Variable recruitment of distal tuft dendrites shapes new hippocampal place fields.

Hippocampal pyramidal neurons support episodic memory by integrating complementary information streams into new 'place fields'. Distal tuft dendrites are widely thought to initiate place field formation by locally generating prolonged, globally-spreading Ca 2+ spikes known as plateau potentials. However, the hitherto experimental inaccessibility of distal tuft dendrites in the hippocampus has rendered their in vivo function entirely unknown. Here we gained direct optical access to this elusive dendritic compartment. We report that distal tuft dendrites do not serve as the point of origin for place field-forming plateau potentials. Instead, the timing and extent of peri-formation distal tuft recruitment is variable and closely predicts multiple properties of resultant place fields. Therefore, distal tuft dendrites play a more powerful role in hippocampal feature selectivity than simply initiating place field formation. Moreover, place field formation is not accompanied by global Ca 2+ influx as previously thought. In addition to shaping new somatic place fields, distal tuft dendrites possess their own local place fields. Tuft place fields are back-shifted relative to that of their soma and appear to maintain somatic place fields via post-formation plateau potentials. Through direct in vivo observation, we provide a revised dendritic basis for hippocampal feature selectivity during navigational learning.

Pudgy mouse rib deformities emanate from abnormal paravertebral longitudinal cartilage/bone accumulations.

The pudgy (pu/pu) mouse, caused by a recessive mutation in the Notch family Delta like-3 gene (Dll3), has severe rib, vertebral body and intervertebral disc abnormalities. Using whole-mount preparations and serial histologic sections we demonstrate: 1) localized paravertebral longitudinal cartilage/bone accumulations (PVLC/BAs) invariably associated with branched, fused and asymmetrically spaced ribs that emanate from it laterally; 2) abnormal rib formation immediately adjacent to abnormal vertebral body and intervertebral disc formation in asymmetric right/left fashion; and 3) patterns of rib deformation that differ in each mouse. Normal BALB/c embryo and age-matched non-affected pu/+ mice assessments allow for pu/pu comparisons. The Dll3 Notch family gene is involved in normal somitogenesis via the segmentation clock mechanism. Although pathogenesis of rib deformation is initially triggered by the Dll3 gene mutation, these findings of abnormal asymmetric costo-vertebral region structure imply that differing patterns cannot be attributed to this single gene mutation alone. All findings implicate a dual mechanism of malformation: the Dll3 gene mutation leading to subtle timing differences in traveling oscillation waves of the segmentation clock and further subsequent misdirection of tissue formation by altered chemical reaction-diffusion and epigenetic landscape responses. PVLC/BAs appear as primary supramolecular structures underlying severe rib malformation associated both with time-sensitive segmentation clock mutations and subsequent reactions.

The role of vesicle trafficking genes in osteoblast differentiation and function.

Using Col2.3GFP transgenic mice expressing GFP in maturing osteoblasts, we isolated Col2.3GFP+ enriched osteoblasts from 3 sources. We performed RNA-sequencing, identified 593 overlapping genes and confirmed these genes are highly enriched in osteoblast differentiation and bone mineralization annotation categories. The top 3 annotations are all associated with endoplasmic reticulum and Golgi vesicle transport. We selected 22 trafficking genes that have not been well characterized in bone for functional validation in MC3T3-E1 pre-osteoblasts. Transient siRNA knockdown of trafficking genes including Sec24d, Gosr2, Rab2a, Stx5a, Bet1, Preb, Arf4, Ramp1, Cog6 and Pacs1 significantly increased mineralized nodule formation and expression of osteoblast markers. Increased mineralized nodule formation was suppressed by concurrent knockdown of P4ha1 and/or P4ha2, encoding collagen prolyl 4-hydroxylase isoenzymes. MC3T3-E1 pre-osteoblasts with knockdown of Cog6, Gosr2, Pacs1 or Arf4 formed more and larger ectopic mineralized bone nodules in vivo, which was attenuated by concurrent knockdown P4ha2. Permanent knockdown of Cog6 and Pacs1 by CRISPR/Cas9 gene editing in MC3T3-E1 pre-osteoblasts recapitulated increased mineralized nodule formation and osteoblast differentiation. In summary, we have identified several vesicle trafficking genes with roles in osteoblast function. Our findings provide potential targets for regulating bone formation.

