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Objective: Vortioxetine is a monoaminergic drug with a novel multimodal mechanism of action. We investigated its efficacy on depressive symptoms, cognitive function, and quality of life among cancer patients., Methods: In this multicenter, open-label, single-arm, observational study, patients received flexible doses of Vortioxetine for a period of six months. All participants were assessed at baseline and scheduled for monitoring at weeks 2, 4, 8, 12, 16, 20, and 24. Depression severity was assessed using Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI) scale. The Perceived Deficiency Questionnaire (PDQ-5) assessed the perceived cognitive difficulties in concentration, executive functioning, and memory. The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC) was used to assess the patients' quality of life. Side effects of vortioxetine were monitored using the Antidepressant Side-Effect Checklist (ASEC)., Results: Patients experienced a reduction in MADRS scores from 29.89 ± 5.997 at baseline to 11.59 ± 4.629 by Week 24. The PDQ-5 scores showed significant change from Week-4, whereas the EORTC role, emotional, and cognitive functioning scores showed a significant change from Week 2 onwards. CGI-Severity scores decreased from a baseline of 4.39 ± 0.746 to 2.41 ± 1.085 by Week 24. During the 24-Weeks of therapy, around three-quarters of the patients (73.3%) had one or more adverse events reported on the ASEC. The most frequently reported TEAEs were dry mouth, insomnia, somnolence, and headache, with more than a 30% incidence rate., Conclusion: Vortioxetine seems promising in the management of depression and enhancement of cognitive function and quality of life of cancer patients with Major Depressive Disorder., .

Background: Previous studies have shown that pesticide bans were associated with reduced fatal pesticide self-poisoning cases in high, and low-and-middle-income countries. We aimed to investigate the characteristics of pesticide poisoning patients admitted to two Malaysian hospitals and the early impact of the national paraquat ban implemented on 1st January 2020 in a culturally heterogenous South-East-Asian upper-middle-income setting., Methods: Data were collected from an East (Bintulu) and a West (Ipoh) Malaysian hospital medical records in 2015-2021 and 2018-2021, respectively. Logistic regression analyses were conducted to investigate the association of aspects such as socio-demographic and clinical characteristics, paraquat ban with the types of pesticides involved (paraquat versus non-paraquat versus unknown) ,and the outcomes (fatal versus non-fatal)., Results: From the study sample of 212 pesticide poisoning patients aged 15 years or above, the majority were self-poisoning cases (75.5%) with a disproportionate over-representation of Indian ethnic minority (44.8%). Most pesticide poisoning cases had socio-environmental stressors (62.30%). The commonest stressors were domestic interpersonal conflicts (61.36%). 42.15% of pesticide poisoning survivors had a psychiatric diagnosis. Paraquat poisoning accounted for 31.6% of all patients and 66.7% of fatalities. Case fatality was positively associated with male gender, current suicidal intent, and paraquat poisoning. After the paraquat ban, the proportion of pesticide poisoning cases using paraquat decreased from 35.8 to 24.0%, and the overall case-fatality dropped slightly from 21.2 to 17.3%., Conclusions: Socio-environmental stressors in specific domestic interpersonal conflicts, seemed more prominent in pesticide poisoning compared to psychiatric diagnosis. Paraquat accounted for the majority of pesticide-associated deaths occurring in hospitals in the study areas. There was preliminary evidence that the 2020 paraquat ban led to a fall in case fatality from pesticide poisoning., (© 2023. The Author(s).)

