The default mode network: where the idiosyncratic self meets the shared social world.

The default mode network (DMN) is classically considered an 'intrinsic' system, specializing in internally oriented cognitive processes such as daydreaming, reminiscing and future planning. In this Perspective, we suggest that the DMN is an active and dynamic 'sense-making' network that integrates incoming extrinsic information with prior intrinsic information to form rich, context-dependent models of situations as they unfold over time. We review studies that relied on naturalistic stimuli, such as stories and movies, to demonstrate how an individual's DMN neural responses are influenced both by external information accumulated as events unfold over time and by the individual's idiosyncratic past memories and knowledge. The integration of extrinsic and intrinsic information over long timescales provides a space for negotiating a shared neural code, which is necessary for establishing shared meaning, shared communication tools, shared narratives and, above all, shared communities and social networks.

Outcomes of hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by combined immunodeficiency, eczema, microthrombocytopenia, autoimmunity, and lymphoid malignancies. Gene therapy (GT) to modify autologous CD34+ cells is an emerging alternative treatment with advantages over standard allogeneic hematopoietic stem cell transplantation for patients who lack well-matched donors, avoiding graft-versus-host-disease. We report the outcomes of a phase 1/2 clinical trial in which 5 patients with severe WAS underwent GT using a self-inactivating lentiviral vector expressing the human WAS complementary DNA under the control of a 1.6-kB fragment of the autologous promoter after busulfan and fludarabine conditioning. All patients were alive and well with sustained multilineage vector gene marking (median follow-up: 7.6 years). Clinical improvement of eczema, infections, and bleeding diathesis was universal. Immune function was consistently improved despite subphysiologic levels of transgenic WAS protein expression. Improvements in platelet count and cytoskeletal function in myeloid cells were most prominent in patients with high vector copy number in the transduced product. Two patients with a history of autoimmunity had flares of autoimmunity after GT, despite similar percentages of WAS protein-expressing cells and gene marking to those without autoimmunity. Patients with flares of autoimmunity demonstrated poor numerical recovery of T cells and regulatory T cells (Tregs), interleukin-10-producing regulatory B cells (Bregs), and transitional B cells. Thus, recovery of the Breg compartment, along with Tregs appears to be protective against development of autoimmunity after GT. These results indicate that clinical and laboratory manifestations of WAS are improved with GT with an acceptable safety profile. This trial is registered at clinicaltrials.gov as #NCT01410825.

MAPL loss dysregulates bile and liver metabolism in mice.

Mitochondrial and peroxisomal anchored protein ligase (MAPL) is a dual ubiquitin and small ubiquitin-like modifier (SUMO) ligase with roles in mitochondrial quality control, cell death and inflammation in cultured cells. Here, we show that MAPL function in the organismal context converges on metabolic control, as knockout mice are viable, insulin-sensitive, and protected from diet-induced obesity. MAPL loss leads to liver-specific activation of the integrated stress response, inducing secretion of stress hormone FGF21. MAPL knockout mice develop fully penetrant spontaneous hepatocellular carcinoma. Mechanistically, the peroxisomal bile acid transporter ABCD3 is a primary MAPL interacting partner and SUMOylated in a MAPL-dependent manner. MAPL knockout leads to increased bile acid production coupled with defective regulatory feedback in liver in vivo and in isolated primary hepatocytes, suggesting cell-autonomous function. Together, our findings establish MAPL function as a regulator of bile acid synthesis whose loss leads to the disruption of bile acid feedback mechanisms. The consequences of MAPL loss in liver, along with evidence of tumor suppression through regulation of cell survival pathways, ultimately lead to hepatocellular carcinogenesis.

Mouse midbrain dopaminergic neurons survive loss of the PD-associated mitochondrial protein CHCHD2.

