@article {69703, title = {Ketamine induces plasticity in a norepinephrine-astroglial circuit to promote behavioral perseverance.}, journal = {Neuron}, year = {2024}, month = {2024 Dec 16}, pages = {1-15}, abstract = {

Transient exposure to ketamine can trigger lasting changes in behavior and mood. We found that brief ketamine exposure causes long-term suppression of futility-induced passivity in larval zebrafish, reversing the "giving-up" response that normally occurs when swimming fails to cause forward movement. Whole-brain imaging revealed that ketamine hyperactivates the norepinephrine-astroglia circuit responsible for passivity. After ketamine washout, this circuit exhibits hyposensitivity to futility, leading to long-term increased perseverance. Pharmacological, chemogenetic, and optogenetic manipulations show that norepinephrine and astrocytes are necessary and sufficient for ketamine{\textquoteright}s long-term perseverance-enhancing aftereffects. In\ vivo calcium imaging revealed that astrocytes in adult mouse cortex are similarly activated during futility in the tail suspension test and that acute ketamine exposure also induces astrocyte hyperactivation. The cross-species conservation of ketamine{\textquoteright}s modulation of noradrenergic-astroglial circuits and evidence that plasticity in this pathway can alter the behavioral response to futility hold promise for identifying new strategies to treat affective disorders.

}, issn = {1097-4199}, doi = {10.1016/j.neuron.2024.11.011}, url = {https://doi.org/10.1016/j.neuron.2024.11.011}, author = {Duque, Marc and Chen, Alex B and Hsu, Eric and Narayan, Sujatha and Rymbek, Altyn and Begum, Shahinoor and Saher, Gesine and Cohen, Adam E and Olson, David E and Li, Yulong and Prober, David A and Bergles, Dwight E and Fishman, Mark C and Engert, Florian and Ahrens, Misha B} } @article {69444, title = {The kinase ZYG-1 phosphorylates the cartwheel protein SAS-5 to drive centriole assembly in C. elegans}, journal = {EMBO Rep}, year = {2024}, month = {2024 May 14}, abstract = {

Centrioles organize centrosomes, the cell{\textquoteright}s primary microtubule-organizing centers (MTOCs). Centrioles double in number each cell cycle, and mis-regulation of this process is linked to diseases such as cancer and microcephaly. In C. elegans, centriole assembly is controlled by the Plk4 related-kinase ZYG-1, which recruits the SAS-5-SAS-6 complex. While the kinase activity of ZYG-1 is required for centriole assembly, how it functions has not been established. Here we report that ZYG-1 physically interacts with and phosphorylates SAS-5 on 17 conserved serine and threonine residues in vitro. Mutational scanning reveals that serine 10 and serines 331/338/340 are indispensable for proper centriole assembly. Embryos expressing SAS-5 exhibit centriole assembly failure, while those expressing SAS-5 possess extra centrioles. We show that in the absence of serine 10 phosphorylation, the SAS-5-SAS-6 complex is recruited to centrioles, but is not stably incorporated, possibly due to a failure to coordinately recruit the microtubule-binding protein SAS-4. Our work defines the critical role of phosphorylation during centriole assembly and reveals that ZYG-1 might play a role in preventing the formation of excess centrioles.

}, issn = {1469-3178}, doi = {10.1038/s44319-024-00157-y}, author = {Sankaralingam, Prabhu and Wang, Shaohe and Liu, Yan and Oegema, Karen F and O{\textquoteright}Connell, Kevin F} } @article {69168, title = {KMT2 family of H3K4 methyltransferases: enzymatic activity-dependent and -independent functions.}, journal = {Journal of Molecular Biology}, year = {2024}, month = {2024 Jan 22}, pages = {168453}, abstract = {