Introduction: Psychological distress had been documented since the beginning of the COVID-19 outbreak in 2019. The aim of the study is to describe the psychological impact among those who were hospitalized for COVID-19 infection within 6 months after being discharged from the hospital. The psychological impact in this study is defined as depression, anxiety, and stress., Materials and Methods: This was a cross-sectional study conducted from July 2020 till August 2021 in a regional state hospital, north of Malaysia. All patients requiring hospitalization for COVID-19 were approached within the first 2 weeks after admission to administer the Depression, Anxiety and Stress Scale - 21 Items (DASS-21) scale. Follow-up phone calls were made within 3 months of discharged to enquire about the DASS-21 items as well as the Impact of Event Scale-Revised (IES-R) scale items. Participants above the age of 18 and technology savvy to answer an online questionnaire were recruited for the study. We excluded participants with a known history of psychotic disorder from the study. We utilised the DASS-21 to screen for depression, anxiety, and stress, as well as the IES-R to identify symptoms of post-traumatic stress disorder. Participants could answer the questionnaires in either English or Bahasa Malaysia. For comparison of two categorical data, a chi-square was applied. A univariate analysis was first conducted and all variables with a p ≤0.3 was then entered into the multivariate analysis for the final output. Other than the univariate analysis, all other p values <0.05 were considered to be statistically significant. All data collected were tabulated and analysed in the SPSS v21.0 system., Results: A total of 306 out of 696 COVID-19 patients responded. The mean age for the participants was 31.69 (SD:11.19) years old. From the total, 54.2% were ladies, 78.8% were Malay, 50.7% were unmarried, 55.2% had higher education, and 67.6% were employed at the time of the survey. We found 20.5% of the participants were depressed, 38.9% had moderate anxiety, and 17.3% were stressed. From the total, 31.7% of the participants were deemed to have had some symptoms of post-traumatic stress disorder (PTSD) ranging from mild to severe. From the final multivariate analysis, it was found that depression (p=0.02) had a 2.78 times likeliness of having PTSD, anxiety (p<0.001) had a 3.35 times likeliness of having PTSD and stressed patients (p=0.02) 2.86 times likeliness of having PTSD when compared to those without PTSD., Conclusion: Patients reported to suffer from symptoms of PTSD and might benefit from psychological interventions to mitigate the impact in the long run.

RTL1/PEG11, which has been associated with anxiety disorders, is a retrotransposon-derived imprinted gene in the placenta. However, imprinting patterns and functions of RTL1 in the brain have not been well-investigated. We found Rtl1 was paternally, but not maternally, expressed in brain stem, thalamus, and hypothalamus of mice, and imprinting status of RTL1 was maintained in human brain. Paternal Rtl1 knockout (Rtl1m+/p-) mice had higher neonatal death rates due to impaired suckling, and low body weights beginning on embryonic day 16.5. High paternal expression of Rtl1 was detected in the locus coeruleus (LC) and Rtl1m+/p- mice showed an increased delay in time of onset for action potentials and inward currents with decreased neuronal excitability of LC neurons. Importantly, Rtl1m+/p- mice exhibited behaviors associated with anxiety, depression, fear-related learning and memory, social dominance, and low locomotor activity. Taken together, our findings demonstrate RTL1 is imprinted in brain, mediates emotional and social behaviors, and regulates excitability in LC neurons., (© The Author(s) 2022. Published by Oxford University Press.)

The regulation of genomic function is in part mediated through the physical organization and architecture of the nucleus. Disruption to nuclear organization and architecture is increasingly being recognized by its contribution to many diseases. The LINC complexes - protein structures traversing the nuclear envelope, that physically connect the nuclear interior, and hence the genome, to cytoplasmic cytoskeletal networks are an important component in the physical organization of the genome and its function. This connection, potentially allows for the constant detection of environmental mechanical stimuli, resulting in altered regulation of nuclear architecture and genome function, either directly or via the process of mechanotransduction. Here, we review the influences LINC complexes exert on genome functions and their impact on cellular/organismal health., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Here we show that a major muscle specific isoform of the murine LINC complex protein SUN1 is required for efficient muscle regeneration. The nucleoplasmic domain of the isoform specifically binds to and inhibits Drosha, a key component of the microprocessor complex required for miRNA synthesis. Comparison of the miRNA profiles between wildtype and SUN1 null myotubes identified a cluster of miRNAs encoded by a non-translated retrotransposon-like one antisense ( Rtl1as ) transcript that are decreased in the WT myoblasts due to SUN1 inhibition of Drosha. One of these miRNAs miR-127 inhibits the translation of the Rtl1 sense transcript, that encodes the retrotransposon-like one protein (RTL1), which is also required for muscle regeneration and is expressed in regenerating/dystrophic muscle. The LINC complex may therefore regulate gene expression during muscle regeneration by controlling miRNA processing. This provides new insights into the molecular pathology underlying muscular dystrophies and how the LINC complex may regulate mechanosignaling., Competing Interests: TL, XY, RC, MI, GB, AF, CS No competing interests declared, (© 2019, Loo et al.)

