinical utility based ...on its lack of reproducibility in predicting patients’ outcome. We aimed at establishing a uniform molecular classification using DNA methylation profiling. Nine molecular subgroups were identified in a large cohort of 500 tumors, 3 in each anatomical compartment of the CNS, spine, posterior fossa, supratentorial. Two supratentorial subgroups are characterized by prototypic fusion genes involving RELA and YAP1, respectively. Regarding clinical associations, the molecular classification proposed herein outperforms the current histopathological classification and thus might serve as a basis for the next World Health Organization classification of CNS tumors.
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•DNA methylation profiling of ependymomas identifies nine molecular subgroups•YAP1 and RELA fusions characterize two distinct groups of supratentorial ependymoma•Patients with PFA or supratentorial RELA-positive ependymoma show dismal prognosis•Risk stratification by molecular subgrouping is superior to histological grading
Pajtler et al. classify 500 ependymal tumors using DNA methylation profiling into nine molecular subgroups. This molecular classification outperforms the current histopathological grading in the risk stratification of patients.
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