Glycerate from intestinal fructose metabolism induces islet cell damage and glucose intolerance.

Dietary fructose, especially in the context of a high-fat western diet, has been linked to type 2 diabetes. Although the effect of fructose on liver metabolism has been extensively studied, a significant portion of the fructose is first metabolized in the small intestine. Here, we report that dietary fat enhances intestinal fructose metabolism, which releases glycerate into the blood. Chronic high systemic glycerate levels induce glucose intolerance by slowly damaging pancreatic islet cells and reducing islet sizes. Our findings provide a link between dietary fructose and diabetes that is modulated by dietary fat.

Preliminary Evaluation of a Smartphone App for Refractive Error Measurement.

Purpose: The purpose of this study was to evaluate the potential feasibility of using a smartphone app in myopia screening. Methods: The app estimates myopic refractive error by measuring the far point distance for reading three 20/20 Tumbling E letters. In total, 113 myopic subjects with astigmatism no greater than -1.75 diopters (D) were enrolled from 5 sites. The mean age was 22 ± 8.5 years. The app measurement was compared with noncycloplegic subjective refraction measurement or autorefractor if subjective refraction was not available. In addition, 22 subjects were tested with the app for repeatability. Results: For 201 eyes included, the range of spherical equivalent refraction error was 0 to -10.2 D. The app measurement and clinical measurement was highly correlated (Pearson R = 0.91, P < 0.001). There was a small bias (0.17 D) in the app measurement overall, and it was significantly different across the 5 sites due to different age of subjects enrolled at those sites (P = 0.001) - young adults in their 20s were underestimated the most by 0.49 D, whereas children were overestimated by 0.29 D. The mean absolute deviation of the app measurement was 0.65 D. The repeatability of multiple testing in terms of 95% limit of agreement was ±0.61 D. Conclusions: Overall, the app measurement is consistent with clinical measurement performed by vision care professionals. The repeatability is comparable with that of some autorefractors. Age-associated human factors may influence the app measurement. Translational Relevance: The app could be potentially used as a mass screening tool for myopia.

A Testing and Quarantine Algorithm for Individual International Travelers Using Published Data on WHO-Approved Vaccines and Bayes' Theorem.

Policies such as border closures and quarantines have been widely used during the COVID-19 pandemic. Policy modifications and updates, however, must be adjusted as global vaccination rates increase. We calculated the risks of individual travelers based on their expected transmission and benchmarked them against that of an unvaccinated traveler quarantined for 14 days without testing. All individuals with a negative preboarding test can be released with a negative arrival test, when both tests have a sensitivity ≥ 90% and a specificity ≥ 97%, performance characteristics that could be accomplished by rapid antigen tests. This assumption is valid for an incidence rate up to 0.1 (prior to testing) and effective reproduction number (Rt) up to 4 in the arrival country. In a sensitivity analysis scenario where the incidence rate is 0.4 and Rt is 16, a negative preboarding test and a negative arrival test, both with a sensitivity ≥ 98% and a specificity ≥ 97%, can ensure that a traveler has a lower expected transmission than an unvaccinated person who is quarantined for 14 days. In most cases, fully vaccinated travelers (with or without booster) and a negative preboarding test can be released with a negative rapid antigen test upon arrival, allowing travelers to depart the airport within 30 min.

Interactive mental health assessments for Chinese Canadians: A pilot randomized controlled trial in nurse practitioner-led primary care clinic.

