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Human induced pluripotent stem cells (iPSCs) can be differentiated into neurons, providing living human neurons to model brain diseases. However, it is unclear how different types of molecules work together to regulate stem cell and neuron biology in healthy and disease states. In this study, we conducted integrated proteomics, lipidomics, and metabolomics analyses with confident identification, accurate quantification, and reproducible measurements to compare the molecular profiles of human iPSCs and iPSC-derived neurons. Proteins, lipids, and metabolites related to mitosis, DNA replication, pluripotency, glycosphingolipids, and energy metabolism were highly enriched in iPSCs, whereas synaptic proteins, neurotransmitters, polyunsaturated fatty acids, cardiolipins, and axon guidance pathways were highly enriched in neurons. Mutations in the GRNgene lead to the deficiency of the progranulin (PGRN) protein, which has been associated with various neurodegenerative diseases. Using this multiomics platform, we evaluated the impact of PGRN deficiency on iPSCs and neurons at the whole-cell level. Proteomics, lipidomics, and metabolomics analyses implicated PGRN’s roles in neuroinflammation, purine metabolism, and neurite outgrowth, revealing commonly altered pathways related to neuron projection, synaptic dysfunction, and brain metabolism. Multiomics data sets also pointed toward the same hypothesis that neurons seem to be more susceptible to PGRN loss compared to iPSCs, consistent with the neurological symptoms and cognitive impairment from patients carrying inherited GRNmutations.

Systemic lupus erythematosus (SLE) is prototypical autoimmune disease driven by pathological T cell–B cell interactions1,2. Expansion of T follicular helper (TFH) and T peripheral helper (TPH) cells, two T cell populations that provide help to B cells, is a prominent feature of SLE3,4. Human TFHand TPHcells characteristically produce high levels of the B cell chemoattractant CXCL13 (refs. 5,6), yet regulation of T cell CXCL13 production and the relationship between CXCL13+T cells and other T cell states remains unclear. Here, we identify an imbalance in CD4+T cell phenotypes in patients with SLE, with expansion of PD-1+/ICOS+CXCL13+T cells and reduction of CD96hiIL-22+T cells. Using CRISPR screens, we identify the aryl hydrocarbon receptor (AHR) as a potent negative regulator of CXCL13 production by human CD4+T cells. Transcriptomic, epigenetic and functional studies demonstrate that AHR coordinates with AP-1 family member JUN to prevent CXCL13+TPH/TFHcell differentiation and promote an IL-22+phenotype. Type I interferon, a pathogenic driver of SLE7, opposes AHR and JUN to promote T cell production of CXCL13. These results place CXCL13+TPH/TFHcells on a polarization axis opposite from T helper 22 (TH22) cells and reveal AHR, JUN and interferon as key regulators of these divergent T cell states.

AbstractBackground:Tuberculosis (TB) infection prevention and control (IPC) in healthcare facilities is key to reducing transmission risk. A framework for systematically improving TB IPC through training and mentorship was implemented in 9 healthcare facilities in China from 2017 to 2019.Methods:Facilities conducted standardized TB IPC assessments at baseline and quarterly thereafter for 18 months. Facility-based performance was assessed using quantifiable indicators for IPC core components and administrative, environmental, and respiratory protection controls, and as a composite of all control types We calculated the percentage changes in scores over time and differences by IPC control type and facility characteristics.Results:Scores for IPC core components increased by 72% during follow-up when averaged across facilities. The percentage changes for administrative, environmental, and respiratory protection controls were 39%, 46%, and 30%, respectively. Composite scores were 45% higher after the intervention. Overall, scores increased most during the first 6 months. There was no association between IPC implementation and provincial economic development or volume of TB services.Conclusions:TB IPC policies and practices showed most improvement early during implementation and did not differ consistently by facility characteristics. The training component of the project helped increase the capacity of healthcare professionals to manage TB transmission risks. Lessons learned here will inform national TB IPC guidance.

