Connectomes across development reveal principles of brain maturation.

An animal's nervous system changes as its body grows from birth to adulthood and its behaviours mature1-8. The form and extent of circuit remodelling across the connectome is unknown3,9-15. Here we used serial-section electron microscopy to reconstruct the full brain of eight isogenic Caenorhabditis elegans individuals across postnatal stages to investigate how it changes with age. The overall geometry of the brain is preserved from birth to adulthood, but substantial changes in chemical synaptic connectivity emerge on this consistent scaffold. Comparing connectomes between individuals reveals substantial differences in connectivity that make each brain partly unique. Comparing connectomes across maturation reveals consistent wiring changes between different neurons. These changes alter the strength of existing connections and create new connections. Collective changes in the network alter information processing. During development, the central decision-making circuitry is maintained, whereas sensory and motor pathways substantially remodel. With age, the brain becomes progressively more feedforward and discernibly modular. Thus developmental connectomics reveals principles that underlie brain maturation.

Identification of novel compound heterozygous ZFP36L2 variants implicated in oocyte maturation defects and female infertility.

PURPOSE: To explore the pathogenesis of oocyte maturation defects. METHODS: Whole exome sequencing was conducted to identify potential variants, which were then confirmed within the pedigree through Sanger sequencing. The functional characterization of the identified variants responsible for the disease, including their subcellular localization, protein levels, and interactions with other proteins, was verified through transient transfection in HeLa cells in vitro. Additionally, we employed real-time RT-PCR and single-cell RNA sequencing to examine the impact of ZFP36L2 pathogenic variants on mRNA metabolism in both HeLa cells and mouse or human oocytes. RESULTS: A novel compound heterozygous variant in ZFP36L2 (c.186T > G, p.His62Gln and c.869 C > T, p.Pro290Leu) was discovered in a patient with oocyte maturation defects. Our findings indicate that these variants lead to compromised binding capacity of the ZFP36L2-CONT6L complex and impaired mRNA degradation in HeLa cells and mouse oocytes. Furthermore, we characterized the changes in the human oocyte transcriptome associated with ZFP36L2 variants, with a particular emphasis on cell division, mitochondrial function, and ribosome metabolism. CONCLUSIONS: This study broadens the mutation spectrum of ZFP36L2 and constitutes the first report of human oocyte transcriptome alterations linked to ZFP36L2 variants. In conjunction with existing knowledge of ZFP36L2, our research lays the groundwork for genetic counseling aimed at addressing female infertility.

Ear microbiota and middle ear disease: a longitudinal pilot study of Aboriginal children in a remote south Australian setting.

BACKGROUND: Otitis media (OM) is a major disease burden in Australian Aboriginal children, contributing to serious long-term health outcomes. We report a pilot analysis of OM in children attending an outreach ear and hearing clinic in a remote south Australian community over a two-year period. Our study focuses on longitudinal relationships between ear canal microbiota characteristics with nasopharyngeal microbiota, and clinical and treatment variables. RESULTS: Middle ear health status were assessed in 19 children (aged 3 months to 8 years) presenting in remote western South Australia and medical interventions were recorded. Over the two-year study period, chronic suppurative OM was diagnosed at least once in 7 children (37%), acute OM with perforation in 4 children (21%), OM with effusion in 11 children (58%), while only 1 child had no ear disease. Microbiota analysis of 19 children (51 sets of left and right ear canal swabs and nasopharyngeal swabs) revealed a core group of bacterial taxa that included Corynebacterium, Alloiococcus, Staphylococcus, Haemophilus, Turicella, Streptococcus, and Pseudomonas. Within-subject microbiota similarity (between ears) was significantly greater than inter-subject similarity, regardless of differences in ear disease (p = 0.0006). Longitudinal analysis revealed changes in diagnosis to be associated with more pronounced changes in microbiota characteristics, irrespective of time interval. Ear microbiota characteristics differed significantly according to diagnosis (P (perm) = 0.0001). Diagnoses featuring inflammation with tympanic membrane perforation clustering separately to those in which the tympanic membrane was intact, and characterised by increased Proteobacteria, particularly Haemophilus influenzae, Moraxella catarrhalis, and Oligella. While nasopharyngeal microbiota differed significantly in composition to ear microbiota (P (perm) = 0.0001), inter-site similarity was significantly greater in subjects with perforated tympanic membranes, a relationship that was associated with the relative abundance of H. influenzae in ear samples (rs = - 0.71, p = 0.0003). Longitudinal changes in ear microbiology reflected changes in clinical signs and treatment. CONCLUSIONS: Children attending the ear and hearing clinic in a remote Aboriginal community present with a broad spectrum of OM conditions and severities, consistent with other remote Aboriginal communities. Ear microbiota characteristics align with OM diagnosis and change with disease course. Nasopharyngeal microbiota characteristics are consistent with the contribution of acute upper respiratory infection to OM aetiology.