INTRODUCTION: Mental health conditions like depression and anxiety are on the rise, but access to care remains a challenge. Immigrants and racialized communities including Chinese Canadians experience high level of access barriers including communication with clinicians. With the aim to facilitate mental health communications, we tested an Interactive Computer-assisted Client Assessment Survey (iCCAS) in Cantonese/Mandarin and English at a nurse practitioner-led primary care clinic in Toronto. The iCCAS offers a touch-screen, pre-consultation survey with questions on depression, anxiety, post-traumatic stress, alcohol abuse, and social context. The program generates point-of-care reports for the clinician and patient. METHODS: A pilot randomized controlled trial examined the intervention impact on mental health discussion and symptom detection, compared with the usual care, followed by clinicians' qualitative interviews. RESULTS: Fifty self-identified Chinese adult patients participated (iCCAS = 26, Usual Care = 24), response rate 79.4%. Participant mean age was 44.8 years and 92% were immigrants. There was an increase of 19% and 15% in the mental health discussion and detection of symptoms in the iCCAS group compared with the usual care. More participants in the iCCAS group were referred to a social worker or psychiatrist. Patients found the use of iCCAS easy and clinicians identified its benefits for themselves (eg, early identification and comfort) and patients (eg, self-awareness and anonymity) and proposed practice-integration. DISCUSSION: The studied tool holds promise for enhancing clinician-patient mental health communications in primary care settings for overseas Chinese. Implications are discussed for in-person and virtual healthcare which could also inform responses to mental health crisis related to COVID-19.

Histopathology of osteogenesis imperfecta bone. Supramolecular assessment of cells and matrices in the context of woven and lamellar bone formation using light, polarization and ultrastructural microscopy.

Diaphyseal long bone cortical tissue from 30 patients with lethal perinatal Sillence II and progressively deforming Sillence III osteogenesis imperfecta (OI) has been studied at multiple levels of structural resolution. Interpretation in the context of woven to lamellar bone formation by mesenchymal osteoblasts (MOBLs) and surface osteoblasts (SOBLs) respectively demonstrates lamellar on woven bone synthesis as an obligate self-assembly mechanism and bone synthesis following the normal developmental pattern but showing variable delay in maturation caused by structurally abnormal or insufficient amounts of collagen matrix. The more severe the variant of OI is, the greater the persistence of woven bone and the more immature the structural pattern; the pattern shifts to a structurally stronger lamellar arrangement once a threshold accumulation for an adequate scaffold of woven bone has been reached. Woven bone alone characterizes lethal perinatal variants; variable amounts of woven and lamellar bone occur in progressively deforming variants; and lamellar bone increasingly forms rudimentary and then partially compacted osteons not reaching full compaction. At differing levels of microscopic resolution: lamellar bone is characterized by short, obliquely oriented lamellae with a mosaic appearance in progressively deforming forms; polarization defines tissue conformations and localizes initiation of lamellar formation; ultrastructure of bone forming cells shows markedly dilated rough endoplasmic reticulum (RER) and prominent Golgi bodies with disorganized cisternae and swollen dispersed tubules and vesicles, structural indications of storage disorder/stress responses and mitochondrial swelling in cells with massively dilated RER indicating apoptosis; ultrastructural matrix assessments in woven bone show randomly oriented individual fibrils but also short pericellular bundles of parallel oriented fibrils positioned obliquely and oriented randomly to one another and in lamellar bone show unidirectional fibrils that deviate at slight angles to adjacent bundles and obliquely oriented fibril groups consistent with twisted plywood fibril organization. Histomorphometric indices, designed specifically to document woven and lamellar conformations in normal and OI bone, establish ratios for: i) cell area/total area X 100 indicating the percentage of an area occupied by cells (cellularity index) and ii) total area/number of cells (pericellular matrix domains). Woven bone is more cellular than lamellar bone and OI bone is more cellular than normal bone, but these findings occur in a highly specific fashion with values (high to low) encompassing OI woven, normal woven, OI lamellar and normal lamellar conformations. Conversely, for the total area/number of cells ratio, pericellular matrix accumulations in OI woven are smallest and normal lamellar largest. Since genotype-phenotype correlation is not definitive, interposing histologic/structural analysis allowing for a genotype-histopathologic-phenotype correlation will greatly enhance understanding and clinical management of OI.

Symptoms and Experience of Depression Among Chinese Communities in the West: A Scoping Review.