Mass spectrometry (MS) analysis is often challenged by contaminations from detergents, salts, and polymers that compromise data quality and can damage the chromatography and MS instruments. However, researchers often discover contamination issues only after they acquire the data. There is no existing contaminant assay that is sensitive enough to detect trace amounts of contaminants from a few microliters of samples prior to MS analysis. To address this crucial need in the field, we developed a sensitive, rapid, and cost-effective contaminant spot check and removal assay (ContamSPOT) to detect and quantify trace amounts of contaminants, such as detergents, salts, and other chemicals commonly used in the MS sample preparation workflow. Only 1 μL of the sample was used prior to MS injection to quantify contaminants by ContamSPOT colorimetric or fluorometric assay on a thin layer chromatography (TLC) plate. We also optimized contaminant removal methods to salvage samples with minimal loss when ContamSPOT showed a positive result. ContamSPOT was then successfully applied to evaluate commonly used bottom-up proteomic methods regarding the effectiveness of removing detergent, peptide recovery, reproducibility, and proteome coverage. We expect ContamSPOT to be widely adopted by MS laboratories as a last-step quality checkpoint prior to MS injection. We provided a practical decision tree and a step-by-step protocol with a troubleshooting guide to facilitate the use of ContamSPOT by other researchers. ContamSPOT can also provide a unique readout of sample cleanliness for developing new MS-based sample preparation methods in the future.

The Superconducting Low-inductance Undulatory Galvanometer (SLUG) microwave amplifier is distinct from a conventional SQUID amplifier in that the signal to be amplified is directly injected into the SQUID loop, allowing high frequency operation. Here, we discuss a planar SLUG amplifier constructed with nanobridge weak-links fabricated from a single niobium layer. DC characterisation of the SLUG gain element is presented for two nanobridge fabrication techniques. Measurements show that junctions fabricated from Ne focused-ion-beam, and from 100 keV electron-beam lithography, have significantly different DC characteristics with critical currents on the order of 100 $\mu$A and 1 mA, respectively. Both variants exhibit maximum forward transfer functions greater than 1.5 mV/$\Phi_{0}$, which is larger than those reported in Nb SIS-junction SLUGs. Theoretical modelling has shown that an amplifier containing a planar, nanobridge SLUG as a gain element is expected to exhibit gain exceeding 15 dB with large instantaneous bandwidth, and can be designed to operate well in excess of 20 GHz.

Circular RNAs (ciRNAs) are emerging as new players in the regulation of gene expression. However, how ciRNAs are involved in neuropathic pain is poorly understood. Here, we identify the nervous-tissue-specific ciRNA-Fmn1and report that changes in ciRNA-Fmn1expression in spinal cord dorsal horn neurons play a key role in neuropathic pain after nerve injury. ciRNA-Fmn1was significantly downregulated in ipsilateral dorsal horn neurons after peripheral nerve injury, at least in part because of a decrease in DNA helicase 9 (DHX9), which regulates production of ciRNA-Fmn1by binding to DNA-tandem repeats. Blocking ciRNA-Fmn1downregulation reversed nerve-injury-induced reductions in both the binding of ciRNA-Fmn1to the ubiquitin ligase UBR5 and the level of ubiquitination of albumin (ALB), thereby abrogating the nerve-injury-induced increase of ALB expression in the dorsal horn and attenuating the associated pain hypersensitivities. Conversely, mimicking downregulation of ciRNA-Fmn1in naïve mice reduced the UBR5-controlled ubiquitination of ALB, leading to increased expression of ALB in the dorsal horn and induction of neuropathic-pain-like behaviors in naïve mice. Thus, ciRNA-Fmn1downregulation caused by changes in binding of DHX9 to DNA-tandem repeats contributes to the genesis of neuropathic pain by negatively modulating UBR5-controlled ALB expression in the dorsal horn.

Niobium nanobridge SQUIDs have shown exceptional noise performance with potential applications in quantum information processing, weak signal detection and single spin detection where the nanobridge geometry should enable efficient electromagnetic coupling to implanted spins. Combining such devices with dispersive microwave readout circuitry allows the spin sensitivity to be further improved by overcoming the standard thermal limit. Here we report on the fabrication and dispersive microwave readout of an array of niobium nanobridge rf SQUIDs incorporated into a superconducting resonator, including the optimization of the nanobridge fabrication process by electron beam lithography. We show the measured flux-tuneability of the resonance is in good agreement with theory, and we also discuss how the nonlinearity of the weak-link in the resonator structure allows for the mediation of parametric effects to enhance performance.

We report a high-spin iron system supported by two dipyrromethene ligands for ring-opening polymerization of ε-caprolactone. The four-coordination iron(II) complex, (dipyrrin)2Fe, features an S= 2 electronic configuration. It readily reacts with 2,4,6-tri-tert-butylphenoxyl radical (tBu3ArO•) by one-electron oxidation to afford (dipyrrin)2Fe-OArtBu3, a high-spin S= 5/2 iron(III) aryloxide complex. At 0.1 mol % loading, this ferric aryloxide efficiently performs CL polymerization, producing PCLs with a high molecular weight (Mn = 84,871) and narrow polydispersity (PDI = 1.23–1.26).