Mutations in the mitochondrial protein CHCHD2 cause autosomal dominant Parkinson's disease characterized by the preferential loss of substantia nigra dopamine (DA) neurons. Therefore, understanding the function of CHCHD2 in neurons may provide vital insights into how mitochondrial dysfunction contributes to neurodegeneration in PD. To investigate the normal requirement and function of CHCHD2 in neurons, we first examined CHCHD2 levels and showed that DA neurons have higher CHCHD2 levels than other neuron types, both in vivo and in co-culture. We then generated mice with either a targeted deletion of CHCHD2 in DA neurons or a deletion in the brain or total body. All three models were viable, and loss of CHCHD2 in the brain did not cause degeneration of DA neurons. Mice lacking CHCHD2 in DA neurons did display sex-specific changes to locomotor activity, but we did not observe differences in assays of muscle strength, exercise endurance or motor coordination. Furthermore, mitochondria derived from mice lacking CHCHD2 did not display abnormalities in OXPHOS function. Lastly, resilience to CHCHD2 deletion could not be explained by functional complementation by its paralog CHCHD10, as deletion of both CHCHD10 and CHCHD2 did not cause degeneration of DA neurons in the midbrain. These findings support the hypothesis that pathogenic CHCHD2 mutations cause PD through a toxic gain-of-function, rather than loss-of-function mechanism.

Unraveling the Electrocatalytic Activity in HMF Oxidation to FDCA by Fine-Tuning the Degree of NiOOH Phase Over Ni Nanoparticles Supported on Graphene Oxide.

The development of an efficient electrocatalyst for HMF oxidation to FDCA has been in the early stages. Herein, the NiNPs/GO-Ni-foam is fabricated as an electrocatalyst for FDCA production. However, the electrocatalytic performance of the untreated NiNPs/GO-Ni-foam is observed with moderate Faradaic efficiency (FE) (73.0%) and FDCA yield (80.2%). By electrochemically treating the NiNPs/GO-Ni-foam in an alkaline solution with positive potential at different treatment durations, the degree of NiOOH on metal surfaces is changed. The distinctive electrocatalytic activity obtained when using the different NiOOH degrees allows to understand the crucial impact of NiOOH species in HMF electrooxidation. Enhancing the portion of the NiOOH phase on the electrocatalyst surface improves electrocatalytic activity in terms of FE and FDCA yield up to 94.8±4.8% and 86.9±4.1%, respectively. Interestingly, as long as the NiOOH portion on the electrocatalyst surface is preserved or regenerated, the electrocatalyst performance can be intact even after several catalytic cycles. The theoretical study via density functional theory (DFT) also agrees with the experimental observations and confirms that the NiOOH phase facilitates the electrochemical transformation of HMF to FDCA through the HMFCA pathway, and the potential limiting step of the overall reaction is the oxidation of FFCA to FDCA.

Sparsentan is superior to losartan in the gddY mouse model of IgA nephropathy.

BACKGROUND: The mechanism leading to the development of IgA nephropathy (IgAN) remains to be completely understood. Endothelin-1 (ET-1) as well as angiotensin II (AngII) promote glomerular injury, tubulointerstitial inflammation, and fibrosis leading to chronic kidney disease. Sparsentan, a dual endothelin angiotensin receptor antagonist (DEARA), recently received accelerated approval in United States for the reduction of proteinuria in adults with IgAN at high risk of disease progression. To elucidate the mechanisms by which sparsentan is efficacious in IgAN, we examined the effect of treatment in gddY mice, a spontaneous IgAN mouse model, versus the monoselective angiotensin II type 1 receptor (AT1R) antagonist, losartan, on the development of renal injury at doses resulting in similar blood pressure lowering. METHODS: Four-week-old gddY mice were given control chow, chow containing sparsentan, or drinking water containing losartan until 12 or 20 weeks old. RESULTS: Remarkably, the albumin:creatine ratio (ACR) was attenuated more rapidly and to a greater extent in mice treated with sparsentan than those treated with losartan. The decrease in ACR from baseline after 4 weeks of treatment correlated with beneficial effects of sparsentan on glomerulosclerosis and protection of podocytes and glycocalyx after 16 weeks of treatment across treatment groups; thus, sparsentan treatment delayed development of renal injury to a greater extent than losartan. Expression of mRNA for ET-1, ETAR, and AT1R and proinflammatory genes was upregulated in 12-week-old gddY mice and was prevented by sparsentan and losartan to a comparable extent. CONCLUSIONS: The results of this study, and in light of the results of the phase 3 PROTECT trial, provide a novel perspective and understanding of the mechanisms by which sparsentan has a beneficial renoprotective effect against IgAN compared to AT1R antagonism alone.

Dual inhibition of the endothelin and angiotensin receptor ameliorates renal and inner ear pathologies in Alport mice.

