Early Adolescent Views on the Mediating Role of Social Network Sites Use on Peer Relations

With the proliferation and ever-growing popularity of social networking sites (SNSs) over the past decade, their impact amongst children and youth has made SNSs an integral part of their social lives. Subsequently, questions and concerns have arisen about young people’s engagement with SNSs and their implications for their social development. Current research on the impact of SNSs on peer relations is only starting to be understood and still a matter of intense debate. To date, little research has focused specifically on the early adolescent phase or considered the impact based on pupils’ social prominence or gender. This study built on previous research by examining the way early adolescents use SNSs with consideration of gender and social prominence. The study also explored the views of early adolescents on the perceived impact of SNS use on their peer relationships. The mixed-methods study was conducted with Year 8 pupils and involved the completion of 180 questionnaires followed by 14 semi-structured interviews. Analysis of the data showed that early adolescents frequently and avidly used SNSs and there were significant gender differences related to their use of SNSs. Many participants perceived that SNSs affected their relations with peers in both beneficial and detrimental ways. Key findings showed that SNSs were perceived to broaden opportunities to enhance peer relations, but at other times, complicated or amplified the social dynamics or experiences with peers online. Limitations, implications for EP practice and recommendations for future research are discussed

Inhibition of Pol I Transcription a New Chance in the Fight Against Cancer

While new cancer treatments continue to improve patient outcomes, for some cancers there have been limited or no improvements for a long time. It is for these cases radically new approaches are required. Recent publications proposing ribosome biogenesis, in particular RNA polymerase I transcription, as a suitable target for cancer treatment has been gaining momentum. For example, we demonstrated that CX-5461, a specific RNA polymerase I transcription inhibitor, is effective in treating an aggressive subtype of acute myeloid leukemia, regardless of p53 status. Notably, CX-5461 reduces the leukemia initiating/stem cells, the cell population believed to be responsible for chemotherapy resistance and disease relapse in numerous cancers. Targeting ribosome biogenesis, once considered merely a “housekeeping process,” is showing promise in a continuously growing list of cancers including lymphoma, prostate, and now acute myeloid leukemia. Evidence suggests the therapeutic efficacy of RNA polymerase I therapy in preclinical models is mediated through a variety of mechanisms including nucleolar stress activation of p53, DNA damage-like activation of ataxia-telangiectasia mutated/ataxia-telangiectasia and Rad3 related, and cellular differentiation. Overall, the available data suggests the potential for targeting ribosome biogenesis to be effective in a broad spectrum of cancers. The outcomes of 2 phase 1/2 trials of CX-5461 in hematological malignancies and breast cancer are eagerly awaited.This work was supported by project grants from the National Health and Medical Research Council program grant (#1053792), and the Cancer Council of Victoria grant-in-aid (#1084545)

Mice deficient in the putative phospholipid flippase ATP11C exhibit altered erythrocyte shape, anemia, and reduced erythrocyte life span

Transmembrane lipid transporters are believed to establish and maintain phospholipid asymmetry in biological membranes; however, little is known about the in vivo function of the specific transporters involved. Here, we report that developing erythrocytes from mice lacking the putative phosphatidylserine flippase ATP11Cshowed a lower rate ofPStranslocation in vitro compared with erythrocytes from wild-type littermates. Furthermore, the mutant mice had an elevated percentage of phosphatidylserineexposing mature erythrocytes in the periphery. Although erythrocyte development in ATP11C-deficient mice was normal, the mature erythrocytes had an abnormal shape (stomatocytosis), and the life span of mature erythrocytes was shortened relative to that in control littermates, resulting in anemia in the mutant mice. Thus, our findings uncover an essential role for ATP11C in erythrocyte morphology and survival and provide a new candidate for the rare inherited blood disorder stomatocytosis with uncompensated anemia.This work was supported in part by National Health and Medical Research Council Grant GNT1061288. Supported by National Health and Medical Research Council Career Development Fellowship GNT1035858 and by the Ramaciotti Foundation