ABSTRACTAspergillus flavusinfects various crops with aflatoxins, and leads to aspergillosis opportunistically. Though H3K36 methylation plays an important role in fungal toxin metabolism and virulence, no data about the biological function of H3K36 methylation in A. flavusvirulence has been reported. Our study showed that the Set2 histone methyltransferase family, AshA and SetB, involves in morphogenesis and mycotoxin anabolism by regulating related transcriptional factors, and they are important for fungal virulence to crops and animals. Western-blotting and double deletion analysis revealed that AshA mainly regulates H3K36me2, whereas SetB is mainly responsible for H3K36me3 in the nucleus. By construction of domain deletion A. flavusstrain and point mutation strains by homologous recombination, the study revealed that SET domain is indispensable in mycotoxin anabolism and virulence of A. flavus, and N455 and V457 in it are the key amino acid residues. ChIP analysis inferred that the methyltransferase family controls fungal reproduction and regulates the production of AFB1 by directly regulating the production of the transcriptional factor genes, including wetA, steA, aflRand amylase, through H3K36 trimethylation in their chromatin fragments, based on which this study proposed that, by H3K36 trimethylation, this methyltransferase family controls AFB1 anabolism through transcriptional level and substrate utilization level. This study illuminates the epigenetic mechanism of the Set2 family in regulating fungal virulence and mycotoxin production, and provides new targets for controlling the virulence of the fungus A. flavus.AUTHOR SUMMARYThe methylation of H3K36 plays an important role in the fungal secondary metabolism and virulence, but no data about the regulatory mechanism of H3K36 methylation in the virulence of A. flavushave been reported. Our study revealed that, in the histone methyltransferase Set2 family, AshA mainly catalyzes H3K36me2, and involves in the methylation of H3K36me1, and SetB mainly catalyzes H3K36me3 and H3K36me1. Through domain deletion and point mutation analysis, this study also revealed that the SET domain was critical for the normal biological function of the Set2 family and that N455 and V457 in the domain were critical for AshA. By ChIP-seq and ChIP-qPCR analysis, H3K36 was found to be trimethylation modified in the promotors and ORF positions of wetA, steA, aflRand the amylase gene (AFLA_084340), and further qRT-PCR results showed that these methylation modifications regulate the expression levels of these genes. According to the results of ChIP-seq analysis, we proposed that, by H3K36 trimethylation, this methyltransferase family controls the metabolism of mycotoxin through transcriptional level and substrate utilization level. All the results from this study showed that Set2 family is essential for fungal secondary metabolism and virulence, which lays a theoretical groundwork in the early prevention and treatment of A. flavuspollution, and also provides an effective strategy to fight against other pathogenic fungi.

The capture and separation of fluorinated gases (F-gases) from N2has the potential to not only reduce greenhouse gas emissions but also provide economic benefits for the semiconductor industry. In this work, two Ni-based metal–organic frameworks (MOFs), Ni-MOF(Ni(ina)2, ina = isonicotinic acid) and amine-functionalized NH2–Ni-MOF(Ni(3-ain)2, 3-ain = 3-aminoisonicotinic acid), were constructed for capturing F-gases (CF4and NF3). At ambient conditions, both materials exhibit very high CF4sorption capacities (2.92 mmol g–1for Ni-MOFand 2.69 mmol g–1for NH2–Ni-MOF). In addition, NH2–Ni-MOFexhibited a record selectivity of 46.3 for the CF4/N2mixture at 298 K and 100 kPa, surpassing all benchmark adsorbents, including Ni-MOF(34.7). The kinetic adsorption tests demonstrated that Ni-MOFand NH2–Ni-MOFperformed well for CF4/N2and NF3/N2mixtures. According to grand canonical Monte Carlo (GCMC) simulations, CF4or NF3interacts with NH2–Ni-MOFby multiple van der Waals interactions, resulting in stronger interaction than N2. More importantly, dynamic breakthrough experiments verified the practical separation potential of the two materials for CF4/N2and NF3/N2mixtures.