Rho GTPases in cancer radiotherapy and metastasis.

Despite treatment advances, radioresistance and metastasis markedly impair the benefits of radiotherapy to patients with malignancies. Functioning as molecular switches, Rho guanosine triphosphatases (GTPases) have well-recognized roles in regulating various downstream signaling pathways in a wide range of cancers. In recent years, accumulating evidence indicates the involvement of Rho GTPases in cancer radiotherapeutic efficacy and metastasis, as well as radiation-induced metastasis. The functions of Rho GTPases in radiotherapeutic efficacy are divergent and context-dependent; thereby, a comprehensive integration of their roles and correlated mechanisms is urgently needed. This review integrates current evidence supporting the roles of Rho GTPases in mediating radiotherapeutic efficacy and the underlying mechanisms. In addition, their correlations with metastasis and radiation-induced metastasis are discussed. Under the prudent application of Rho GTPase inhibitors based on critical evaluations of biological contexts, targeting Rho GTPases can be a promising strategy in overcoming radioresistance and simultaneously reducing the metastatic potential of tumor cells.

Cancellation of elective surgery: rates, reasons and effect on patient satisfaction.

Background: The cancellation of elective surgeries is a major problem that increases wait times, exacerbates costs and can negatively affect patients, both psychologically and physically. Our objectives were to investigate the reasons for cancellations across specialties at a single centre, to compare these reasons with previous data from the same centre between 2005 and 2009 and to examine how cancellations affected patients' lives and views of the medical system in cases when the cancellations were potentially preventable. Methods: Cancellation records of all elective surgeries scheduled between June 1, 2012, and Jan. 31, 2016, at a medium-sized, tertiary care, academic centre were retrospectively reviewed. We evaluated the rates and reasons for cancellation and interviewed a subset of patients whose surgery was cancelled for a potentially preventable reason (i.e., operating room running late, bed shortage, emergency case took place of scheduled surgery). Results: Across 11 surgical specialties, 2933 of 20 881 surgeries (14.0%) were cancelled and of these, 2448 (83.5%) were for administrative or structural reasons. Compared with the data collected previously for general, gynecological and urological procedures, cancellation rates increased from 8.1% to 11.8%. Although patients reported inconvenience, they were generally satisfied with the availability and the quality of the health care they received. Conclusion: Consistent with the previous study, our data suggest that most cancellations occur because of administrative or structural processes that are potentially preventable. Targeting these processes may help to reduce cancellations for elective surgeries and thereby improve economic efficiency and patient outcomes.

Contexte: L'annulation des chirurgies électives est un problème majeur qui allonge les temps d'attente, fait gonfler les coûts et peut affecter négativement les patients, tant psychologiquement que physiquement. Nos objectifs étaient de découvrir les raisons des annulations dans les diverses spécialités d'un seul centre, afin de comparer ces raisons à des données antérieures du même centre recueillies entre 2005 et 2009 et d'examiner en quoi les annulations affectent la vie des patients et leur perception du système médical dans les cas où les annulations auraient pu être évitées. Méthodes: Les dossiers d'annulation de toutes les chirurgies électives entre le 1er juin 2012 et le 31 janvier 2016 dans un centre hospitalier universitaire de soins tertiaires de taille moyenne ont été analysés de manière rétrospective. Nous avons évalué les taux d'annulation et les motifs, et interrogé un groupe de patients dont la chirurgie a été annulée pour des raisons potentiellement évitables (p. ex., retards au bloc opératoire, manque de lits, priorisation de cas plus urgents). Résultats: Entre les 11 spécialités chirurgicales, 2933 des 20 881 chirurgies (14,0 %) ont été annulées et parmi elles, 2448 (83,5 %) pour des raisons administratives ou structurelles. Comparativement aux données précédemment recueillies pour les interventions générales, gynécologiques et urologiques, les taux d'annulation ont augmenté de 8,1 % à 11,8 %. Même si les patients ont déploré des inconvénients, ils se sont généralement déclarés satisfaits de la qualité des soins reçus et de leur accessibilité. Conclusion: Comme lors de l'étude précédente, nos données suggèrent que les causes les plus fréquentes d'annulation sont liées à des marches à suivre administratives ou structurelles qui sont potentiellement évitables. Cibler ces marches à suivre pourrait contribuer à réduire le nombre d'annulations de chirurgies électives et améliorer de ce fait l'efficience économique et les résultats chez les patients.