Alport syndrome (AS), a type IV collagen disorder, leads to glomerular disease and, in some patients, hearing loss. AS is treated with inhibitors of the renin-angiotensin system; however, a need exists for novel therapies, especially those addressing both major pathologies. Sparsentan is a single-molecule dual endothelin type-A and angiotensin II type 1 receptor antagonist (DEARA) under clinical development for focal segmental glomerulosclerosis and IgA nephropathy. We report the ability of sparsentan to ameliorate both renal and inner ear pathologies in an autosomal-recessive Alport mouse model. Sparsentan significantly delayed onset of glomerulosclerosis, interstitial fibrosis, proteinuria, and glomerular filtration rate decline. Sparsentan attenuated glomerular basement membrane defects, blunted mesangial filopodial invasion into the glomerular capillaries, increased lifespan more than losartan, and lessened changes in profibrotic/pro-inflammatory gene pathways in both the glomerular and the renal cortical compartments. Notably, treatment with sparsentan, but not losartan, prevented accumulation of extracellular matrix in the strial capillary basement membranes in the inner ear and reduced susceptibility to hearing loss. Improvements in lifespan and in renal and strial pathology were observed even when sparsentan was initiated after development of renal pathologies. These findings suggest that sparsentan may address both renal and hearing pathologies in Alport syndrome patients. © 2023 Travere Therapeutics, Inc and The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Nut consumption during pregnancy is associated with decreased risk of peer problems in 5-year-old Japanese children.

OBJECTIVES: Nuts are nutrient-dense foods rich in unsaturated fatty acids, protein, dietary fiber, vitamins, and minerals. The present prebirth cohort study examined the association between maternal nut intake during pregnancy and the risk of childhood behavioral problems in 5-year-old Japanese children. METHODS: Study subjects were 1199 mother-child pairs. Dietary intake was assessed using a diet history questionnaire. Emotional problems, conduct problems, hyperactivity problems, peer problems, and low prosocial behavior were assessed using the parent-reported version of the Strengths and Difficulties Questionnaire. Adjustments were made for a priori-selected nondietary confounders and potentially related dietary factors. RESULTS: Compared with mothers who had not eaten nuts during pregnancy, mothers who had eaten nuts had a significantly reduced risk of peer problems in children; the adjusted odds ratio was 0.64 (95% confidence interval: 0.42-0.97). There were no measurable associations between maternal consumption of nuts during pregnancy and the risk of childhood emotional problems, conduct problems, hyperactivity problems, and low prosocial behavior. CONCLUSIONS: Maternal consumption of nuts during pregnancy may be associated with a decreased risk of peer problems in 5-year-old children.

AlphaKnot: server to analyze entanglement in structures predicted by AlphaFold methods.

AlphaKnot is a server that measures entanglement in AlphaFold-solved protein models while considering pLDDT confidence values. AlphaKnot has two main functions: (i) providing researchers with a webserver for analyzing knotting in their own AlphaFold predictions and (ii) providing a database of knotting in AlphaFold predictions from the 21 proteomes for which models have been published prior to 2022. The knotting is defined in a probabilistic fashion. The knotting complexity of proteins is presented in the form of a matrix diagram which shows users the knot type for the entire polypeptide chain and for each of its subchains. The dominant knot types as well as the computed locations of the knot cores (i.e. minimal portions of protein backbones that form a given knot type) are shown for each protein structure. Based mainly on the pLDDT confidence values, entanglements are classified as Knots, Unsure, and Artifacts. The database portion of the server can be used, for example, to examine protein geometry and entanglement-function correlations, as a reference set for protein modeling, and for facilitating evolutional studies. The AlphaKnot server can be found at https://alphaknot.cent.uw.edu.pl/.

Melanoma Mimicker: Pigmented Mammary Paget Disease in a Man.

ABSTRACT: Male breast cancer comprises less than 1% of all breast cancer cases. Mammary Paget disease (MPD) represents a subset of breast cancer that presents with skin changes of the nipple and areola, and is frequently misdiagnosed clinically due to similarities with other disease states, leading to an average delay in diagnosis of 1 month to 2 years. Pigmented mammary Paget disease (PMPD) is an uncommon variant of MPD that clinically and histologically resembles malignant melanoma. Due to variable immunohistochemical staining patterns, analysis can be challenging and often requires interpretation of panels for accurate diagnosis. We present a rare case of PMPD in a male, originally diagnosed both clinically and histologically as malignant melanoma, to highlight the diagnostic challenges that this entity presents, and to review staining patterns which may be useful in its diagnosis.

The synthesis and properties of Ca3 Sc2 Si3 O12 :Ce3+ (CSSG) phosphor are utilized for the development of human-centric lighting light-emitting diodes (HCL-LEDs).