Mass spectrometry-based proteomics is constantly challenged by the presence of contaminant background signals. In particular, protein contaminants from reagents and sample handling are almost impossible to avoid. For data-dependent acquisition (DDA) proteomics, an exclusion list can be used to reduce the influence of protein contaminants. However, protein contamination has not been evaluated and is rarely addressed in data-independent acquisition (DIA). How protein contaminants influence proteomic data is also unclear. In this study, we established new protein contaminant FASTA and spectral libraries that are applicable to all proteomic workflows and evaluated the impact of protein contaminants on both DDA and DIA proteomics. We demonstrated that including our contaminant libraries can reduce false discoveries and increase protein identifications, without influencing the quantification accuracy in various proteomic software platforms. With the pressing need to standardize proteomic workflow in the research community, we highly recommend including our contaminant FASTA and spectral libraries in all bottom-up proteomic data analysis. Our contaminant libraries and a step-by-step tutorial to incorporate these libraries in various DDA and DIA data analysis platforms can be valuable resources for proteomic researchers, freely accessible at https://github.com/HaoGroup-ProtContLib.

Photosensitized energy transfer (EnT) phenomena occur frequently in a variety of photophysical and photochemical processes and have traditionally been treated with the donor–acceptor distance-dependent Förster and Dexter models. However, incorrect arguments and formulae were employed by ignoring energy resonance conditions and the selection rules of the state-to-state transition in special cases, especially for the sensitive intramolecular EnT of lanthanide complexes. Herein, we proposed an innovative model of energy-degeneracy-crossing-controlled EnT, which can be experimentally confirmed by time-resolved two-dimensional photoluminescence measurements. The computationally determined energy resonance region provides the most effective channel to achieve metal-to-ligand EnT beyond the distance-dependent model and sensitively bifurcates into symmetry-allowed or -forbidden channels for some representative europium antenna complexes. The outcomes of the multidisciplinary treatment contribute to a complementary EnT model that can be tuned by introducing a phosphorescence modulator and altering the antenna-related parameters of the ligand-centered energy level of the 3ππ* state and its spin–orbit coupling for the 3ππ* → S0*transition through mechanism-guided crystal engineering and should motivate further development of mechanistic models and applications.

Single-molecule magnets (SMMs) are expected to be promising candidates for the applications of high-density information storage materials and quantum information processing. Lanthanide SMMs have attracted considerable interest in recent years due to their excellent performance. It has always been interesting but not straightforward to study the relaxation and blocking mechanisms by embedding 3d ions into 4f SMMs. Here we report a family of air-stable 3d–4f ion-pair compounds, YFe (1), DyCr (2), DyFe (3), DyCo (4), and Dy0.04Y0.96Fe (5), composed of pentagonal bipyramidal (D5h) LnIIIcations and transition metallocyanate anions. The ion-pair nature makes the dipole–dipole interactions almost the only component of the magnetic interactions that can be clarified and analytically resolved under proper approximation. Therefore, this family provides an intuitive opportunity to investigate the effects of 3d–4f and 4f–4f magnetic interactions on the behavior of site-resolved 4f SMMs. Dynamic magnetic measurements of 1under a 4 kOe external field reveal slow magnetic relaxation originating from the isolated [FeIII]LS(S= 1/2) ions. Under zero dc field, compounds 2–5show similar magnetic relaxation processes coming from the separated pentagonal bipyramidal (D5h) DyIIIions with high Orbach barriers of 592(5), 596(4), 595(3), and 606(4) K, respectively. Comparatively, both compounds 3and 5exhibit two distinct relaxation processes, respectively from the [FeIII]LSand DyIII[Ueff= 596(4) K for 3and 610(7) K for 5] ions, under a 4 kOe dc field. The dipolar interactions between the neighboring TMIII(TM = transition metal, CrIIIor [FeIII]LS) and DyIIIions were revealed to have little effect on the thermal relaxation in compounds 2, 3, and 5, or the coexistence of the two separate relaxation processes in compounds 3and 5under a 4 kOe dc field, but they significantly affect the quantum tunneling of magnetization and the magnetic hysteresis behavior of 2and 3at low temperatures compared to those of 4.

Retinoic acid receptor-related orphan receptor γ (RORc, RORγ, or NR1F3) is the nuclear receptor master transcription factor that drives the function and development of IL-17-producing T helper cells (Th17), cytotoxic T cells (Tc17), and subsets of innate lymphoid cells. Activation of RORγ+T cells in the tumor microenvironment is hypothesized to render immune infiltrates more effective at countering tumor growth. To test this hypothesis, a family of benzoxazines was optimized to provide LYC-55716 (37c), a potent, selective, and orally bioavailable small-molecule RORγ agonist. LYC-55716 decreases tumor growth and enhances survival in preclinical tumor models and was nominated as a clinical development candidate for evaluation in patients with solid tumors.