Ligand-Protected Au55 with a Novel Structure and Remarkable CO2 Electroreduction Performance.

A Au55 nanocluster with the composition of [Au55 (p-MBT)24 (Ph3 P)6 ](SbF6 )3 (p-MBT=4-methylbenzenethiolate) is synthesized via direct reduction of gold-phosphine and gold-thiolate precursors. Single-crystal X-ray diffraction reveals that this Au55 nanocluster features a face-centered cubic (fcc) Au55 kernel, different from the well-known two-shell cuboctahedral arrangement in Au55 (Ph3 P)12 Cl6 . The Au55 cluster shows a wide optical absorption band with optical energy gap (Eg =1.28 eV). It is found that the exclusion of chloride is crucial for the formation of the title cluster, otherwise rod-like [Au25 (SR)5 (PPh3 )10 Cl2 ]2+ is obtained. The strategy to run synthetic reaction in the absence of halide leads to new members of phosphine/thiolate co-protected metal nanoclusters. The Au55 nanocluster exhibits high catalytic activity and selectivity for electrochemical reduction of CO2 to CO; the Faradaic efficiency (FE) reaches 94.1 % at -0.6 V vs. reversible hydrogen electrode (RHE).

[Risk factors for minimally invasive surfactant administration failure in preterm infants with respiratory distress syndrome].

OBJECTIVE: To identify risk factors for minimally invasive surfactant administration (MISA) failure in the treatment of preterm infants with respiratory distress syndrome (RDS) and the influence of MISA failure on neonatal outcome. METHODS: A retrospective analysis was performed for the clinical data of 148 preterm infants with a gestational age of ≤32 weeks and a clinical diagnosis of RDS, who were admitted to the neonatal intensive care unit of eight tertiary hospitals in Beijing, Tianjin and Hebei Province from July 1, 2017 to December 31, 2018 and were treated with MISA (bovine pulmonary surfactant, PS). According to whether MISA failure (defined as the need for mechanical ventilation within 72 hours after MISA) was observed, the infants were divided into two groups: MISA failure group (n=16) and MISA success (n=132). A logistic regression analysis was used to investigate the risk factors for MISA failure and its influence on neonatal outcome. RESULTS: The MISA failure rate was 10.8% (16/148). The logistic regression analysis showed that a high incidence rate of grade >II RDS before PS administration, low mean arterial pressure and high pulse pressure before administration, a low dose of initial PS administration, and long injection time and operation time were the risk factors for MISA failure (OR=5.983, 1.210, 1.183, 1.055, 1.036, and 1.058 respectively, P<0.05). After the control for the above risk factors, the logistic regression analysis showed that the MISA failure group had a significantly higher incidence rate of bronchopulmonary dysplasia (BPD) (OR=8.537, P<0.05). CONCLUSIONS: A high grade of RDS, a low mean arterial pressure, and a high pulse pressure before administration are independent risk factors for MISA failure, and a low dose of initial PS administration, a long injection time, and a long operation time may increase the risk of MISA failure. MISA failure may increase the incidence rate of BPD in preterm infants.

Alkynyl Approach toward the Protection of Metal Nanoclusters.