Histone-lysine N-methyltransferase 2 (KMT2) methyltransferases play critical roles in gene regulation, cell differentiation, animal development, and human diseases. KMT2 biological roles are often attributed to their methyltransferase activities on lysine 4 of histone H3 (H3K4). However, recent data indicate that KMT2 proteins also possess non-enzymatic functions. In this review, we discuss the current understanding of KMT2 family, with a focus on their enzymatic activity-dependent and -independent functions. Six mammalian KMT2 proteins of three subgroups, KMT2A/B (MLL1/2), KMT2C/D (MLL3/4), and KMT2F/G (SETD1A/B or SET1A/B), have shared and distinct protein domains, catalytic substrates, genomic localizations, and associated complex subunits. Recent studies have revealed the central role of KMT2C/D in enhancer regulation, differentiation, and development and have highlighted KMT2C/D enzymatic activity-dependent and independent roles in mouse embryonic development and cell differentiation. Catalytic dependent and independent roles for KMT2A/B and KMT2F/G in gene regulation, differentiation, and development are less understood. Finally, we provide our perspectives and lay out future research directions that may help advance the investigation on enzymatic activity-dependent and -independent biological roles and working mechanisms of KMT2 methyltransferases.

}, issn = {1089-8638}, doi = {10.1016/j.jmb.2024.168453}, author = {Van, Hieu T and Xie, Guojia and Dong, Peng and Liu, Zhe and Ge, Kai} } @article {69126, title = {Ketamine modulates a norepinephrine-astroglial circuit to persistently suppress futility-induced passivity.}, journal = {bioRxiv}, year = {2023}, month = {2023 Dec 29}, abstract = {

Mood-altering compounds hold promise for the treatment of many psychiatric disorders, such as depression, but connecting their molecular, circuit, and behavioral effects has been challenging. Here we find that, analogous to effects in rodent learned helplessness models, ketamine pre-exposure persistently suppresses futility-induced passivity in larval zebrafish. While antidepressants are thought to primarily act on neurons, brain-wide imaging in behaving zebrafish showed that ketamine elevates intracellular calcium in astroglia for many minutes, followed by persistent calcium downregulation post-washout. Calcium elevation depends on astroglial α1-adrenergic receptors and is required for suppression of passivity. Chemo-/optogenetic perturbations of noradrenergic neurons and astroglia demonstrate that the aftereffects of glial calcium elevation are sufficient to suppress passivity by inhibiting neuronal-astroglial integration of behavioral futility. Imaging in mouse cortex reveals that ketamine elevates astroglial calcium through conserved pathways, suggesting that ketamine exerts its behavioral effects by persistently modulating evolutionarily ancient neuromodulatory systems spanning neurons and astroglia.

}, doi = {10.1101/2022.12.29.522099}, url = {https://doi.org/10.1101/2022.12.29.522099}, author = {Marc Duque and Alex B. Chen and Eric Hsu and Sujatha Narayan and Altyn Rymbek and Shahinoor Begum and Gesine Saher and Adam E. Cohen and David E. Olson and David A. Prober and Dwight E. Bergles and Mark C. Fishman and Florian Engert and Misha B. Ahrens} } @article {68515, title = {Ketamine triggers a switch in excitatory neuronal activity across neocortex.}, journal = {Nature Neuroscience}, year = {2022}, month = {2022 Nov 24}, abstract = {

The brain can become transiently disconnected from the environment while maintaining vivid, internally generated experiences. This so-called {\textquoteright}dissociated state{\textquoteright} can occur in pathological conditions and under the influence of psychedelics or the anesthetic ketamine (KET). The cellular and circuit mechanisms producing the dissociative state remain poorly understood. We show in mice that KET causes spontaneously active neurons to become suppressed while previously silent neurons become spontaneously activated. This switch occurs in all cortical layers and different cortical regions, is induced by both systemic and cortical application of KET and is mediated by suppression of parvalbumin and somatostatin interneuron activity and inhibition of NMDA receptors and HCN channels. Combined, our results reveal two largely non-overlapping cortical neuronal populations-one engaged in wakefulness, the other contributing to the KET-induced brain state-and may lay the foundation for understanding how the brain might become disconnected from the surrounding environment while maintaining internal subjective experiences.