Advanced beyond-silicon electronic technology requires both channel materials and also ultralow-resistance contacts to be discovered1,2. Atomically thin two-dimensional semiconductors have great potential for realizing high-performance electronic devices1,3. However, owing to metal-induced gap states (MIGS)4–7, energy barriers at the metal–semiconductor interface—which fundamentally lead to high contact resistance and poor current-delivery capability—have constrained the improvement of two-dimensional semiconductor transistors so far2,8,9. Here we report ohmic contact between semimetallic bismuth and semiconducting monolayer transition metal dichalcogenides (TMDs) where the MIGS are sufficiently suppressed and degenerate states in the TMD are spontaneously formed in contact with bismuth. Through this approach, we achieve zero Schottky barrier height, a contact resistance of 123 ohm micrometres and an on-state current density of 1,135 microamps per micrometre on monolayer MoS2; these two values are, to the best of our knowledge, the lowest and highest yet recorded, respectively. We also demonstrate that excellent ohmic contacts can be formed on various monolayer semiconductors, including MoS2, WS2and WSe2. Our reported contact resistances are a substantial improvement for two-dimensional semiconductors, and approach the quantum limit. This technology unveils the potential of high-performance monolayer transistors that are on par with state-of-the-art three-dimensional semiconductors, enabling further device downscaling and extending Moore’s law.

Constraint-induced therapy (CIT) is highly effective yet not accessible to many families. Integrating commercial exergaming in home-based CIT may support the availability and attainability of the intervention. The study compared the effects of supplementary use of Nintendo Wii in home-based CIT with dose-equivalent conventional CIT. Eighteen children with cerebral palsy were randomly assigned to 8 weeks of CIT (CIT) or 4 weeks of CIT, followed by 4 weeks of Wii-augmented CIT (CIT-Wii). Outcome measures included the Bruininks–Oseretsky Test of Motor Proficiency (Manual Dexterity), the ABILHAND-Kids, the WeeFIM (Self-Care), the Test of Playfulness, the Engagement Questionnaire, and the Parenting Stress Index–Short Form. Both groups significantly improved motor outcomes and playfulness. The CIT group demonstrated greater improvement in self-care skills, whereas parental stress decreased only in the CIT-Wii group. CIT-Wii yields no significant difference in treatment effects from conventional CIT and may provide psychosocial benefits.

A chain complex [Dy(L)(NO3)2CH3OH]n(1) and a dinuclear compound [Dy2(L)2(NO3)4(CH3OH)2]·2CH3OH (2) were synthesized by the assembly of a novel pyridine-N-oxide-containing ligand with dysprosium nitrate under different reaction temperatures, where two coordinating nitrates are located in para or ortho position with respect to each other around dysprosium ions. Magnetic studies indicate that the chain complex with two para-coordinating nitrates shows fast quantum tunnelling of the magnetization under zero direct-current field, while the dinuclear complex with two ortho-coordinating nitrates exhibits a thermal-activated process with an effective energy barrier of 51 K. Theoretical and magneto-structural correlation studies indicate that position change of coordinating nitrates can significantly modulate the crystal field around dysprosium ion and further lead to their different relaxation behaviors.

Fusarium pseudograminearumis a devastating pathogen that causes Fusariumcrown rot (FCR) in wheat and poses a significant threat to wheat production in terms of grain yield and quality. However, the mechanism by which F. pseudograminearuminfects wheat remains unclear. In this study, we aimed to elucidate these mechanisms by constructing a T-DNA insertion mutant library for the highly virulent strain WZ-8A of F. pseudograminearum.By screening this mutant library, we identified nine independent mutants that displayed impaired pathogenesis in barley leaves. Among these mutants, one possessed a disruption in the gene FpRCO1that is an ortholog of Saccharomyces cerevisiae RCO1and an essential component of the Rpd3S histone deacetylase complex in F. pseudograminearum. To further investigate the role of FpRCO1in F. pseudograminearum, we employed a split-marker approach to knock out FpRCO1in F. pseudograminearumWZ-8A. FpRCO1deletion mutants exhibit reduced vegetative growth, conidium production, and virulence in wheat coleoptiles and barley leaves, whereas the complementary strain restores these phenotypes. Moreover, under stress conditions, the FpRCO1deletion mutants exhibited increased sensitivity to NaCl, sorbitol, and SDS, but possessed reduced sensitivity to H2O2compared to these characteristics in the wild-type strain. RNA-seq analysis revealed that deletion of FpRCO1affected gene expression (particularly the downregulation of TRIgene expression), thus resulting in significantly reduced deoxynivalenol (DON) production. In summary, our findings highlight the pivotal role of FpRCO1in regulating vegetative growth and development, asexual reproduction, DON production, and pathogenicity of F. pseudograminearum. This study provides valuable insights into the molecular mechanisms underlying F. pseudograminearuminfection in wheat and may pave the way for the development of novel strategies to combat this devastating disease.