The past decades have witnessed great advances in the synthesis, structure determination, and properties investigation of coinage metal nanoclusters. These monodisperse clusters have well-defined molecular structures, which is advantageous in correlating structures and properties. Metal nanoclusters are large molecules consisting of many components, so it is a big challenge to prepare them in a rational way. Strenuous efforts have been made to control their geometric and electronic structures, in order to optimize their various properties. A metal nanocluster normally contains a metal core and a peripheral ligand shell. The ligands do not only function as simple stabilizing agents. It has been revealed that these ligands are able to influence the formation processes of the nanoclusters, and they may also dictate the sizes, shapes, and properties of nanoclusters. There are mainly three types of ligands that are widely used as surface anchors on coinage metal nanoclusters: thiolates, phosphines, and halides. Recent ligand engineering has extended the scope to alkynyl ligands. As alkynyl ligands are versatile in interacting with metal atoms, interesting alkynyl-metal interfacial structures including linear, L-shaped, and V-shaped staple motifs can be generated, as well as a series of novel coinage metal nanoclusters that exhibit intriguing molecular geometries. The staple motifs do not simply resemble the surface structures of thiolate-protected nanoclusters, because the incorporation of alkynyl ligands may significantly alter diverse properties of nanoclusters. Compared with thiolate-protected gold nanoclusters, alkynyl-protected ones with identical metal cores exhibit distinctly different absorption profiles and show much improved catalytic activities for semihydrogenation of alkynes. In addition, the participation of alkynyl ligands could profoundly affect the luminescent properties of nanoclusters. These "ligand effects" are mainly attributed to the different nature of alkynyl ligands, as electronic perturbation through π-conjugated units may largely modulate the electronic structure of the whole cluster. In this Account, we describe the development of coinage metal nanoclusters protected with alkynyl ligands. We will first briefly bring up the emergence of alkynyl ligands as anchoring groups on the surfaces of nanoclusters. Then we present the direct reduction method for the synthesis of the following four categories of nanoclusters: (a) gold nanoclusters with mixed-ligand shells, (b) all alkynyl-protected gold nanoclusters, (c) heterobimetallic gold nanoclusters, and (d) silver nanoclusters. Their molecular structures are described, and their various alkynyl-metal interfacial structures are compared with thiolate-metal staples. Finally, ligand effects on the properties of the clusters, including optical absorption, luminescence, and catalysis, are discussed. The alkynyl ligands play an important role in terms of both structural and property aspects. We believe this Account will attract increasing attention to alkynyl ligands, which have shown promising potential in generating new structures and properties of coinage metal nanoclusters.

Isolation and Total Structure Determination of an All-Alkynyl-Protected Gold Nanocluster Au144.

Total structure determination of a ligand-protected gold nanocluster, Au144 , has been successfully carried out. The composition of title nanocluster is Au144 (C≡CAr)60 (1; Ar=2-FC6 H4 -). The cluster 1 exhibits a quasi-spherical Russian doll-like architecture, comprising a Au54 two-shelled Mackay icosahedron (Au12 @Au42 ), which is further enclosed by a Au60 anti-Mackay icosahedral shell. The Au114 kernel is enwrapped by thirty linear ArC≡C-Au-C≡CAr staple motifs. The absorption spectrum of 1 shows two bands at 560 and 620 nm. This spectrum is distinctly different from that of thiolated Au144 , which was predicted to have an almost identical metal kernel and very similar ligands arrangement in 1. These facts indicate the molecule-like behavior of 1 and significant involvement of ligands in the electronic structure of 1. The cluster 1 is hitherto the largest coinage metal nanocluster with atomically precise molecular structure in the alkynyl family. The work not only addresses the concern of structural information of Au144 , which had been long-pursued, but also provides an interesting example showing ligand effects on the optical properties of ligand protected metal nanoclusters.

Atomically Precise Bimetallic Au19Cu30 Nanocluster with an Icosidodecahedral Cu30 Shell and an Alkynyl-Cu Interface.

Bimetallic nanoclusters Au19Cu30 with chemical composition of [Au19Cu30(C≡CR)22(Ph3P)6Cl2](NO3)3 (where RC≡C is from 3-ethynylthiophene (H3C4S-3-C≡CH) or ethynylbenzene (PhC≡CH)) has been synthesized. Single X-ray structural analysis reveals that Au19Cu30 has a multishelled core structure of Au@Au12@Cu30@Au6, comprising a centered icosahedral Au13 (Au@Au12) surrounded by an icosidodecahedral Cu30 shell and an outmost shell of a chairlike hexagonal Au6. The alkynyl carbon is bound to the hollow sites on the Au19Cu30 nanocluster surface, which is a novel interfacial binding mode in alkynyl-protected alloy nanoclusters. The Cu30 icosidodecahedron is unprecedented and Au19Cu30 represents the first alkynyl-protected Au-Cu alloy nanocluster.