Ketamine has shown effectiveness as a rapid-acting antidepressant with antisuicidal effects in terms of reduction of suicidal ideation in the short term. However, the evidence for long-term maintenance ketamine therapy for treatment-resistant depression (TRD) and suicidal behavior is limited. This case series (N=13) highlights the role of adjunctive serial maintenance ketamine infusions in restoring functionality in treatment-resistant unipolar and bipolar (mixed) depression with significant suicide risk and multiple comorbidities, including alcohol dependence. Two cases of TRD achieved functional remission with long-term maintenance ketamine treatment. The first case illustrates the potential synergistic interaction between ketamine and lamotrigine to achieve a sustained antidepressant response in the patient for 7 months. The second case may possibly be the longest reported case of maintenance ketamine therapy, with treatment continuing for 5 years to date. Ketamine treatment showed acute effectiveness in another 7 cases, especially in terms of reduction of suicidal ideation, albeit without significant long-term antidepressant effect. Factors that may contribute to lack of effectiveness of serial ketamine include inadequate mood stabilization in TRD in bipolar spectrum diagnoses, concomitant benzodiazepine use, complex comorbidities, and adverse effects such as significant hypertension and severe dissociation. Future systematic controlled studies are warranted to establish the efficacy and safety profile of long-term ketamine as maintenance therapy for TRD with suicidal behavior.

One of the more dramatic examples of cellular reorganization occurs during spermiogenesis in which a roughly spherical spermatid is transformed into a mature sperm cell. A highlight of this process involves nuclear remodeling whereby the round spermatid nucleus is sculpted into an elongated and polar structure. This transformation in nuclear architecture features chromatin condensation, changes in the composition and organization of the nuclear lamina and redistribution and elimination of nuclear pore complexes. The manchette, a cytoplasmic microtubule-based structure is thought to play a crucial role in the remodeling process. Here we show that SUN4, a spermatid nuclear membrane protein has an essential function in coupling the manchette to the nuclear periphery. In the absence of SUN4, manchette microtubules appear highly disorganized and the nucleus itself fails to elongate. Consequently, mice deficient in SUN4 display globozoospermia with associated infertility., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The paternally expressed imprinted retrotransposon-like 1 (Rtl1) is a retrotransposon-derived gene that has evolved a function in eutherian placentation. Seven miRNAs, including miR-127, are processed from a maternally expressed antisense Rtl1 transcript (Rtl1as) and regulate Rtl1 levels through RNAi-mediated post-transcriptional degradation. To determine the relative functional role of Rtl1as miRNAs in Rtl1 dosage, we generated a mouse specifically deleted for miR-127. The miR-127 knockout mice exhibit placentomegaly with specific defects within the labyrinthine zone involved in maternal-fetal nutrient transfer. Although fetal weight is unaltered, specific Rtl1 transcripts and protein levels are increased in both the fetus and placenta. Phenotypic analysis of single (ΔmiR-127/Rtl1 or miR-127/ΔRtl1) and double (ΔmiR-127/ΔRtl1) heterozygous miR-127- and Rtl1-deficient mice indicate that Rtl1 is the main target gene of miR-127 in placental development. Our results demonstrate that miR-127 is an essential regulator of Rtl1, mediated by a trans-homologue interaction between reciprocally imprinted genes on the maternally and paternally inherited chromosomes., (© 2015. Published by The Company of Biologists Ltd.)

p21-activated kinases (Paks) have been identified in a variety of eukaryotic cells as key effectors of the Cdc42 family of guanosine triphosphatases. Pak kinases play important roles in regulating the filamentous actin cytoskeleton. In this study, we describe a function for the Schizosaccharomyces pombe Pak-related protein Pak1p/Orb2p in cytokinesis. Pak1p localizes to the actomyosin ring during mitosis and cytokinesis. Loss of Pak1p function leads to accelerated cytokinesis. Pak1p mediates phosphorylation of myosin II regulatory light chain Rlc1p at serine residues 35 and 36 in vivo. Interestingly, loss of Pak1p function or substitution of serine 35 and serine 36 of Rlc1p with alanines, thereby mimicking a dephosphorylated state of Rlc1p, leads to defective coordination of mitosis and cytokinesis. This study reveals a new mechanism involving Pak1p kinase that helps ensure the fidelity of cytokinesis.