}, issn = {1546-1726}, doi = {10.1038/s41593-022-01203-5}, author = {Cichon, Joseph and Wasilczuk, Andrzej Z and Looger, Loren L and Contreras, Diego and Kelz, Max B and Proekt, Alex} } @article {68226, title = {Kinetic principles underlying pioneer function of GAGA transcription factor in live cells.}, journal = {Nature Structural and Molecular Biology}, volume = {29}, year = {2022}, month = {2022 Jul 01}, pages = {665-676}, abstract = {

How pioneer factors interface with chromatin to promote accessibility for transcription control is poorly understood in vivo. Here, we directly visualize chromatin association by the prototypical GAGA pioneer factor (GAF) in live Drosophila hemocytes. Single-particle tracking reveals that most GAF is chromatin bound, with a stable-binding fraction showing nucleosome-like confinement residing on chromatin for more than 2 min, far longer than the dynamic range of most transcription factors. These kinetic properties require the full complement of GAF{\textquoteright}s DNA-binding, multimerization and intrinsically disordered domains, and are autonomous from recruited chromatin remodelers NURF and PBAP, whose activities primarily benefit GAF{\textquoteright}s neighbors such as Heat Shock Factor. Evaluation of GAF kinetics together with its endogenous abundance indicates that, despite on-off dynamics, GAF constitutively and fully occupies major chromatin targets, thereby providing a temporal mechanism that sustains open chromatin for transcriptional responses to homeostatic, environmental and developmental signals.

}, keywords = {Animals, Chromatin, DNA-Binding Proteins, Drosophila, Drosophila Proteins, Kinetics, Transcription Factors}, issn = {1545-9985}, doi = {10.1038/s41594-022-00800-z}, author = {Tang, Xiaona and Li, Taibo and Liu, Sheng and Wisniewski, Jan and Zheng, Qinsi and Rong, Yikang and Lavis, Luke D and Wu, Carl} } @article {68420, title = {KIRCD8 T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19.}, journal = {Science}, volume = {376}, year = {2022}, month = {04/2022}, pages = {eabi9591}, abstract = {

In this work, we find that CD8 T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) are the human equivalent of Ly49CD8 regulatory T cells in mice and are increased in the blood and inflamed tissues of patients with a variety of autoimmune diseases. Moreover, these CD8 T cells efficiently eliminated pathogenic gliadin-specific CD4 T cells from the leukocytes of celiac disease patients in vitro. We also find elevated levels of KIRCD8 T cells, but not CD4 regulatory T cells, in COVID-19 patients, correlating with disease severity and vasculitis. Selective ablation of Ly49CD8 T cells in virus-infected mice led to autoimmunity after infection. Our results indicate that in both species, these regulatory CD8 T cells act specifically to suppress pathogenic T cells in autoimmune and infectious diseases.

}, keywords = {Animals, Autoimmune Diseases, CD8-Positive T-Lymphocytes, COVID-19, Humans, Mice, Receptors, KIR, T-Lymphocytes, Regulatory}, issn = {1095-9203}, doi = {10.1126/science.abi9591}, author = {Li, Jing and Zaslavsky, Maxim and Su, Yapeng and Guo, Jing and Sikora, Michael J and van Unen, Vincent and Christophersen, Asbj{\o}rn and Chiou, Shin-Heng and Chen, Liang and Li, Jiefu and Ji, Xuhuai and Wilhelmy, Julie and McSween, Alana M and Palanski, Brad A and Mallajosyula, Venkata Vamsee Aditya and Bracey, Nathan A and Dhondalay, Gopal Krishna R and Bhamidipati, Kartik and Pai, Joy and Kipp, Lucas B and Dunn, Jeffrey E and Hauser, Stephen L and Oksenberg, Jorge R and Satpathy, Ansuman T and Robinson, William H and Dekker, Cornelia L and Steinmetz, Lars M and Khosla, Chaitan and Utz, Paul J and Sollid, Ludvig M and Chien, Yueh-Hsiu and Heath, James R and Fernandez-Becker, Nielsen Q and Nadeau, Kari C and Saligrama, Naresha and Davis, Mark M} } @article {65322, title = {Kilohertz two-photon fluorescence microscopy imaging of neural activity in vivo.}, journal = {Nature Methods}, volume = {17}, year = {2020}, month = {2020 Mar 02}, pages = {287-290}, abstract = {

Understanding information processing in the brain requires monitoring neuronal activity at high spatiotemporal resolution. Using an ultrafast two-photon fluorescence microscope empowered by all-optical laser scanning, we imaged neuronal activity in vivo at up to 3,000 frames per second and submicrometer spatial resolution. This imaging method enabled monitoring of both supra- and subthreshold electrical activity down to 345 μm below the brain surface in head-fixed awake mice.