In this study, cerium ion (Ce3+ )-doped calcium scandium silicate garnet (Ca3 Sc2 Si3 O12 , abbreviated CSSG) phosphors were successfully synthesized using the sol-gel method. The crystal phase, morphology, and photoluminescence properties of the synthesized phosphors were thoroughly investigated. Under excitation by a blue light-emitting diode (LED) chip (450 nm), the CSSG phosphor displayed a wide emission spectrum spanning from green to yellow. Remarkably, the material exhibited exceptional thermal stability, with an emissivity ratio at 150°C to that at 25°C reaching approximately 85%. Additionally, the material showcased impressive optical performance when tested with a blue LED chip, including a color rendering index (CRI) exceeding 90, an R9 value surpassing 50, and a biological impact ratio (M/P) above 0.6. These noteworthy findings underscore the potential applications of CSSG as a white light-converting phosphor, particularly in the realm of human-centered lighting.

Discovery of Alkyl Triphenylphosphonium Pinostrobin Derivatives as Potent Anti-Breast Cancer Agents.

Pinostrobin demonstrated anticancer properties, but its hydrophobic feature led to a reduction in bioavailability. The mitochondria-targeted approach successfully synthesized eight new alkyl triphenylphosphonium pinostrobin derivatives (1-8) with good yield in this study. Seven compounds (1-3, 5-8) showed greater cytotoxic potency against the human MCF-7 breast cancer cell line than pinostrobin. Molecular docking studies were performed with two important targets in hormone-dependent anticancer strategies, estrogen receptor α (ERα) ligand binding domains, 3ERT (antagonist recognition and antiproliferative function), and 1GWR (agonist recognition and pro-proliferative function). In addition, the MD simulation study of the two most potent compounds (2 and 3) complexed with both ERα forms suggested that compounds 2 and 3 could serve as favourable antagonists. Furthermore, the in silico ADMET prediction indicated that compounds 2 and 3 could be potential drug candidates.

Adverse childhood experiences and early initiation of substance use: A survival analysis.

OBJECTIVE: Early adversity, such as adverse childhood experiences (ACEs), is a risk factor for the development of substance use disorder (SUD). ACEs are associated with earlier initiation of substance use. This study examined the relationship between ACEs and age of initiation of substance use using survival analysis. It is hypothesized that individuals with higher ACEs will have an earlier age of initiation. METHOD: Participants were recruited from the University of Kentucky's Laboratory for Human Behavioral Pharmacology. Participants were 18 years or older, English speaking, and actively engaged in substance use. Participants were not in substance abuse treatment nor were they seeking treatment. ACE scores were calculated, and age of substance use initiation was recorded. A Cox proportional hazard model was used to examine the effect of ACE score on age of substance use initiation. RESULTS: A total of 107 participants completed the study. An average number of 2.3 ACEs (SD = 2.2) were endorsed with 24% of participants reporting 4 or more ACEs. Higher ACE scores were associated with cigarette smoking and non-medical prescription opioid use onset ( hazard ratio (HR) = 1.14, 95% CI=1.02-1.28, p = 0.02, and HR=1.19, 95% CI = 1.04-1.37, p = 0.01, respectively. CONCLUSIONS: A significant association was found between higher ACE scores and earlier initiation of cigarette and non-medical prescription opioid use, consistent with prior research. Primary prevention of ACEs, screening for ACEs during childhood, and interventions for ACEs if detected, may help to reduce the risk of substance use/SUD in adulthood.

Hyponutrition among newly diagnosed gastric cancer.

OBJECTIVES: This study aims to determine the malnutrition status among Vietnamese patients newly diagnosed with gastric cancer (GC). BACKGROUND: GC remains the top rank of common and deadly diseases. With limited clinical manifestation, most GC patients were diagnosed at late stages when tumor is not radically resected. Malnutrition was associated with poor prognosis of GC, such as prolonged hospitalization, limited treatment efficacy and low survival rate. METHODS: The cross-sectional descriptive study recruited 77 patients newly diagnosed with GC and 90 healthy individuals (HC). The data used for this study were approved by the local Ethical Committee. The data were analysed on STATA 14.0 and GraphPad Prism 8.0. RESULTS: We observed the male dominant distribution in GC cohort and over 65% of GC were firstly diagnosed at advanced stages (III and IV). Anemia was detected in about 50% of GC patients. Hyponutrition was prevalent in newly diagnosed GC. We found the decreased tendency of anemia related indexes from HC to early stages (I and II) and advanced stages (III and IV) of GC patients. CONCLUSION: Anemia and hypoproteinemia occurred frequently among Vietnamese newly diagnosed GC. The nutrition therapy would benefit GC patients (Tab. 4, Fig. 4, Ref. 20).

