Translocation of the papillomavirus L2/vDNA complex across the limiting membrane requires the onset of mitosis.

The human papillomavirus type 16 (HPV16) L2 protein acts as a chaperone to ensure that the viral genome (vDNA) traffics from endosomes to the trans-Golgi network (TGN) and eventually the nucleus, where HPV replication occurs. En route to the nucleus, the L2/vDNA complex must translocate across limiting intracellular membranes. The details of this critical process remain poorly characterized. We have developed a system based on subcellular compartmentalization of the enzyme BirA and its cognate substrate to detect membrane translocation of L2-BirA from incoming virions. We find that L2 translocation requires transport to the TGN and is strictly dependent on entry into mitosis, coinciding with mitotic entry in synchronized cells. Cell cycle arrest causes retention of L2/vDNA at the TGN; only release and progression past G2/M enables translocation across the limiting membrane and subsequent infection. Microscopy of EdU-labeled vDNA reveals a rapid and dramatic shift in vDNA localization during early mitosis. At late G2/early prophase vDNA egresses from the TGN to a pericentriolar location, accumulating there through prometaphase where it begins to associate with condensed chromosomes. By metaphase and throughout anaphase the vDNA is seen bound to the mitotic chromosomes, ensuring distribution into both daughter nuclei. Mutations in a newly defined chromatin binding region of L2 potently blocked translocation, suggesting that translocation is dependent on chromatin binding during prometaphase. This represents the first time a virus has been shown to functionally couple the penetration of limiting membranes to cellular mitosis, explaining in part the tropism of HPV for mitotic basal keratinocytes.

MLL-rearranged acute myeloid leukemia: Influence of the genetic partner in allo-HSCT response and prognostic factor of MLL 3' region mRNA expression.

OBJECTIVE: MLL gene is involved in more than 80 known genetic fusions in acute leukemia. To study the relevance of MLL partner gene and selected gene's expression, in this work, we have studied a cohort of 20 MLL-rearranged acute myeloid leukemia (AML). METHODS: Twenty MLL-rearranged AML patients along with a control cohort of 138 AML patients are included in this work. By RT-PCR and sequencing, MLL genetic fusion was characterized, and relative gene expression quantification was carried out for EVI1, MEIS1, MLL-3', RUNX1, SETBP1, HOXA5, and FLT3 genes. Risk stratification and association of MLL genetic partner and gene expression to overall survival, in the context of received therapy, were performed. RESULTS: MLLr cohort showed to have an OS more similar to intermediate-risk AML. Type of MLL genetic partner showed to be relevant in allo-HSCT response; having MLLT1 and MLLT3, a better benefit from it. Expression of MLL-3' region, EVI1 and FLT3, showed association with OS in patients undergoing allo-HSCT. CONCLUSION: We show that the MLL genetic partner could have implications in allo-HSCT response, and we propose three genes whose expression could be useful for the prognosis of this leukemia in patients undergoing allo-HSCT: 3' region of MLL, EVI1, and FLT3.

Hematological Neoplasms with Eosinophilia.

Eosinophils in peripheral blood account for 0.3-5% of leukocytes, which is equivalent to 0.05-0.5 × 109/L. A count above 0.5 × 109/L is considered to indicate eosinophilia, while a count equal to or above 1.5 × 109/L is defined as hypereosinophilia. In bone marrow aspirate, eosinophilia is considered when eosinophils make up more than 6% of the total nuclear cells. In daily clinical practice, the most common causes of reactive eosinophilia are non-hematologic, whether they are non-neoplastic (allergic diseases, drugs, infections, or immunological diseases) or neoplastic (solid tumors). Eosinophilia that is associated with a hematological malignancy may be reactive or secondary to the production of eosinophilopoietic cytokines, and this is mainly seen in lymphoid neoplasms (Hodgkin lymphoma, mature T-cell neoplasms, lymphocytic variant of hypereosinophilic syndrome, and B-acute lymphoblastic leukemia/lymphoma). Eosinophilia that is associated with a hematological malignancy may also be neoplastic or primary, derived from the malignant clone, usually in myeloid neoplasms or with its origin in stem cells (myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions, acute myeloid leukemia with core binding factor translocations, mastocytosis, myeloproliferative neoplasms, myelodysplastic/myeloproliferative neoplasms, and myelodysplastic neoplasms). There are no concrete data in standardized cytological and cytometric procedures that could predict whether eosinophilia is reactive or clonal. The verification is usually indirect, based on the categorization of the accompanying hematologic malignancy. This review focuses on the broad differential diagnosis of hematological malignancies with eosinophilia.