GPR56/ADGRG1 regulates development and maintenance of peripheral myelin

Myelin is a multilamellar sheath generated by specialized glia called Schwann cells (SCs) in the peripheral nervous system (PNS), which serves to protect and insulate axons for rapid neuronal signaling. In zebrafish and rodent models, we identify GPR56/ADGRG1 as a conserved regulator of PNS development and health. We demonstrate that, during SC development, GPR56-dependent RhoA signaling promotes timely radial sorting of axons. In the mature PNS, GPR56 is localized to distinct SC cytoplasmic domains, is required to establish proper myelin thickness, and facilitates organization of the myelin sheath. Furthermore, we define plectin-a scaffolding protein previously linked to SC domain organization, myelin maintenance, and a series of disorders termed "plectinopathies"-as a novel interacting partner of GPR56. Finally, we show that Gpr56 mutants develop progressive neuropathy-like symptoms, suggesting an underlying mechanism for peripheral defects in some human patients with GPR56 mutations. In sum, we define Gpr56 as a new regulator in the development and maintenance of peripheral myelin

Fibroblastic reticular cells provide a supportive niche for lymph node–resident macrophages

The lymph node (LN) is home to resident macrophage populations that are essential for immune function and homeostasis, but key factors controlling this niche are undefined. Here, we show that fibroblastic reticular cells (FRCs) are an essential component of the LN macrophage niche. Genetic ablation of FRCs caused rapid loss of macrophages and monocytes from LNs across two in vivo models. Macrophages co‐localized with FRCs in human LNs, and murine single‐cell RNA‐sequencing revealed that FRC subsets broadly expressed master macrophage regulator CSF1. Functional assays containing purified FRCs and monocytes showed that CSF1R signaling was sufficient to support macrophage development. These effects were conserved between mouse and human systems. These data indicate an important role for FRCs in maintaining the LN parenchymal macrophage niche

Dimensionality of Carbon Nanomaterials Determines the Binding and Dynamics of Amyloidogenic Peptides: Multiscale Theoretical Simulations

Experimental studies have demonstrated that nanoparticles can affect the rate of protein self-assembly, possibly interfering with the development of protein misfolding diseases such as Alzheimer's, Parkinson's and prion disease caused by aggregation and fibril formation of amyloid-prone proteins. We employ classical molecular dynamics simulations and large-scale density functional theory calculations to investigate the effects of nanomaterials on the structure, dynamics and binding of an amyloidogenic peptide apoC-II(60-70). We show that the binding affinity of this peptide to carbonaceous nanomaterials such as C60, nanotubes and graphene decreases with increasing nanoparticle curvature. Strong binding is facilitated by the large contact area available for π-stacking between the aromatic residues of the peptide and the extended surfaces of graphene and the nanotube. The highly curved fullerene surface exhibits reduced efficiency for π-stacking but promotes increased peptide dynamics. We postulate that the increase in conformational dynamics of the amyloid peptide can be unfavorable for the formation of fibril competent structures. In contrast, extended fibril forming peptide conformations are promoted by the nanotube and graphene surfaces which can provide a template for fibril-growth

Associations of Baseline Sleep Microarchitecture with Cognitive Function After 8 Years in Middle-Aged and Older Men from a Community-Based Cohort Study

Published: 24 May 2023. Corrected by: Corrigendum to: Associations of Baseline Sleep Microarchitecture with Cognitive Function After 8 Years in Middle-Aged and Older Men from a Community-Based Cohort Study (Nat Sci Sleep. 2023, 15, 389–406.) In vol. 15 (2023), pp. 433-434. The authors advise that the funding section on page 404 is incorrect.Purpose: Prospective studies examining associations between baseline sleep microarchitecture and future cognitive function recruited from small samples with predominantly short follow-up. This study examined sleep microarchitecture predictors of cognitive function (visual attention, processing speed, and executive function) after 8 years in community-dwelling men. Patients and Methods: Florey Adelaide Male Ageing Study participants (n=477) underwent home-based polysomnography (2010– 2011), with 157 completing baseline (2007– 2010) and follow-up (2018– 2019) cognitive assessments (trail-making tests A [TMT-A] and B [TMT-B] and the standardized mini-mental state examination [SMMSE]). Whole-night F4-M1 sleep EEG recordings were processed following artifact exclusion, and quantitative EEG characteristics were obtained using validated algorithms. Associations between baseline sleep microarchitecture and future cognitive function (visual attention, processing speed, and executive function) were examined using linear regression models adjusted for baseline obstructive sleep apnoea, other risk factors, and cognition. Results: The final sample included men aged (mean [SD]) 58.9 (8.9) years at baseline, overweight (BMI 28.5 [4.2] kg/m2), and well educated (75.2% ≥Bachelor, Certificate, or Trade), with majorly normal baseline cognition. Median (IQR) follow-up was 8.3 (7.9, 8.6) years. In adjusted analyses, NREM and REM sleep EEG spectral power was not associated with TMT-A, TMT-B, or SMMSE performance (all p> 0.05). A significant association of higher N3 sleep fast spindle density with worse TMT-B performance (B=1.06, 95% CI [0.13, 2.00], p=0.026) did not persist following adjustment for baseline TMT-B performance. Conclusion: In this sample of community-dwelling men, sleep microarchitecture was not independently associated with visual attention, processing speed, or executive function after 8 years.Jesse L Parker, Andrew Vakulin, Yohannes Adama Melaku, Gary A Wittert, Sean A Martin, Angela L D, Rozario, Peter G Catcheside, Bastien Lechat, Barbara Toson, Alison J Teare, Sarah L Appleton, Robert J Adam