Despite the increasing presence of Chinese communities in the West, their experiences of depression and the variations in symptoms or presentation are not well understood. Using Arksey and O'Malley's methodical framework, we conducted a scoping review of the published literature, using electronic databases MEDLINE and PsycINFO, and searched for articles published since 1999. Out of 1177 articles identified, 21 met the inclusion criteria. Thematic synthesis revealed valuable scholarly work on (1) depression rates, migration, and contextual determinants, (2) causation beliefs and help seeking, (3) acculturation and symptoms, (4) presenting symptoms and somatization, and (5) culturally sensitive assessment and care. Overall, this review has identified the importance of contextual determinants in the development of depression, low rates of seeking of professional help, subtle variations in somatization, and knowledge gaps in culturally sensitive care. The findings suggest that, rather than treating migration as a cause of mental distress, the accompanying conditions and events need to be further examined and addressed as potential risk or protective factors. Subtle variations in somatization are also evident, and future scholarly work should examine the notion of cultural scripts-namely, that people attend and react to particular experiences in culturally based ways. For this reason (among others), practice models need to develop strategies for culturally sensitive care, such as co-construction of illness narratives and finding common ground. Given the stigma of mental illness and the low level of seeking professional help, the role of primary care should be expanded. Further studies investigating mental health issues beyond depression are also warranted in the studied community.

Wavelength selective separation of metal ions using electroactive ligands.

The separation of metal ions can be challenging because of similarities in charge density, size, and binding affinities. Here, we introduce a new photochemical separation strategy that relies on the intrinsically unique photophysical properties of metal ion complexes and the selective transformation of an electroactive ligand.

Luminescent zero-dimensional organic metal halide hybrids with near-unity quantum efficiency.

Single crystalline zero-dimensional (0D) organic-inorganic hybrid materials with perfect host-guest structures have been developed as a new generation of highly efficient light emitters. Here we report a series of lead-free organic metal halide hybrids with a 0D structure, (C4N2H14X)4SnX6 (X = Br, I) and (C9NH20)2SbX5 (X = Cl), in which the individual metal halide octahedra (SnX64-) and quadrangular pyramids (SbX52-) are completely isolated from each other and surrounded by the organic ligands C4N2H14X+ and C9NH20+, respectively. The isolation of the photoactive metal halide species by the wide band gap organic ligands leads to no interaction or electronic band formation between the metal halide species, allowing the bulk materials to exhibit the intrinsic properties of the individual metal halide species. These 0D organic metal halide hybrids can also be considered as perfect host-guest systems, with the metal halide species periodically doped in the wide band gap matrix. Highly luminescent, strongly Stokes shifted broadband emissions with photoluminescence quantum efficiencies (PLQEs) of close to unity were realized, as a result of excited state structural reorganization of the individual metal halide species. Our discovery of highly luminescent single crystalline 0D organic-inorganic hybrid materials as perfect host-guest systems opens up a new paradigm in functional materials design.

Multimolecular assemblies on high surface area metal oxides and their role in interfacial energy and electron transfer.

High surface area metal oxides offer a unique substrate for the assembly of multiple molecular components at an interface. The choice of molecules, metal oxide, and the nature of the assembly method can have a profound influence on the mechanism, rate, and efficiency of photoinduced energy and electron transfer events at the interface. Owing to their diversity and high level of control, these interfacial assemblies are of interest for numerous applications including solar energy conversion, photoelectrosynthesis, photo-writable memory, and more. Although these assemblies are generated with very different goals in mind, they rely on similar surface binding motifs and molecular structure-property relationships. Therefore, the goal of this review is to summarize the various strategies (i.e. co-deposition, axial coordination, metal ion linkages, electrostatics, host-guest interactions, etc.) for assembling chromophores, hosts, electron donors/acceptors, and insulating co-adsorbent molecules on mesoporous metal oxide substrates. The assembly, synthesis, and characterization, as well as subsequent photoinduced events (i.e. cross-surface energy/electron transfer, interchromophore energy transfer, electron injection, and others) are discussed for the various assembly strategies.

Increasing the Open-Circuit Voltage of Dye-Sensitized Solar Cells via Metal-Ion Coordination.