Homoleptic Alkynyl-Protected Gold Nanoclusters: Au44 (PhC≡C)28 and Au36 (PhC≡C)24.

For the first time total structure determination of homoleptic alkynyl-protected gold nanoclusters is reported. The nanoclusters are synthesized by direct reduction of PhC≡CAu, to give Au44 (PhC≡C)28 and Au36 (PhC≡C)24 . The Au44 and Au36 nanoclusters have fcc-type Au36 and Au28 kernels, respectively, as well as surrounding PhC≡C-Au-C2 (Ph)Au-C≡CPh dimeric "staples" and simple PhC≡C bridges. The structures of Au44 (PhC≡C)28 and Au36 (PhC≡C)24 are similar to Au44 (SR)28 and Au36 (SR)24 , but the UV/Vis spectra are different. The protecting ligands influence the electronic structures of nanoclusters significantly. The synthesis of these two alkynyl-protected gold nanoclusters indicates that a series of gold nanoclusters in the general formula Aux (RC≡C)y as counterparts to Aux (SR)y can be expected.

Atomically Precise Alkynyl-Protected Metal Nanoclusters as a Model Catalyst: Observation of Promoting Effect of Surface Ligands on Catalysis by Metal Nanoparticles.

Metal nanoclusters whose surface ligands are removable while keeping their metal framework structures intact are an ideal system for investigating the influence of surface ligands on catalysis of metal nanoparticles. We report in this work an intermetallic nanocluster containing 62 metal atoms, Au34Ag28(PhC≡C)34, and its use as a model catalyst to explore the importance of surface ligands in promoting catalysis. As revealed by single-crystal diffraction, the 62 metal atoms in the cluster are arranged as a four-concentric-shell Ag@Au17@Ag27@Au17 structure. All phenylalkynyl (PA) ligands are linearly coordinated to the surface Au atoms with staple "PhC≡C-Au-C≡CPh" motif. Compared with reported thiolated metal nanoclusters, the surface PA ligands on Au34Ag28(PhC≡C)34 are readily removed at relatively low temperatures, while the metal core remains intact. The clusters before and after removal of surface ligands are used as catalysts for the hydrolytic oxidation of organosilanes to silanols. It is, for the first time, demonstrated that the organic-capped metal nanoclusters work as active catalysts much better than those with surface ligands partially or completely removed.

An Atomically Precise Au10 Ag2 Nanocluster with Red-Near-IR Dual Emission.

A red-near-IR dual-emissive nanocluster with the composition [Au10 Ag2 (2-py-C≡C)3 (dppy)6 ](BF4 )5 (1; 2-py-C≡C is 2-pyridylethynyl, dppy=2-pyridyldiphenylphosphine) has been synthesized. Single-crystal X-ray structural analysis reveals that 1 has a trigonal bipyramidal Au10 Ag2 core that contains a planar Au4 (2-py-C≡C)3 unit sandwiched by two Au3 Ag(dppy)3 motifs. Cluster 1 shows intense red-NIR dual emission in solution. The visible emission originates from metal-to-ligand charge transfer (MLCT) from silver atoms to phosphine ligands in the Au3 Ag(dppy)3 motifs, and the intense NIR emission is associated with the participation of 2-pyridylethynyl in the frontier orbitals of the cluster, which is confirmed by a time-dependent density functional theory (TD-DFT) calculation.

Au19 nanocluster featuring a V-shaped alkynyl-gold motif.