}, issn = {1548-7105}, doi = {10.1038/s41592-020-0762-7}, author = {Wu, Jianglai and Liang, Yajie and Chen, Shuo and Hsu, Ching-Lung and Chavarha, Mariya and Evans, Stephen W and Shi, Dongqing and Lin, Michael Z and Tsia, Kevin K and Ji, Na} } @article {49329, title = {Kilohertz frame-rate two-photon tomography.}, journal = {Nature Methods}, volume = {16}, year = {2019}, month = {2019 Jul 29}, pages = {778-86}, abstract = {

Point-scanning two-photon microscopy enables high-resolution imaging within scattering specimens such as the mammalian brain, but sequential acquisition of voxels fundamentally limits imaging speed. We developed a two-photon imaging technique that scans lines of excitation across a focal plane at multiple angles and uses prior information to recover high-resolution images at over 1.4 billion voxels per second. Using a structural image as a prior for recording neural activity, we imaged visually-evoked and spontaneous glutamate release across hundreds of dendritic spines in mice at depths over 250 microns and frame-rates over 1 kHz. Dendritic glutamate transients in anaesthetized mice are synchronized within spatially-contiguous domains spanning tens of microns at frequencies ranging from 1-100 Hz. We demonstrate high-speed recording of acetylcholine and calcium sensors, 3D single-particle tracking, and imaging in densely-labeled cortex. Our method surpasses limits on the speed of raster-scanned imaging imposed by fluorescence lifetime.

}, doi = {10.1101/357269}, author = {Kazemipour, Abbas and Novak, Ondrej and Flickinger, Daniel and Marvin, Jonathan S and Abdelfattah, Ahmed S and King, J. and Borden, PM and Kim, JJ and Al-Abdullatif, SH and Deal, PE and Miller, EW and Schreiter, ER and Druckmann, S and Svoboda, K and Looger, LL and Podgorski, K} } @article {65033, title = {Kilohertz in vivo imaging of neural activity.}, journal = {bioRxiv}, year = {2019}, month = {2019 Feb 06}, abstract = {

Understanding information processing in the brain requires us to monitor neural activity in vivo at high spatiotemporal resolution. Using an ultrafast two-photon fluorescence microscope (2PFM) empowered by all-optical laser scanning, we imaged neural activity in vivo at 1,000 frames per second and submicron spatial resolution. This ultrafast imaging method enabled monitoring of electrical activity down to 300 μm below the brain surface in head fixed awake mice.

}, doi = {10.1101/543058}, author = {Jianglai Wu and Yajie liang and Ching-Lung Hsu and Mariya Chavarha and Stephen Evans and Dongqing Shi and Michael Lin and Kevin Tsia and Na Ji} } @article {68758, title = {The Kinetochore-Microtubule Coupling Machinery Is Repurposed in Sensory Nervous System Morphogenesis}, journal = {Developmental Cell}, volume = {48}, year = {2019}, month = {03/2019}, pages = {864-872.e7}, abstract = {

Summary Dynamic coupling of microtubule ends to kinetochores, built on the centromeres of chromosomes, directs chromosome segregation during cell division. Here, we report that the evolutionarily ancient kinetochore-microtubule\ coupling machine, the KMN (Knl1/Mis12/Ndc80-complex) network, plays a critical role in neuronal morphogenesis. We show that the KMN network concentrates in microtubule-rich dendrites of developing sensory neurons that collectively extend in a multicellular morphogenetic event that occurs during C.\ elegans embryogenesis. Post-mitotic degradation of KMN components in sensory neurons disrupts dendritic extension, leading to patterning and functional defects in the sensory nervous system. Structure-guided mutations revealed that the molecular interface that couples kinetochores to spindle microtubules also functions in neuronal development. These results identify a cell-division-independent function for the chromosome-segregation machinery and define a microtubule-coupling-dependent event in sensory nervous system morphogenesis.