Considerable efforts are dedicated to increasing the open-circuit voltage (Voc) of dye-sensitized solar cells (DSSCs) by slowing charge recombination dynamics using atomic layer deposition, alkyl-substituted dyes, coadsorbents, and other strategies. In this report, we introduce metal-ion coordination to a metal oxide bound dye as an alternative means of increasing Voc. Metal-ion coordination has minimal influence on the photophysical and electrochemical properties of the N3 dye, but presumably because of increased steric hindrance at the interface, it slows charge recombination kinetics and increases Voc by upwards of 130 mV relative to the parent N3 DSSC. With respect to the nature of the metal ion, the trend in decreasing short-circuit current (Jsc) and increasing Voc correlates with the charge of the coordinated metal ion (MIV → MIII → MII). We attribute this trend to electrostatic interactions between the metal cation and I- or I3-, with the more highly charged cations maintaining a higher concentration of mediator anions in proximity to the surface and, as a result, increasing the regeneration and recombination rates.

Electronic Structure and Properties of Berkelium Iodates.

The reaction of 249Bk(OH)4 with iodate under hydrothermal conditions results in the formation of Bk(IO3)3 as the major product with trace amounts of Bk(IO3)4 also crystallizing from the reaction mixture. The structure of Bk(IO3)3 consists of nine-coordinate BkIII cations that are bridged by iodate anions to yield layers that are isomorphous with those found for AmIII, CfIII, and with lanthanides that possess similar ionic radii. Bk(IO3)4 was expected to adopt the same structure as M(IO3)4 (M = Ce, Np, Pu), but instead parallels the structural chemistry of the smaller ZrIV cation. BkIII-O and BkIV-O bond lengths are shorter than anticipated and provide further support for a postcurium break in the actinide series. Photoluminescence and absorption spectra collected from single crystals of Bk(IO3)4 show evidence for doping with BkIII in these crystals. In addition to luminescence from BkIII in the Bk(IO3)4 crystals, a broad-band absorption feature is initially present that is similar to features observed in systems with intervalence charge transfer. However, the high-specific activity of 249Bk (t1/2 = 320 d) causes oxidation of BkIII and only BkIV is present after a few days with concomitant loss of both the BkIII luminescence and the broadband feature. The electronic structure of Bk(IO3)3 and Bk(IO3)4 were examined using a range of computational methods that include density functional theory both on clusters and on periodic structures, relativistic ab initio wave function calculations that incorporate spin-orbit coupling (CASSCF), and by a full-model Hamiltonian with spin-orbit coupling and Slater-Condon parameters (CONDON). Some of these methods provide evidence for an asymmetric ground state present in BkIV that does not strictly adhere to Russel-Saunders coupling and Hund's Rule even though it possesses a half-filled 5f 7 shell. Multiple factors contribute to the asymmetry that include 5f electrons being present in microstates that are not solely spin up, spin-orbit coupling induced mixing of low-lying excited states with the ground state, and covalency in the BkIV-O bonds that distributes the 5f electrons onto the ligands. These factors are absent or diminished in other f7 ions such as GdIII or CmIII.

Self-Assembled Bilayers on Nanocrystalline Metal Oxides: Exploring the Non-Innocent Nature of the Linking Ions.

Self-assembled bilayers on nanocrystalline metal oxide films are an increasingly popular strategy for modulating electron and energy transfer at dye-semiconductor interfaces. A majority of the work to date has relied on ZrII and ZnIV linking ions to assemble the films. In this report, we demonstrate that several different cations (CdII, CuII, FeII, LaIII, MnII, and SnIV) are not only effective in generating the bilayer assemblies but also have a profound influence on the stability and photophysical properties of the films. Bilayer films with ZrIV ions exhibited the highest photostability on both TiO2 and ZrO2. Despite the metal ions having a minimal influence on the absorption/emission energies and oxidation potentials of the dye, bilayers composed of CuII, FeII, and MnII exhibit significant excited-state quenching. The excited-state quenching decreases the electron injection yield but also, for CuII and MnII bilayers, significantly slows the back electron transfer kinetics.

Low-Dimensional Organic Tin Bromide Perovskites and Their Photoinduced Structural Transformation.