A novel Au19 nanocluster with a composition of [Au19(PhC≡C)9(Hdppa)3](SbF6)2 was synthesized (Hdppa = N,N-bis(diphenylphosphino)amine). Single crystal X-ray structural analysis reveals that the cluster comprises a centered icosahedral Au13 core hugged by three V-shaped PhC≡C-Au-C≡C(Ph)-Au-C≡CPh motifs. Such motif is observed for the first time in an alkynyl-protected gold nanocluster. The Au19 cluster shows two main optical-absorption bands at 1.25 and 2.25 eV, confirmed by time-dependent density functional theory. Orbital analysis indicates that PhC≡C- groups can actively participate in the frontier orbitals of the whole cluster. The new Au19 cluster and the novel alkynyl-gold motif open the door to understanding the alkynyl-gold interface and discovering many potential members of this new class of gold clusters.

Highly Active Gold(I)-Silver(I) Oxo Cluster Activating sp³ C-H Bonds of Methyl Ketones under Mild Conditions.

The activation of C(sp(3))-H bonds is challenging, due to their high bond dissociation energy, low proton acidity, and highly nonpolar character. Herein we report a unique gold(I)-silver(I) oxo cluster protected by hemilabile phosphine ligands [OAu3Ag3(PPhpy2)3](BF4)4 (1), which can activate C(sp(3))-H bonds under mild conditions for a broad scope of methyl ketones (RCOCH3, R = methyl, phenyl, 2-methylphenyl, 2-aminophenyl, 2-hydroxylphenyl, 2-pyridyl, 2-thiazolyl, tert-butyl, ethyl, isopropyl). Activation happens via triple deprotonation of the methyl group, leading to formation of heterometallic Au(I)-Ag(I) clusters with formula RCOCAu4Ag4(PPhpy2)4(BF4)5 (PPhpy2 = bis(2-pyridyl)phenylphosphine). Cluster 1 can be generated in situ via the reaction of [OAu3Ag(PPhpy2)3](BF4)2 with 2 equiv of AgBF4. The oxo ion and the metal centers are found to be essential in the cleavage of sp(3) C-H bonds of methyl ketones. Interestingly, cluster 1 selectively activates the C-H bonds in -CH3 rather than the N-H bonds in -NH2 or the O-H bond in -OH which is traditionally thought to be more reactive than C-H bonds. Control experiments with butanone, 3-methylbutanone, and cyclopentanone as substrates show that the auration of the C-H bond of the terminal methyl group is preferred over secondary or tertiary sp(3) C-H bonds; in other words, the C-H bond activation is influenced by steric effect. This work highlights the powerful reactivity of metal clusters toward C-H activation and sheds new light on gold(I)-mediated catalysis.

Reduction of Mitochondrial Function by FCCP During Mouse Cleavage Stage Embryo Culture Reduces Birth Weight and Impairs the Metabolic Health of Offspring.

The periconceptual environment represents a critical window for programming fetal growth trajectories and susceptibility to disease; however, the underlying mechanism responsible for programming remains elusive. This study demonstrates a causal link between reduction of precompaction embryonic mitochondrial function and perturbed offspring growth trajectories and subsequent metabolic dysfunction. Incubation of embryos with carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP), which uncouples mitochondrial oxidative phosphorylation, significantly reduced mitochondrial membrane potential and ATP production in 8-cell embryos and the number of inner cell mass cells within blastocysts; however, blastocyst development was unchanged. This perturbed embryonic mitochondrial function was concomitant with reduced birth weight in female offspring following embryo transfer, which persisted until weaning. FCCP-treated females also exhibited increased adiposity at 4 wk, increased adiposity gain between 4 and 14 wk, glucose intolerance at 8 wk, and insulin resistance at 14 wk. Although FCCP-treated males also exhibited reduced glucose tolerance, but their insulin sensitivity and adiposity gain between 4 and 14 wk was unchanged. To our knowledge, this is one of the first studies to demonstrate that reducing mitochondrial function and, thus, decreasing ATP output in the precompacting embryo can influence offspring phenotype. This is of great significance as a large proportion of patients requiring assisted reproductive technologies are of advanced maternal age or have a high body mass index, both of which have been independently linked with perturbed early embryonic mitochondrial function.

Female offspring sired by diet induced obese male mice display impaired blastocyst development with molecular alterations to their ovaries, oocytes and cumulus cells.