Two-dimensional (2D) materials are drawing growing attention for next-generation electronics and optoelectronics owing to its atomic thickness and unique physical properties. One of the challenges posed by 2D materials is the large source/drain (S/D) series resistance due to their thinness, which may be resolved by thickening the source and drain regions. Recently explored lateral graphene–MoS21−3 and graphene–WS21,4 heterostructures shed light on resolving the mentioned issues owing to their superior ohmic contact behaviors. However, recently reported field-effect transistors (FETs) based on graphene–TMD heterostructures have only shown n-type characteristics. The lack of p-type transistor limits their applications in complementary metal-oxide semiconductor electronics. In this work, we demonstrate p-type FETs based on graphene–WSe2lateral heterojunctions grown with the scalable CVD technique. Few-layer WSe2is overlapped with the multilayer graphene (MLG) at MLG–WSe2junctions such that the contact resistance is reduced. Importantly, the few-layer WSe2only forms at the junction region while the channel is still maintained as a WSe2monolayer for transistor operation. Furthermore, by imposing doping to graphene S/D, 2 orders of magnitude enhancement in Ion/Ioffratio to ∼108and the unipolar p-type characteristics are obtained regardless of the work function of the metal in ambient air condition. The MLG is proposed to serve as a 2D version of emerging raised source/drain approach in electronics.

A new pillared-layer coordination polymer, [Co3(pybz)2(pico)2]n(1; pybz = 4-(pyridin-4-yl)benzoate, pico = 3-hydroxypicolinate), contains rare 2D [Co3(pico)2]n2n+layers formed by linear cobalt(II) trimers through the unusual μ4-κN,O:κO′-μ2:κO′′-μ2bridging mode of pico ligands, which are further cross-pillared by exotridentate bridging pybz ligands to form a three-dimensional structure with an unusual uninodal 8-connected body-centered-cubic topology. The bulk magnetic behavior of 1exhibits ferrimagnetic long-range ordering below 2.6 K, which mainly arises from the cooperative magnetic effect of the intra- and intertrimer arrangements in the 2D magnetic system based on the nature of the exchange modes of μ2-hydroxyl, μ2-carboxylate oxygen, and 1,1,3-μ3-carboxylate bridges.

Proximity-based in situ labeling techniques offer a unique way to capture both stable and transient protein–protein and protein–organelle interactions. Combining this technology with mass spectrometry (MS)-based proteomics allows us to obtain snapshots of molecular microenvironments with nanometer resolution, facilitating the discovery of complex and dynamic protein networks. However, a number of technical challenges still exist, such as interferences from endogenously biotinylated proteins and other highly abundant bystanders, how to select the proper controls to minimize false discoveries, and experimental variations among biological/technical replicates. Here, we developed a new method to capture the proteomic microenvironment of the neuronal endolysosomal network by knocking in (KI) an engineered ascorbate peroxidase (APEX) gene to the endogenous locus of lysosome-associated membrane protein 1 (LAMP1). We found that normalizing proximity labeling proteomics data to the endogenously biotinylated protein (PCCA) can greatly reduce variations and enable fair comparisons among different batches of APEX labeling and different APEX probes. We conducted a comparative evaluation between this KI-LAMP1-APEX method and our two overexpression LAMP1-APEX probes, achieving complementary coverage of both known and new lysosomal membrane and lysosomal-interacting proteins in human iPSC-derived neurons. To summarize, this study demonstrated new analytical tools to characterize lysosomal functions and microenvironment in human neurons and filled critical gaps in the field for designing and optimizing proximity labeling proteomic experiments.