Hybrid organic-inorganic metal halide perovskites possess exceptional structural tunability, with three- (3D), two- (2D), one- (1D), and zero-dimensional (0D) structures on the molecular level all possible. While remarkable progress has been realized in perovskite research in recent years, the focus has been mainly on 3D and 2D structures, with 1D and 0D structures significantly underexplored. The synthesis and characterization of a series of low-dimensional organic tin bromide perovskites with 1D and 0D structures is reported. Using the same organic and inorganic components, but at different ratios and reaction conditions, both 1D (C4 N2 H14 )SnBr4 and 0D (C4 N2 H14 Br)4 SnBr6 can be prepared in high yields. Moreover, photoinduced structural transformation from 1D to 0D was investigated experimentally and theoretically in which photodissociation of 1D metal halide chains followed by structural reorganization leads to the formation of a more thermodynamically stable 0D structure.

Metal ion mediated electron transfer at dye-semiconductor interfaces.

Here we demonstrate that the incorporation of Cu2+ linking ions into self-assembled bilayer films significantly perturbs the electron transfer rate at dye-semiconductor interfaces. Despite near unity quenching of the excited state of the dye by the Cu2+ ions, a charge separated state with slowed recombination is observed.

One-dimensional organic lead halide perovskites with efficient bluish white-light emission.

Organic-inorganic hybrid metal halide perovskites, an emerging class of solution processable photoactive materials, welcome a new member with a one-dimensional structure. Herein we report the synthesis, crystal structure and photophysical properties of one-dimensional organic lead bromide perovskites, C4N2H14PbBr4, in which the edge sharing octahedral lead bromide chains [PbBr4 2-]∞ are surrounded by the organic cations C4N2H14 2+ to form the bulk assembly of core-shell quantum wires. This unique one-dimensional structure enables strong quantum confinement with the formation of self-trapped excited states that give efficient bluish white-light emissions with photoluminescence quantum efficiencies of approximately 20% for the bulk single crystals and 12% for the microscale crystals. This work verifies once again that one-dimensional systems are favourable for exciton self-trapping to produce highly efficient below-gap broadband luminescence, and opens up a new route towards superior light emitters based on bulk quantum materials.

Energy and Electron Transfer Cascade in Self-Assembled Bilayer Dye-Sensitized Solar Cells.

Current high efficiency dye-sensitized solar cells (DSSCs) rely on the incorporation of multiple chromophores, via either codeposition or preformed assemblies, as a means of increasing broad band light absorption. These strategies have some inherent limitations including decreased total light absorption by each of the dyes, low surface loadings, and complex synthetic procedures. In this report, we introduce an alternative strategy, self-assembled bilayers, as a simple, stepwise method of incorporating two complementary chromophores into a DSSC. The bilayer devices exhibit a 10% increase in Jsc, Voc, and η over the monolayer devices due to increased incident photon-to-electron conversion efficiency across the entire visible spectrum and slowed recombination losses at the interface. Directional energy and electron transfer toward the metal oxide surface are key steps in the bilayer photon-to-current generation process. These results are important as they open the door to a new architecture for harnessing broadband light in dye-sensitized devices.

BET bromodomain inhibition promotes neurogenesis while inhibiting gliogenesis in neural progenitor cells.

Neural stem cells and progenitor cells (NPCs) are increasingly appreciated to hold great promise for regenerative medicine to treat CNS injuries and neurodegenerative diseases. However, evidence for effective stimulation of neuronal production from endogenous or transplanted NPCs for neuron replacement with small molecules remains limited. To identify novel chemical entities/targets for neurogenesis, we had established a NPC phenotypic screen assay and validated it using known small-molecule neurogenesis inducers. Through screening small molecule libraries with annotated targets, we identified BET bromodomain inhibition as a novel mechanism for enhancing neurogenesis. BET bromodomain proteins, Brd2, Brd3, and Brd4 were found to be downregulated in NPCs upon differentiation, while their levels remain unaltered in proliferating NPCs. Consistent with the pharmacological study using bromodomain selective inhibitor (+)-JQ-1, knockdown of each BET protein resulted in an increase in the number of neurons with simultaneous reduction in both astrocytes and oligodendrocytes. Gene expression profiling analysis demonstrated that BET bromodomain inhibition induced a broad but specific transcription program enhancing directed differentiation of NPCs into neurons while suppressing cell cycle progression and gliogenesis. Together, these results highlight a crucial role of BET proteins as epigenetic regulators in NPC development and suggest a therapeutic potential of BET inhibitors in treating brain injuries and neurodegenerative diseases.