Efficacy and safety of nilotinib 300mg twice daily in patients with chronic myeloid leukemia in chronic phase who are intolerant to prior tyrosine kinase inhibitors: Results from the Phase IIIb ENESTswift study

Background Some patients receiving a tyrosine kinase inhibitor (TKI) for the first-line treatment of chronic phase chronic myeloid leukemia (CML-CP) experience intolerable adverse events. Management strategies include dose adjustments, interrupting or discontinuing therapy, or switching to an alternative TKI. Methods This multicenter, single-arm, Phase IIIb study included CML-CP patients intolerant of, but responsive to, first-line treatment with imatinib or dasatinib. All patients were switched to nilotinib 300 mg bid for up to 24 months. The primary endpoint was achievement of MR4.5 (BCR-ABL transcript level of ≤0.0032% on the International Scale) by 24 months. Results Twenty patients were enrolled in the study (16 imatinib-intolerant, 4 dasatinib-intolerant); which was halted early because of low recruitment. After the switch to nilotinib 300mg bid, MR4.5 at any time point up to month 24 was achieved in 10 of 20 patients (50%) in the full analysis set. Of the non-hematological adverse events associated with intolerance to prior imatinib or dasatinib, 74% resolved within 12 weeks of switching to nilotinib 300mg bid. Conclusion Nilotinib 300mg bid shows minimal cross intolerance in patients with CML-CP who have prior toxicities to other TKIs and can lead to deep molecular responses

GSTZ1 genotypes correlate with dichloroacetate pharmacokinetics and chronic side effects in multiple myeloma patients in a pilot phase 2 clinical trial

Dichloroacetate (DCA) is an investigational drug targeting the glycolytic hallmark of cancer by inhibiting pyruvate dehydrogenase kinases (PDK). It is metabolized by GSTZ1, which has common polymorphisms altering enzyme or promoter activity. GSTZ1 is also irreversibly inactivated by DCA. In the first clinical trial of DCA in a hematological malignancy, DiCAM (DiChloroAcetate in Myeloma), we have examined the relationship between DCA concentrations, GSTZ1 genotype, side effects, and patient response. DiCAM recruited seven myeloma patients in partial remission. DCA was administered orally for 3 months with a loading dose. Pharmacokinetics were performed on day 1 and 8. Trough and peak concentrations of DCA were measured monthly. GSTZ1 genotypes were correlated with drug concentrations, tolerability, and disease outcomes. One patient responded and two patients showed a partial response after one month of DCA treatment, which included the loading dose. The initial half‐life of DCA was shorter in two patients, correlating with heterozygosity for GSTZ1*A genotype, a high enzyme activity variant. Over 3 months, one patient maintained DCA trough concentrations approximately threefold higher than other patients, which correlated with a low activity promoter genotype (−1002A, rs7160195) for GSTZ1. This patient displayed the strongest response, but also the strongest neuropathy. Overall, serum concentrations of DCA were sufficient to inhibit the constitutive target PDK2, but unlikely to inhibit targets induced in cancer. Promoter GSTZ1 polymorphisms may be important determinants of DCA concentrations and neuropathy during chronic treatment. Novel dosing regimens may be necessary to achieve effective DCA concentrations in most cancer patients while avoiding neuropathy.This work was supported by The Canberra Hospital Private Practice Trust Fund, Cancer Council ACT Project Grant APP1103848, and the Monaro Committee for Cancer Researc