Short-term effects of community-based marine reserves on green abalone, as revealed by population studies.

Marine reserves (MRs) are implemented worldwide to protect, restore, and manage marine ecosystems and species. However, it is important to document the positive effects those marine reserves have on slow-growth, temperate invertebrates such as abalone. Abalone, Haliotis spp., are marine gastropods of high economic value extracted worldwide for decades, which has led to fisheries-driven population decreases. In this work, we focused on a case study and assessed the short-term (1-2 years) effects of marine reserves established and managed by a local fishing cooperative at Guadalupe Island, Mexico. We evaluated the population status of green abalone, H. fulgens, by conducting (1) an assessment of the green abalone population around Guadalupe Island through subtidal monitoring and (2) an evaluation of the effect of two recently established marine reserves on population parameters such as the increase in density (individuals·m2), biomass, number of aggregated abalone, egg production, and proportion of individuals bigger than 150 mm (minimum harvest size) compared to fished areas. To assess the population around Guadalupe Island, we surveyed 11,160 m2 during 2020 and 2021. We recorded 2327 green abalones with a mean ± SE shell length of 135.978 ± 0.83 mm and a mean density of 0.21 ± 0.02 individuals·m2. All variables were statistically higher at the MRs except for shell length in 2021. In this work, we report for the first time the green abalone population status at Guadalupe Island and a positive short-term biological response to community-based marine reserves. This study suggests that a network of MRs combined with good management could help abalone populations in the short term in Guadalupe Island, potentially leading to more sustainable fishing practices and social-ecological resilience.

Incidence and Clinical Implications of Anatomical Variations in the Pancreas and Its Ductal System: A Systematic Review and Meta-Analysis.

OBJECTIVE: This systematic review analyzes the anatomical variants in the pancreas and its ductal system to report on their association with pancreatic pathologies. METHODS: We conducted a search of the MEDLINE, Scopus, Web of Science, Google Scholar, CINAHL, and LILACS databases from their inception to July 2023. The methodological quality was assessed with the Anatomical Quality Assessment (AQUA) tool. Finally, the pooled prevalence was estimated using a random effects model. RESULTS: 55 studies were found that met the eligibility criteria. The overall prevalence of pancreas divisum (PD) was 18% (95% CI = 15-21%). The prevalence of PD associated with pancreatitis was 30% (95% CI = 1-61%). CONCLUSIONS: An anatomical variant of the pancreas such as PD may be the cause of bile duct obstruction, resulting in various clinical complications, such as pancreatitis. Hence, knowing this variant is extremely important for surgeons, especially for those who treat the gastroduodenal region.

Chaperonin-mediated folding of viral proteins.

Chaperonins are universally conserved molecular machines that facilitate the proper -folding of nascent and partially folded polypeptides into their respective three-dimensional structures. These multimeric protein complexes utilize the energy derived from ATP hydrolysis to fuel a protein-folding mechanism that consists of multiple rounds of substrate binding, encapsulation, and eventual expulsion back into the cytosolic environment. In this portion of the chapter, the structure and function of group I and group II chaperonins are discussed. Furthermore, the general mechanism of chaperonin-mediated protein folding is addressed in addition to illustrating how viral phages such as Lambda, T4, and RB49 exploit the host machinery for the proper folding of viral gene products. Lastly, the phiEL chaperonin from phage EL is revealed to be the first virally encoded chaperonin and is proposed to function independently of the host chaperonin machinery. The molecular architecture of the phiEL chaperonin, coupled with its unique functional abilities, renders its characterization a challenge and further highlights its novelty as a potentially whole new class of chaperonins.

Insights Into the Role of Heat Shock Protein 27 in the Development of Neurodegeneration.