PURPOSE: To investigate the impacts that a paternal high fat diet (HFD) has on embryology, ovarian/cumulus cell gene expression and COC metabolism from female offspring, using a mouse model. METHODS: Founder male mice were either fed a control diet (CD) or a HFD for 12 weeks. The HFD induced obesity but not diabetes, and founder males were then mated to normal weight CD fed female mice. Female offspring were maintained on a CD, super-ovulated, mated and the resultant zygotes were cultured to the blastocyst stage for embryo morphology, blastocyst cell number and apoptosis assessment. Ovaries and cumulus cells from offspring were collected for gene expression analysis of selected genes that maintain chromatin remodeling and endoplasmic reticulum (ER), metabolic and inflammatory homeostasis. Cumulus/oocyte complexes were also investigated for glucose uptake and lipid accumulation. RESULTS: Female offspring sired by obese fathers produced embryos with delayed development and impaired quality, displayed increases in ovarian expression of Glut1, Glut3 and Glut4, and an increase in cumulus cell expression of Glut4. Interestingly their COCs did take up more glucose, but did accumulate more lipid. CONCLUSIONS: A paternal HFD is associated with subfertility in female offspring despite the offspring being fed a CD and this subfertility is concomitant with ovarian/cumulus cell molecular alterations and increased lipid accumulation.

Alkynyl-protected Au23 nanocluster: a 12-electron system.

A 23-gold-atom nanocluster was prepared by NaBH4-mediated reduction of a solution of PhC≡CAu and Ph3PAuSbF6 in CH2Cl2. The cluster composition was determined to be [Au23(PhC≡C)9(Ph3P)6](2+) and single-crystal X-ray diffraction revealed that the cluster has an unprecedented Au17 kernel protected by three PhC2-Au-C2 (Ph)-Au-C2 Ph motifs and six Ph3P groups. The Au17 core can be viewed as the fusion of two Au10 units sharing a Au3 triangle. Electronic structure analysis from DFT calculations suggests that the stability of this unusual 12-electron cluster is a result of the splitting of the superatomic 1D orbitals under D3h symmetry of the Au17 kernel. The discovery and determination of the structure of the Au23 cluster demonstrates the versatility of the alkynyl ligand in leading to the formation of new cluster compounds.

A Near-Infrared-Emissive Alkynyl-Protected Au24 Nanocluster.

An alkynyl-protected gold nanocluster [Au24(C≡CPh)14(PPh3)4](SbF6)2 has been prepared by a direct reduction method. Single-crystal X-ray diffraction reveals that the molecular structure contains a Au22 core that is made of two Au13-centered cuboctahedra that share a square face. Two staple-like PhC≡C-Au-C≡CPh motifs are located around the center of the rod-like Au22 core. This Au24 nanocluster is highly emissive in the near-infrared region with λ(max)=925 nm and the nature of the HOMO-LUMO transition is investigated by time-dependent DFT calculations.

Up-regulation of P21 inhibits TRAIL-mediated extrinsic apoptosis, contributing resistance to SAHA in acute myeloid leukemia cells.

BACKGROUND/AIM: P21, a multifunctional cell cycle-regulatory molecule, regulates apoptotic cell death. In this study we examined the effect of altered p21 expression on the sensitivity of acute myeloid leukemia cells in response to HDAC inhibitor SAHA treatment and investigated the underlying mechanism. METHODS: Stably transfected HL60 cell lines were established in RPMI-1640 with supplementation of G-418. Cell viability was measured by MTT assay. Western blot was applied to assess the protein expression levels of target genes. Cell apoptosis was monitored by AnnexinV-PE/7AAD assay. RESULTS: We showed HL60 cells that that didn't up-regulate p21 expression were more sensitive to SAHA-mediated apoptosis than NB4 and U937 cells that had increased p21 level. Enforced expression of p21 in HL60 cells reduced sensitivity to SAHA and blocked TRAIL-mediated apoptosis. Conversely, p21 silencing in NB4 cells enhanced SAHA-mediated apoptosis and lethality. Finally, we found that combined treatment with SAHA and rapamycin down-regulated p21 and enhanced apoptosis in AML cells. CONCLUSION: We conclude that up-regulated p21 expression mediates resistance to SAHA via inhibition of TRAIL apoptotic pathway. P21 may serve as a candidate biomarker to predict responsiveness or resistance to SAHA-based therapy in AML patients. In addition, rapamycin may be an effective agent to override p21-mediated resistance to SAHA in AML patients.