Expanded vaccination practice in 2-year-old children and maternal knowledge on expanded vaccination in Tien Giang, Vietnam.

Background: Vaccination plays a central role in protecting children against severe diseases and preventing child mortality. Objectives: This study aimed to determine the rate and factors associated with complete and timely vaccination in 2-year-old children, as well as maternal knowledge on expanded vaccination in Go Cong Tay district, Tien Giang province, Vietnam. Methods: A cross-sectional descriptive study was conducted on 558 2-year-old children and their mothers residing in Go Cong Tay district, Tien Giang province, Vietnam. The study employed a systematic random sampling method from June to September 2021. Results: The rate of complete vaccination in children was 74.7%. Factors associated with the rate of complete vaccination were occupation (OR=0.3; 95%CI: 0.1-0.7; p=0.006), economic status (OR=3.8; 95%CI: 1.7-8.6; p=0.001), and maternal general knowledge on expanded vaccination (OR=1.7; 95%CI: 1.1-2.6; p=0.01). The rate of timely vaccination was 47.8%. Factors associated with the rate of timely vaccination were maternal age group (OR=3.1; 95%CI: 1.6-6.0; p=0.001; OR=3.0; 95%CI: 1.3-6.6; p=0.006) and economic status (OR=0.4; 95%CI: 0.2-0.9; p=0.04). The rate of both complete and timely vaccination was 22.6%. Factors associated with the rate of complete and timely vaccination were maternal age group (OR=3.1; 95%CI: 1.3-7.2; p=0.009; OR=3.3; 95%CI: 1.2-9.1; p=0.02) and maternal general knowledge on expanded vaccination (OR=1.5; 95%CI: 1.0-2.4; p=0.03). The rate of maternal general knowledge on expanded vaccination was 57.5%. Conclusion: The rates of complete and timely vaccination are still low, and various factors influence expanded vaccination. The-refore, it is crucial to continue health education campaigns to improve knowledge on expanded vaccination, remind mothers of vaccination schedules, strengthen confidence in vaccination programs and vaccine safety, attract customers to vaccination services, provide adequate healthcare for children, and ensure vaccination activities during disease outbreaks.

Activation of meiotic recombination by nuclear import of the DNA break hotspot-determining complex in fission yeast.

Meiotic recombination forms crossovers important for proper chromosome segregation and offspring viability. This complex process involves many proteins acting at each of the multiple steps of recombination. Recombination initiates by formation of DNA double-strand breaks (DSBs), which in the several species examined occur with high frequency at special sites (DSB hotspots). In Schizosaccharomyces pombe, DSB hotspots are bound with high specificity and strongly activated by linear element (LinE) proteins Rec25, Rec27 and Mug20, which form colocalized nuclear foci with Rec10, essential for all DSB formation and recombination. Here, we test the hypothesis that the nuclear localization signal (NLS) of Rec10 is crucial for coordinated nuclear entry after forming a complex with other LinE proteins. In NLS mutants, all LinE proteins were abundant in the cytoplasm, not the nucleus; DSB formation and recombination were much reduced but not eliminated. Nuclear entry of limited amounts of Rec10, apparently small enough for passive nuclear entry, can account for residual recombination. LinE proteins are related to synaptonemal complex proteins of other species, suggesting that they also share an NLS, not yet identified, and undergo protein complex formation before nuclear entry.This article has an associated First Person interview with Mélody Wintrebert, joint first author of the paper.

The mutation spectrum of SLC25A13 gene in citrin deficiency: identification of novel mutations in Vietnamese pediatric cohort with neonatal intrahepatic cholestasis.