}, keywords = {Chromosome Segregation, dendrite, kinetochore, KMN network, Knl1, microtubule, Mis12 complex, Mitosis, Morphogenesis, Ndc80 complex, Nervous System, sensory neuron}, issn = {1534-5807}, doi = {https://doi.org/10.1016/j.devcel.2019.02.002}, url = {https://www.sciencedirect.com/science/article/pii/S1534580719300577}, author = {Dhanya K. Cheerambathur and Bram Prevo and Tiffany-Lynn Chow and Neil Hattersley and Shaohe Wang and Zhiling Zhao and Taekyung Kim and Adina Gerson-Gurwitz and Karen Oegema and Rebecca Green and Arshad Desai} } @article {64996, title = {Knock-in rats expressing Cre and Flp recombinases at the Parvalbumin locus.}, journal = {bioRxiv}, year = {2018}, month = {2018 Aug 07}, abstract = {

Rats have the ability to learn and perform sophisticated behavioral tasks, making them very useful for investigating neural circuit functions. In contrast to the extensive mouse genetic toolkit, the paucity of recombinase-expressing rat models has limited the ability to monitor and manipulate molecularly-defined neural populations in this species. Here we report the generation and validation of two knock-in rat strains expressing either\ Cre\ or\ Flp\ recombinase under the control of\ Parvalbumin (Pvalb), a gene expressed in the critical {\textquotedblleft}fast-spiking{\textquotedblright} subset of inhibitory interneurons (FSIs). These strains were generated with CRISPR-Cas9 gene editing and show highly specific and penetrant labeling of\ Pvalb-expressing neurons, as demonstrated by\ in situ\ hybridization and immunohistochemistry. We validated these models in both prefrontal cortex and striatum using both\ ex vivo\ and\ in vivo\ approaches, including whole-cell recording, optogenetics, extracellular physiology and photometry. Our results demonstrate the utility of these new transgenic models for a wide range of neuroscience experiments.

}, doi = {10.1101/386474}, author = {Jai Y. Yu and Jeffrey R. Pettibone and Caiying Guo and Shuqin Zhang and Thomas L. Saunders and Elizabeth D. Hughes and Wanda E. Filipiak and Michael G. Zeidler and Kevin J. Bender and Frederic Hopf and Clay N. Smyth and Viktor Kharazia and Anna Kiseleva and Thomas J. Davidson and Loren M. Frank and Joshua D. Berke} } @article {46927, title = {Ketamine Inside Neurons?}, journal = {American Journal of Psychiatry}, volume = {172}, year = {2015}, month = {2015 Jul 17}, pages = {1064-6}, issn = {1535-7228}, doi = {10.1176/appi.ajp.2015.14121537}, author = {Lester, Henry A and Lavis, Luke D and Dougherty, Dennis A} } @article {45182, title = {Kainate receptors mediate signaling in both transient and sustained OFF bipolar cell pathways in mouse retina.}, journal = {Journal of Neuroscience}, volume = {34}, year = {2014}, month = {2014 Apr 30}, pages = {6128-39}, abstract = {

A fundamental question in sensory neuroscience is how parallel processing is implemented at the level of molecular and circuit mechanisms. In the retina, it has been proposed that distinct OFF cone bipolar cell types generate fast/transient and slow/sustained pathways by the differential expression of AMPA- and kainate-type glutamate receptors, respectively. However, the functional significance of these receptors in the intact circuit during light stimulation remains unclear. Here, we measured glutamate release from mouse bipolar cells by two-photon imaging of a glutamate sensor (iGluSnFR) expressed on postsynaptic amacrine and ganglion cell dendrites. In both transient and sustained OFF layers, cone-driven glutamate release from bipolar cells was blocked by antagonists to kainate receptors but not AMPA receptors. Electrophysiological recordings from bipolar and ganglion cells confirmed the essential role of kainate receptors for signaling in both transient and sustained OFF pathways. Kainate receptors mediated responses to contrast modulation up to 20 Hz. Light-evoked responses in all mouse OFF bipolar pathways depend on kainate, not AMPA, receptors.