Small heat shock protein 27 is a critically important chaperone, that plays a key role in several essential and varied physiological processes. These include thermotolerance, apoptosis, cytoskeletal dynamics, cell differentiation, protein folding, among others. Despite its relatively small size and intrinsically disordered termini, it forms large and polydisperse oligomers that are in equilibrium with dimers. This equilibrium is driven by transient interactions between the N-terminal region, the α-crystallin domain, and the C-terminal region. The continuous redistribution of binding partners results in a conformationally dynamic protein that allows it to adapt to different functions where substrate capture is required. However, the intrinsic disorder of the amino and carboxy terminal regions and subsequent conformational variability has made structural investigations challenging. Because heat shock protein 27 is critical for so many key cellular functions, it is not surprising that it also has been linked to human disease. Charcot-Marie-Tooth and distal hereditary motor neuropathy are examples of neurodegenerative disorders that arise from single point mutations in heat shock protein 27. The development of possible treatments, however, depends on our understanding of its normal function at the molecular level so we might be able to understand how mutations manifest as disease. This review will summarize recent reports describing investigations into the structurally elusive regions of Hsp27. Recent insights begin to provide the required context to explain the relationship between a mutation and the resulting loss or gain of function that leads to Charcot-Marie Tooth disease and distal hereditary motor neuropathy.

Severe gastrointestinal injury associated with SARS-CoV-2 infection: Thrombosis or Inflammation?: A retrospective case series study.

OBJECTIVES: Acute gastrointestinal injury (AGI) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has a low incidence of complications in patients admitted to the intensive care unit (ICU). Pathophysiological knowledge related to AGI is limited, as few studies have been published on this topic. Therefore, this study was carried out to identify the clinical and histopathological features of patients with SARS-CoV-2 infection and grade IV AGI. METHODS: This is a retrospective case study of fifteen patients with SARS-CoV-2 infection and grade IV AGI who underwent emergency surgery. RESULTS: This study revealed a mortality rate of 62.5%. The most frequent gastrointestinal symptoms were abdominal distension (100%) and increased gastric residual volume (93.3%). Distended bowel loops on plain abdominal radiography (90%) and intestinal pneumatosis on computed tomography (50%) were the most frequent imaging findings. Surgical exploration revealed intestinal ischemia (66.6%) and necrosis (46.6%), and histopathology showed ischemic and liquefactive necrosis with mixed inflammatory involvement and absence of thrombosis as the cause of AGI. CONCLUSIONS: AGI associated with severe SARS-CoV-2 infection has a high mortality rate and poses a diagnostic challenge in the ICU. The complex pathophysiology and histopathological findings indicate an associated inflammatory phenomenon as the main alteration in the absence of thrombosis, as per the intestinal biopsies of the cases studied. Further clinical studies are required to gain a better understanding of this pathology.

Connexins and Pannexins: Important Players in Neurodevelopment, Neurological Diseases, and Potential Therapeutics.

Cell-to-cell communication is essential for proper embryonic development and its dysfunction may lead to disease. Recent research has drawn attention to a new group of molecules called connexins (Cxs) and pannexins (Panxs). Cxs have been described for more than forty years as pivotal regulators of embryogenesis; however, the exact mechanism by which they provide this regulation has not been clearly elucidated. Consequently, Cxs and Panxs have been linked to congenital neurodegenerative diseases such as Charcot-Marie-Tooth disease and, more recently, chronic hemichannel opening has been associated with adult neurodegenerative diseases (e.g., Alzheimer's disease). Cell-to-cell communication via gap junctions formed by hexameric assemblies of Cxs, known as connexons, is believed to be a crucial component in developmental regulation. As for Panxs, despite being topologically similar to Cxs, they predominantly seem to form channels connecting the cytoplasm to the extracellular space and, despite recent research into Panx1 (Pannexin 1) expression in different regions of the brain during the embryonic phase, it has been studied to a lesser degree. When it comes to the nervous system, Cxs and Panxs play an important role in early stages of neuronal development with a wide span of action ranging from cellular migration during early stages to neuronal differentiation and system circuitry formation. In this review, we describe the most recent available evidence regarding the molecular and structural aspects of Cx and Panx channels, their role in neurodevelopment, congenital and adult neurological diseases, and finally propose how pharmacological modulation of these channels could modify the pathogenesis of some diseases.