Benign prostatic hyperplasia and related lower urinary tract symptoms remain common, costly, and impactful issues for aging males. The etiology and pathogenesis are multifactorial and include steroid hormone changes and inflammation. Noninvasive markers could one day inform personalized medicine, but interindividual variation and lack of healthy age-matched controls hamper research. Experimental models are appealing for insight into disease mechanisms. Here, we present a spatiotemporal proteomics study in a mouse model of hormone-induced urinary dysfunction. Urine samples were collected noninvasively across time: before, during, and after disease onset. A microcomputed tomography analysis implicated the prostate as a spatially relevant contributor to bladder outlet obstruction. Prostates were collected after disease onset and compared with control mice. Notable changes in urine include proteins representing oxidative stress defense and acute phase inflammatory response processes. In the prostate, hormone treatment led to perturbations related to an oxidative stress response and H2O2metabolism. Several protein changes coincided in both urine and the prostate tissue, including glutathione peroxidase 3, glutathione hydrolase 1 proenzyme, and vitamin D-binding protein. This study supports the concept of noninvasive urinary biomarkers for prostate disease diagnostics. Oxidative stress and acute phase inflammatory processes were identified as key consequences of hormone-induced bladder outlet obstruction. Future research into antioxidants and anti-inflammatories in prostate diseases appears promising.

Herein, we report the clinical and genetic features of a patient with Usher syndrome type IB to improve our collective understanding of the disorder. The patient was a teenaged boy with congenital profound hearing loss, progressive visual loss, and vestibular hypoplasia; his parents were phenotypically normal. His pure tone audiometry hearing thresholds were 100 dB at all frequencies, and distortion product otoacoustic emission was not elicited at any frequencies in either ear. Moreover, an auditory brainstem response test at 100 dB normal hearing level revealed no relevant response waves, and a caloric test showed vestibular hypoplasia. Fundus examination revealed retinitis pigmentosa and a reduced visual field. The use of high-throughput sequencing technology to screen the patient’s family lineage for deafness-related genes revealed that the patient carried a compound heterozygous pathogenic variant of MYO7A: c.541C > T and c.6364delG. This pathogenic variant has not previously been reported. Our findings may provide a basis for genetic counseling, effective treatment, and/or gene therapy for Usher syndrome.

New Ln-metal–organic frameworks (Ln-MOFs), {[Ln(2,7-NDS)(IP)(OH)(H2O)2]·mH2O}n[Ln = Sm 1, Eu 2, Gd 3, Tb 4, Dy 5, m= 0.5–0; 2,7-NDS = 2,7-naphthalenedisulfonate, and IP = 1H-imidazo[4,5-f][1,10]-phenanthroline) were obtained by the hydrothermal method. The Ln-MOFs feature one-dimensional double chain structures. The photoluminescent properties of these complexes were investigated. Notably, the Eu-MOF exhibits a broad excitation band from 250 to 400 nm in the UV–vis region, and it presents red emission from the 5D0→ 7FJtransitions (where J= 0–4) of the Eu3+ion. It is noteworthy that it still shows intense emission under near-visible irradiation at 350 nm < λex< 385 nm. Using the Eu-MOF as a luminescent sensor, the detection of Fe3+/Ag+and ornidazole (ODZ)/ronidazole (RDZ) in aqueous medium was realized with long excitation wavelengths of 368 nm or even 385 nm in the near-visible region. This work provides a new approach to designing an efficient red emission with broad-band and near-visible light excitation and with luminescent chemosensor capability for biological applications. In addition, the Eu-MOF red light incorporated Gd-MOF blue-green light, and a white-light emission is realized based on a two-component Gd0.99803Eu0.00197doped complex. Magnetic studies of the Dy-MOF reveal that it has a single-molecule magnet and slow magnetic relaxation behavior with an energy barrier Ueffof 82.39 K.

Lower urinary tract symptoms (LUTS) are common among aging men. Since prostatic inflammation is one of its etiologies, it is plausible that urinary metabolite and protein biomarkers could be identified and used to diagnose inflammation-induced LUTS. We characterized the urine metabolome and proteome in a mouse model of bacterial-induced prostatic inflammation. Mass spectrometry (MS)-based multi-omics analysis was employed to discover urinary protein and metabolite-based biomarkers. The investigation of isobaric dimethylated leucine (DiLeu) labeling on metabolites allowed metabolomics and proteomics analysis on the same liquid chromatography (LC)-MS platform. In total, 143 amine-containing metabolites and 1058 urinary proteins were identified and quantified (data are available via ProteomeXchange with identifier PXD018023); among them, 14 metabolites and 168 proteins were significantly changed by prostatic inflammation. Five metabolic pathways and four inflammation-related biological processes were potentially disrupted. By comparing our findings with urinary biomarkers identified in a mouse model of genetic-induced prostate inflammation and with those previously found to be associated with LUTS in older men, we identified creatine, haptoglobin, immunoglobulin kappa constant and polymeric Ig receptor as conserved biomarkers for prostatic inflammation associated with LUTS. These data suggest that these putative biomarkers could be used to identify men in which prostate inflammation is present and contributing to LUTS.