}, keywords = {Action Potentials, Animals, Drug Interactions, Excitatory Amino Acid Antagonists, Female, Glutamic Acid, Hexamethonium, Light, Male, Mice, Mice, Inbred C57BL, Nicotinic Antagonists, Patch-Clamp Techniques, Photic Stimulation, Propionates, Receptors, Kainic Acid, Retina, Retinal Bipolar Cells, Signal Transduction, Visual Pathways}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.4941-13.2014}, author = {Borghuis, Bart G and Looger, Loren L and Tomita, Susumu and Demb, Jonathan B} } @article {6360, title = {Knockdown of parhyale ultrabithorax recapitulates evolutionary changes in crustacean appendage morphology.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {106}, year = {2009}, month = {2009 Aug 18}, pages = {13892-6}, abstract = {

Crustaceans possess remarkably diverse appendages, both between segments of a single individual as well as between species. Previous studies in a wide range of crustaceans have demonstrated a correlation between the anterior expression boundary of the homeotic (Hox) gene Ultrabithorax (Ubx) and the location and number of specialized thoracic feeding appendages, called maxillipeds. Given that Hox genes regulate regional identity in organisms as diverse as mice and flies, these observations in crustaceans led to the hypothesis that Ubx expression regulates the number of maxillipeds and that evolutionary changes in Ubx expression have generated various aspects of crustacean appendage diversity. Specifically, evolutionary changes in the expression boundary of Ubx have resulted in crustacean species with either 0, 1, 2, or 3 pairs of thoracic maxillipeds. Here we test this hypothesis by altering the expression of Ubx in Parhyale hawaiensis, a crustacean that normally possesses a single pair of maxillipeds. By reducing Ubx expression, we can generate Parhyale with additional maxillipeds in a pattern reminiscent of that seen in other crustacean species, and these morphological alterations are maintained as the animals molt and mature. These results provide critical evidence supporting the proposition that changes in Ubx expression have played a role in generating crustacean appendage diversity and lend general insights into the mechanisms of morphological evolution.

}, keywords = {Animals, Base Sequence, Biological, Biological Evolution, Cloning, Crustacea, Electron, Extremities, Gene Expression Regulation, Genes, Genetic Techniques, Homeobox, Homeodomain Proteins, In Situ Hybridization, Microscopy, Models, Molecular, Molecular Sequence Data, RNA, Scanning, Small Interfering}, issn = {1091-6490}, doi = {10.1073/pnas.0903105106}, author = {Liubicich, Danielle M and Serano, Julia M and Pavlopoulos, Anastasios and Kontarakis, Zacharias and Protas, Meredith E and Kwan, Elaine and Chatterjee, Sandip and Tran, Khoa D and Averof, Michalis and Patel, Nipam H} } @article {2504, title = {Kr{\"u}ppel homolog 1 (Kr-h1) mediates juvenile hormone action during metamorphosis of Drosophila melanogaster.}, journal = {Mechanisms of Development}, volume = {125}, year = {2008}, month = {2008 Jan-Feb}, pages = {91-105}, abstract = {

Juvenile hormone (JH) given at pupariation inhibits bristle formation and causes pupal cuticle formation in the abdomen of Drosophila melanogaster due to its prolongation of expression of the transcription factor Broad (BR). In a microarray analysis of JH-induced gene expression in abdominal integument, we found that Kr{\"u}ppel homolog 1 (Kr-h1) was up-regulated during most of adult development. Quantitative real-time PCR analyses showed that Kr-h1 up-regulation began at 10h after puparium formation (APF), and Kr-h1 up-regulation occurred in imaginal epidermal cells, persisting larval muscles, and larval oenocytes. Ectopic expression of Kr-h1 in abdominal epidermis using T155-Gal4 to drive UAS-Kr-h1 resulted in missing or short bristles in the dorsal midline. This phenotype was similar to that seen after a low dose of JH or after misexpression of br between 21 and 30 h APF. Ectopic expression of Kr-h1 prolonged the expression of BR protein in the pleura and the dorsal tergite. No Kr-h1 was seen after misexpression of br. Thus, Kr-h1 mediates some of the JH signaling in the adult abdominal epidermis and is upstream of br in this pathway. We also show for the first time that the JH-mediated maintenance of br expression in this epidermis is patterned and that JH delays the fusion of the imaginal cells and the disappearance of Dpp in the dorsal midline.

}, keywords = {Animals, Base Sequence, Biological, DNA Primers, Drosophila melanogaster, Drosophila Proteins, Kruppel-Like Transcription Factors, Larva, Metamorphosis, Oligonucleotide Array Sequence Analysis, Polymerase Chain Reaction, Up-Regulation}, issn = {0925-4773}, doi = {10.1016/j.mod.2007.10.002}, author = {Minakuchi, Chieka and Zhou, Xiaofeng and Riddiford, Lynn M} }