Role of disulphide bond formation in folding, secretion, and assembly of human chorionic gonadotropin subunits.

Ability of a glycoprotein hormone to fold and assemble correctly is an essential requirement for the attainment of its biological activity . Cells have a quality control system to assure that when proteins of the endoplasmic reticulum mi sfold or fail to assemble correctly they do not exit the cell. But human chorionic gonadotropin (hCG) is an exception to this rule as is illustrated by the following observations. First, both hCG subunits are secreted efficiently as unassembled monomers. Second, some mis(un)folded forms of hCG-β can be efficiently secreted from cells that do not facilitate the secretion of other misfolded proteins. Third, the efficient secretion of an assembly incompetent α-subunit occurs in spite of lacking both of its non-cystine knot disulphide bonds. And fourth, hCG heterodimers that contain misfolded α-subunits as a result of lack ing cystine knot disulphides are also secreted. In this report, we review direct ex perimental evidence demonstrating that the structural requirements necessary for the secretion of hCG subunits differ from the structural requirements necessary for hCG assembly by using disulphide bond formation as an index with which to monitor the folding, assembly, and secretion of hCG and its α - and β-subunits

Synchronization and Control in Intrinsic and Designed Computation: An Information-Theoretic Analysis of Competing Models of Stochastic Computation

We adapt tools from information theory to analyze how an observer comes to synchronize with the hidden states of a finitary, stationary stochastic process. We show that synchronization is determined by both the process's internal organization and by an observer's model of it. We analyze these components using the convergence of state-block and block-state entropies, comparing them to the previously known convergence properties of the Shannon block entropy. Along the way, we introduce a hierarchy of information quantifiers as derivatives and integrals of these entropies, which parallels a similar hierarchy introduced for block entropy. We also draw out the duality between synchronization properties and a process's controllability. The tools lead to a new classification of a process's alternative representations in terms of minimality, synchronizability, and unifilarity.Comment: 25 pages, 13 figures, 1 tabl

The Pacific Drought Knowledge Exchange: A Co-Production Approach to Deliver Climate Resources to User Groups

Drought is a growing threat to hydrological, ecological, agricultural, and socio-cultural systems of the tropics, especially tropical islands of the Pacific where severe droughts can compromise food and water security. Overcoming barriers to knowledge sharing between land managers and researchers is a critical cross-sector strategy for engaging and mitigating or adapting to drought. Here we describe the establishment and functioning of the Pacific Drought Knowledge Exchange (PDKE), which provides users with easier access to: (1) sector- and geography-specific climate information; (2) better and more comprehensive information; (3) improved technical assistance; and (4) a more collaborative information-transfer environment through participation in knowledge co-production. We focus on our collaborative work with managers of important tropical dryland ecosystems from three distinct geographies to pilot the collaborative development of climate change, climate variability, and drought “portfolios” featuring site-specific historical and forecasted future information. This information was then used to collaboratively produce factsheets that partners used to: (i) better understand past and projected climate for specific management units; (ii) integrate new climate knowledge into management planning; and (iii) support climate-focused educational and outreach efforts. This pilot effort demonstrates the successful application of climate-focused co-production in dry tropical landscapes

Dorsal Raphe Dopamine Neurons Modulate Arousal and Promote Wakefulness by Salient Stimuli

Ventral midbrain dopamine (DA) is unambiguously involved in motivation and behavioral arousal, yet the contributions of other DA populations to these processes are poorly understood. Here, we demonstrate that the dorsal raphe nucleus DA neurons are critical modulators of behavioral arousal and sleep-wake patterning. Using simultaneous fiber photometry and polysomnography, we observed time-delineated dorsal raphe nucleus dopaminergic (DRNDA) activity upon exposure to arousal-evoking salient cues, irrespective of their hedonic valence. We also observed broader fluctuations of DRNDA activity across sleep-wake cycles with highest activity during wakefulness. Both endogenous DRNDA activity and optogenetically driven DRNDA activity were associated with waking from sleep, with DA signal strength predictive of wake duration. Conversely, chemogenetic inhibition opposed wakefulness and promoted NREM sleep, even in the face of salient stimuli. Therefore, the DRNDA population is a critical contributor to wake-promoting pathways and is capable of modulating sleep-wake states according to the outside environment, wherein the perception of salient stimuli prompts vigilance and arousal