p21-activated kinases (PAKs) associate with a guanine nucleotide exchange factor, Pak-interacting exchange factor (PIX), which in turn binds the paxillin-associated adaptor GIT1 that targets the complex to focal adhesions. Here, a detailed structure-function analysis of GIT1 reveals how this multidomain adaptor also participates in activation of PAK. Kinase activation does not occur via Cdc42 or Rac1 GTPase binding to PAK. The ability of GIT1 to stimulate alphaPAK autophosphorylation requires the participation of the GIT N-terminal Arf-GAP domain but not Arf-GAP activity and involves phosphorylation of PAK at residues common to Cdc42-mediated activation. Thus, the activation of PAK at adhesion complexes involves a complex interplay between the kinase, Rho GTPases and protein partners that provide localization cues.

The p21-activated kinase PAK is targeted to focal complexes (FCs) through interactions with the SH3 domains of the PAK-interacting exchange factor PIX and Nck. PIX is a Rac GTP exchange factor that also binds the G-protein-coupled receptor kinase-interacting protein known as GIT1. Overexpression of GIT1 in fibroblasts or epithelial cells causes a loss of paxillin from FCs and stimulates cell motility. This is due to the direct interaction of a C-terminal 125-residue domain of GIT1 with paxillin, under the regulation of PIX. In its activated state, GIT1 can promote FC disassembly independent of actin-myosin contractile events. Additionally, GIT directly couples to a key component of FCs, focal adhesion kinase (FAK), via a conserved Spa2 homology domain. We propose that GIT1 and FAK cooperate to promote motility both by directly regulating focal complex dynamics and by the activation of Rac.

The PAK family of kinases are regulated through interaction with the small GTPases Cdc42 and Rac1, but little is known of the signaling components immediately upstream or downstream of these proteins. We have purified and cloned a new class of Rho-p21 guanine nucleotide exchange factor binding tightly through its N-terminal SH3 domain to a conserved proline-rich PAK sequence with a Kd of 24 nM. This PAK-interacting exchange factor (PIX), which is widely expressed and enriched in Cdc42- and Rac1-driven focal complexes, is required for PAK recruitment to these sites. PIX can induce membrane ruffling, with an associated activation of Rac1. Our results suggest a role for PIX in Cdc42-to-Rac1 signaling, involving the PIX/PAK complex.

The family of p21-activated protein kinases (PAKs) appear to be present in all organisms that have Cdc42-like GTPases. In mammalian cells, PAKs have been implicated in the activation of mitogen-activated protein kinase cascades, but there are no reported effects of these kinases on the cytoskeleton. Recently we have shown that a Drosophila PAK is enriched in the leading edge of embryonic epithelial cells undergoing dorsal closure (N. Harden, J. Lee, H.-Y. Loh, Y.-M. Ong, I. Tan, T. Leung, E. Manser, and L. Lim, Mol. Cell. Biol. 16:1896-1908, 1996), where it colocalizes with structures resembling focal complexes. We show here by transfection that in epithelial HeLa cells alpha-PAK is recruited from the cytoplasm to distinct focal complexes by both Cdc42(G12V) and Rac1(G12V), which themselves colocalize to these sites. By deletion analysis, the N terminus of PAK is shown to contain targeting sequences for focal adhesions which indicate that these complexes are the site of kinase function in vivo. Cdc42 and Rac1 cause alpha-PAK autophosphorylation and kinase activation. Mapping alpha-PAK autophosphorylation sites has allowed generation of a constitutively active kinase mutant. By fusing regions of Cdc42 to the C terminus of PAK, activated chimeras were also obtained. Plasmids encoding these different constitutively active alpha-PAKs caused loss of stress fibers when introduced into both HeLa cells and fibroblasts, which was similar to the effect of introducing Cdc42(G12V) or Rac1(G12V). Significantly dramatic losses of focal adhesions were also observed. These combined effects resulted in retraction of the cell periphery after plasmid microinjection. These data support our previous suggestions of a role for PAK downstream of both Cdc42 and Rac1 and indicate that PAK functions include the dissolution of stress fibers and reorganization of focal complexes.