Inflammation is involved in many prostate pathologies including infection, benign prostatic hyperplasia, and prostate cancer. Preclinical models are critical to our understanding of disease mechanisms, yet few models are genetically tractable. Here, we present a comparative quantitative proteomic analysis of urine from mice with and without prostate-specific inflammation induced by conditional prostate epithelial IL-1β expression. Relative quantification and sample multiplexing was achieved using custom 4-plex N,N-dimethyl leucine (DiLeu) isobaric tags and nanoflow ultrahigh-performance liquid chromatography coupled to high-resolution tandem mass spectrometry. Each set of 4-plex DiLeu reagents allows four urine samples to be analyzed simultaneously, providing high-throughput and accurate quantification of urinary proteins. Proteins involved in the acute phase response, including haptoglobin, inter-α-trypsin inhibitor, and α1-antitrypsin 1-1, were differentially represented in the urine of mice with prostate inflammation. Mass spectrometry-based quantitative urinary proteomics represents a promising bioanalytical strategy for biomarker discovery and the elucidation of molecular mechanisms in urological research.

For the purpose of further exploring the effect of nonperipherally attached substituents on single-ion magnet (SIMs) performance, tetrasubstituted bis[1,8,15,22-tetrakis(3-pentyloxy)phthalocyaninato]terbium double-deckers, in both the reduced form TbH[Pc(α-OC5H11)4]2(1) and the neutral form Tb[Pc(α-OC5H11)4]2(2), were prepared. Single-crystal X-ray diffraction analysis for 2unambiguously demonstrates the pinwheellike molecular structure with C4symmetry. Magnetic investigations of the two bis(phthalocyaninato)terbium double-deckers reveal their characteristic SIM nature. 2exhibits SIM performance superior to that of 1, as revealed by the larger energy barrier of 466 K for the former species and 431 K for the latter species due to the presence of organic radical–f (radical–Tb) interactions. The enhanced SIM performance of 2in comparison to 1actually stems from the presence of radical–f interactions and an enhanced ligand field strength. The latter positive factor is indicated by the electrostatic potential around the terbium ion on the basis of density functional theory (DFT) calculations.

The aminated beta-cyclodextrin (b-CD-N) molecules were first used to modify graphene for fabricating the hybrid film electrode (G/b-CD-N) using a method combining mild water bath heat-treatment and vacuum filtration. As compared with pure graphene film (G) and beta-cyclodextrin (b-CD) modified graphene film (G/b-CD), the prepared G/b-CD-N hybrid film exhibits better hydrophilic property, thermal stability and higher mechanical flexibility. Particularly, the G/b-CD-N hybrid film has a remarkably high areal specific capacitance (614 mF cm[?]2 at 0.5 mA cm[?]2), good mechanical flexibility (maintaining 98.2% for 1000 bending/unbending cycles) and long-term cycle stability (maintaining 96.8% for 10000 charge/discharge cycles). Moreover, the assembled G/b-CD-N based flexible and symmetric all-solid-state supercapacitor shows an excellent volumetric specific capacitance of 22.53 F cm[?]3 at 0.5 mA cm[?]2 and a high energy density of 3.13 mWh cm[?]3 at a power density of 0.014 W cm[?]3. The high comprehensive performances of the developed hybrid film electrodes can be ascribed to the combined effects of b-CD molecules and the amination process. This work provides a new approach for the fabrication of flexible supercapacitor with high performance.

Microwave absorption in radar stealth technology is faced with challenges in terms of its effectiveness in low-frequency regions. Herein, we report a new laser-based method for producing an ultrawideband metamaterial-based microwave absorber with a highly uniform sheet resistance and negative magnetic permeability at resonant frequencies, which results in a wide bandwidth in the L- to S-band. Control of the electrical sheet resistance uniformity has been achieved with less than 5% deviation at 400 Ω sq−1and 6% deviation at 120 Ω sq−1, resulting in a microwave absorption coefficient between 97.2% and 97.7% within a 1.56–18.3 GHz bandwidth for incident angles of 0°–40°, and there is no need for providing energy or an electrical power source during the operation. Porous N- and S-doped turbostratic graphene 2D patterns with embedded magnetic nanoparticles were produced simultaneously on a polyethylene terephthalate substrate via laser direct writing. The proposed low-frequency, wideband, wide-incident-angle, and high-electromagnetic-absorption microwave absorber can potentially be used in aviation, electromagnetic interference (EMI) suppression, and 5G applications.