Prioritise safety, optimise success! Return to rugby postpartum

Pregnancy and childbirth involve substantial physical, physiological and psychological changes. As such, postpartum rugby players should be supported and appropriately prepared to return to the demands of rugby alongside the additional demands of motherhood. This review aims to discuss specific perinatal considerations that inform a rugby player's readiness to return-to-sport postpartum and present an approach to rehabilitation. Before engaging in full rugby training and matchplay, postpartum players should have progressed through the initial phases of rehabilitation and graded sports-specific training to prepare them for the loads they will be exposed to. Additional rehabilitation considerations include minimising deconditioning during pregnancy; medical concerns; the abdominal wall; the pelvic floor; perinatal breast changes, breastfeeding and risk of contact breast injury; body mass; nutritional requirements; hormonal considerations; athlete identity and psychological considerations; joining team training; return to contact and tackle training; evaluating player load tolerance and future research, policy and surveillance needs. A whole-systems, biopsychosocial approach following an evidence informed return-to-sport framework is recommended when rehabilitating postpartum rugby players. Health and exercise professionals are encouraged to use the perinatal-specific recommendations in this review to guide the development of postpartum rehabilitation protocols and resources

Research encounters, reflexivity and supervision

Reflexivity in qualitative and ethnographic social science research can provide a rich source of data, especially regarding the affective, performative and relational aspects of interviews with research subjects. This paper explores by means of three case examples different ways of accessing and using such reflexivity. The examples are drawn from an empirical psycho-social study into the identity transitions of first-time mothers in an inner-city multicultural environment. Fieldnotes and supervision were used to engage with researcher subjectivity, to enhance the productive use of reflexivity and to address the emotional work of research. The methodology of the supervision was psychoanalytic, in its use of a boundaried frame and of psychoanalytic forms of noticing oneself, of staying engaged emotionally as well as creating a reflective distance. The examples illustrate how this can enhance the knowledge gained about the research subjects

Optical dopamine monitoring with dLight1 reveals mesolimbic phenotypes in a mouse model of neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder whose neurodevelopmental symptoms include impaired executive function, attention, and spatial learning that could be due to perturbed mesolimbic dopaminergic circuitry. However, these circuits have never been directly assayed in vivo. We employed the genetically encoded optical dopamine sensor dLight1 to monitor dopaminergic neurotransmission in the ventral striatum of NF1 mice during motivated behavior. Additionally, we developed novel systemic AAV vectors to facilitate morphological reconstruction of dopaminergic populations in cleared tissue. We found that NF1 mice exhibit reduced spontaneous dopaminergic neurotransmission that was associated with excitation/inhibition imbalance in the ventral tegmental area and abnormal neuronal morphology. NF1 mice also had more robust dopaminergic and behavioral responses to salient visual stimuli, which were stimulus-dependent, independent of learning, and rescued by optogenetic inhibition of non-dopaminergic neurons in the VTA. Overall, these studies provide a first in vivo characterization of dopaminergic circuit function in the context of NF1 and reveal novel pathophysiological mechanisms

Amplification and Overexpression of Hsa-miR-30b, Hsa-miR-30d and KHDRBS3 at 8q24.22-q24.23 in Medulloblastoma

Medulloblastoma is the most common malignant brain tumour of childhood. The identification of critical genes involved in its pathogenesis will be central to advances in our understanding of its molecular basis, and the development of improved therapeutic approaches.We performed a SNP-array based genome-wide copy number analysis in medulloblastoma cell lines, to identify regions of genomic amplification and homozygous deletion, which may harbour critical disease genes. A series of novel and established medulloblastoma defects were detected (MYC amplification (n = 4), 17q21.31 high-level gain (n = 1); 9p21.1-p21.3 (n = 1) and 6q23.1 (n = 1) homozygous deletion). Most notably, a novel recurrent region of genomic amplification at 8q24.22-q24.23 was identified (n = 2), and selected for further investigation. Additional analysis by interphase fluorescence in situ hybridisation (iFISH), PCR-based mapping and SNP-array revealed this novel amplification at 8q24.22-q24.23 is independent of MYC amplification at 8q24.21, and is unique to medulloblastoma in over 800 cancer cell lines assessed from different tumour types, suggesting it contains key genes specifically involved in medulloblastoma development. Detailed mapping identified a 3Mb common minimal region of amplification harbouring 3 coding genes (ZFAT1, LOC286094, KHDRBS3) and two genes encoding micro-RNAs (hsa-miR-30b, hsa-miR-30d). Of these, only expression of hsa-miR-30b, hsa-miR-30d and KHDRBS3 correlated with copy number status, and all three of these transcripts also displayed evidence of elevated expression in sub-sets of primary medulloblastomas, measured relative to the normal cerebellum.These data implicate hsa-miR-30b, hsa-miR-30d and KHDRBS3 as putative oncogenic target(s) of a novel recurrent medulloblastoma amplicon at 8q24.22-q24.23. Our findings suggest critical roles for these genes in medulloblastoma development, and further support the contribution of micro-RNA species to medulloblastoma pathogenesis