BACKGROUND: Citrin deficiency (CD), a disorder caused by mutations in the SLC25A13 gene, may result in neonatal intrahepatic cholestasis. This study was purposely to explore the mutation spectrum of SLC25A13 gene in Vietnamese CD patients. METHODS: The 292 unrelated CD patients were first screened for four high-frequency mutations by PCR/PCR-RFLP. Then, Sanger sequencing was performed directly for heterozygous or undetected patients. Novel mutations identified would need to be confirmed by their parents. RESULTS: 12 pathogenic SLC25A13 mutations were identified in all probands, including three deletions c.851_854del (p.R284Rfs*3), c.70-63_133del (p.Y24_72Ifs*10), and c.[1956C>A;1962del] (p.[N652K;F654Lfs*45]), two splice-site mutations (IVS6+5G>A and IVS11+1G>A), one nonsense mutations c.1399C>T (p.R467*), one duplication mutation c.1638_1660dup (p.A554fs*570), one insertion IVSl6ins3kb (p.A584fs*585), and four missense mutation c.2T>C (p.M1T), c.1231G>A (p.V411M), c.1763G>A (p.R588Q), and c.135G>C (p.L45F). Among them, c.851_854del (mut I) was the most identified mutant allele (91.78%) with a total of 247 homozygous and 42 heterozygous genotypes of carriers. Interestingly, two novel mutations were identified: c.70-63_133del (p.Y24_72Ifs*10) and c.[1956C>A;1962del] (p.[N652K;F654Lfs*45]). CONCLUSION: The SLC25A13 mutation spectrum related to intrahepatic cholestasis infants in Vietnam revealed a quite similar pattern to Asian countries' reports. This finding supports the use of targeted SLC25A13 mutation for CD screening in Vietnam and contributed to the SLC25A13 mutation spectra worldwide. It also helps emphasize the role of DNA analysis in treatment, genetic counseling, and prenatal diagnosis.

TGF-ß3 in differentiation and function of Tph-like cells and its relevance to disease activity in patients with systemic lupus erythematosus.

OBJECTIVES: T peripheral helper (Tph) cells have major roles in pathological processes in SLE. We sought to clarify the mechanisms of Tph cell differentiation and their relevance to clinical features in patients with SLE. METHOD: Phenotypes and functions of Tph cell-related markers in human CD4+ T cells purified from volunteers or patients were analysed using flow cytometry and quantitative PCR. Renal biopsy specimens from patients with LN were probed by multicolour immunofluorescence staining. RESULTS: Among multiple cytokines, transforming growth factor (TGF)-ß3 characteristically induced programmed cell death protein 1 (PD-1)hi musculoaponeurotic fibrosarcoma (MAF)+, IL-21+IL-10+ Tph-like cells with a marked upregulation of related genes including PDCD-1, MAF, SOX4 and CXCL13. The induction of Tph-like cells by TGF-ß3 was suppressed by the neutralization of TGF-ß type II receptor (TGF-ßR2). TGF-ß3-induced Tph-like cells efficiently promoted the differentiation of class-switch memory B cells into plasmocytes, resulting in enhanced antibody production. The proportion of Tph cells in the peripheral blood was significantly increased in patients with SLE than in healthy volunteers in concordance with disease activity and severity of organ manifestations such as LN. TGF-ß3 was strongly expressed on macrophages, which was associated with the accumulation of CD4+ C-X-C chemokine receptor (CXCR5)-PD-1+ Tph cells, in the renal tissue of patients with active LN. CONCLUSION: The induction of Tph-like cells by TGF-ß3 mainly produced from tissue macrophages plays a pivotal role in the pathological processes of active LN by enhancing B-cell differentiation in patients with SLE.

Amino acid variants of SARS-CoV-2 papain-like protease have impact on drug binding.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused both a health and economic crisis around the world. Its papain-like protease (PLpro) is one of the protein targets utilized in designing new drugs that would aid vaccines in the fight against the virus. Although there are already several potential candidates for a good inhibitor of this protein, the degree of variability of the protein itself is not taken into account. As an RNA virus, SARS-CoV-2 can mutate to a high degree, but PLpro variability has not been studied to date. Based on sequence data available in databases, we analyzed the mutational potential of this protein. We focused on the effect of observed mutations on inhibitors' binding mode and their efficacy as well as protein's activity. Our analysis identifies five mutations that should be monitored and included in the drug design process: P247S, E263D-Y264H and T265A-Y268C.

Bcl-2 proteins and apoptosis: choose your partner.

The Bcl-2 family protein Bax is a key effector of apoptosis. Lovell et al. (2008) now describe the reconstitution and regulation in liposomes of tBid-mediated membrane penetration and oligomerization of Bax. These and other recent studies shed new light on the control of permeabilization of the mitochondrial outer membrane during apoptosis.