Over the last 25 years, research on biodiversity has expanded dramatically, fuelled by increasing threats to the natural world. However, the number of published studies is heavily weighted towards ...certain taxa, perhaps influencing conservation awareness of and funding for less-popular groups. Few studies have systematically quantified these biases, although information on this topic is important for informing future research and conservation priorities. We investigated: i) which animal taxa are being studied; ii) if any taxonomic biases are the same in temperate and tropical regions; iii) whether the taxon studied is named in the title of papers on biodiversity, perhaps reflecting a perception of what biodiversity is; iv) the geographical distribution of biodiversity research, compared with the distribution of biodiversity and threatened species; and v) the geographical distribution of authors' countries of origin. To do this, we used the search engine Web of Science to systematically sample a subset of the published literature with 'biodiversity' in the title. In total 526 research papers were screened-5% of all papers in Web of Science with biodiversity in the title. For each paper, details on taxonomic group, title phrasing, number of citations, study location, and author locations were recorded. Compared to the proportions of described species, we identified a considerable taxonomic weighting towards vertebrates and an under-representation of invertebrates (particularly arachnids and insects) in the published literature. This discrepancy is more pronounced in highly cited papers, and in tropical regions, with only 43% of biodiversity research in the tropics including invertebrates. Furthermore, while papers on vertebrate taxa typically did not specify the taxonomic group in the title, the converse was true for invertebrate papers. Biodiversity research is also biased geographically: studies are more frequently carried out in developed countries with larger economies, and for a given level of species or threatened species, tropical countries were understudied relative to temperate countries. Finally, biodiversity research is disproportionately authored by researchers from wealthier countries, with studies less likely to be carried out by scientists in lower-GDP nations. Our results highlight the need for a more systematic and directed evaluation of biodiversity studies, perhaps informing more targeted research towards those areas and taxa most depauperate in research. Only by doing so can we ensure that biodiversity research yields results that are relevant and applicable to all regions and that the information necessary for the conservation of threatened species is available to conservation practitioners.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Much of our understanding of protein structure and mechanistic function has been derived from static high‐resolution structures. As structural biology has continued to evolve it has become clear that ...high‐resolution structures alone are unable to fully capture the mechanistic basis for protein structure and function in solution. Recently Hydrogen/Deuterium‐exchange Mass Spectrometry (HDX‐MS) has developed into a powerful and versatile tool for structural biologists that provides novel insights into protein structure and function. HDX‐MS enables direct monitoring of a protein's structural fluctuations and conformational changes under native conditions in solution even as it is carrying out its functions. In this review, we focus on the use of HDX‐MS to monitor these dynamic changes in proteins. We examine how HDX‐MS has been applied to study protein structure and function in systems ranging from large, complex assemblies to intrinsically disordered proteins, and we discuss its use in probing conformational changes during protein folding and catalytic function.
Statement for a Broad Audience
The biophysical and structural characterization of proteins provides novel insight into their functionalities. Protein motions, ranging from small scale local fluctuations to larger concerted structural rearrangements, often determine protein function. Hydrogen/Deuterium‐exchange Mass Spectrometry (HDX‐MS) has proven a powerful biophysical tool capable of probing changes in protein structure and dynamic protein motions that are often invisible to most other techniques.
The human epidermal growth factor receptor (HER) family of tyrosine kinases is deregulated in multiple cancers either through amplification, overexpression, or mutation. ERBB3/HER3, the only member ...with an impaired kinase domain, although amplified or overexpressed in some cancers, has not been reported to carry oncogenic mutations. Here, we report the identification of ERBB3 somatic mutations in ∼11% of colon and gastric cancers. We found that the ERBB3 mutants transformed colonic and breast epithelial cells in a ligand-independent manner. However, the mutant ERBB3 oncogenic activity was dependent on kinase-active ERBB2. Furthermore, we found that anti-ERBB antibodies and small molecule inhibitors effectively blocked mutant ERBB3-mediated oncogenic signaling and disease progression in vivo.
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•Recurrent ERBB3 somatic mutations occur in colon and gastric cancers•ERBB3 mutants with ERBB2 promote ligand-independent oncogenic signaling•Somatic ERBB3 mutants promote tumor formation•Targeted therapeutics block ERBB3 mutant-mediated oncogenic signaling
HIV-1 Env mediates viral entry into host cells and is the sole target for neutralizing antibodies. However, Env structure and organization in its native virion context has eluded detailed ...characterization. Here, we used cryo-electron tomography to analyze Env in mature and immature HIV-1 particles. Immature particles showed distinct Env positioning relative to the underlying Gag lattice, providing insights into long-standing questions about Env incorporation. A 9.1-Å sub-tomogram-averaged reconstruction of virion-bound Env in conjunction with structural mass spectrometry revealed unexpected features, including a variable central core of the gp41 subunit, heterogeneous glycosylation between protomers, and a flexible stalk that allows Env tilting and variable exposure of neutralizing epitopes. Together, our results provide an integrative understanding of HIV assembly and structural variation in Env antigen presentation.
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•Structural analysis of immature HIV shows Env position on Gag hexameric rim•HIV Env has a flexible stalk that allows tilting and variation in stalk exposure•Env’s fusion peptide is dynamic and exposed to solvent in membrane-bound Env•Glycans in unliganded Env shield antigenic sites and vary between protomers
Looking at native HIV virions using cryo-ET shows how Env interacts with Gag and reveals variability in Env conformations that is relevant for understanding interactions with antibodies.
The ability of naturally occurring proteins to change conformation in response to environmental changes is critical to biological function. Although there have been advances in the de novo design of ...stable proteins with a single, deep free-energy minimum, the design of conformational switches remains challenging. We present a general strategy to design pH-responsive protein conformational changes by precisely preorganizing histidine residues in buried hydrogen-bond networks. We design homotrimers and heterodimers that are stable above pH 6.5 but undergo cooperative, large-scale conformational changes when the pH is lowered and electrostatic and steric repulsion builds up as the network histidine residues become protonated. The transition pH and cooperativity can be controlled through the number of histidine-containing networks and the strength of the surrounding hydrophobic interactions. Upon disassembly, the designed proteins disrupt lipid membranes both in vitro and after being endocytosed in mammalian cells. Our results demonstrate that environmentally triggered conformational changes can now be programmed by de novo protein design.
Given the recent advances in molecular pathogenesis of tumors, with better correlation with tumor behavior and prognosis, major changes were made to the new 2021 WHO (CNS5) classification of CNS ...tumors, including updated criteria for diagnosis of glioblastoma. Diagnosis of GBM now requires absence of isocitrate dehydrogenase and histone 3 mutations (IDH-wildtype and H3-wildtype) as the basic cornerstone, with elimination of the IDH-mutated category. The requirements for diagnosis were conventionally histopathological, based on the presence of pathognomonic features such as microvascular proliferation and necrosis. However, even if these histological features are absent, many lower grade (WHO grade 2/3) diffuse astrocytic gliomas behave clinically similar to GBM (grade 4). The 2021 WHO classification introduced new molecular criteria that can be used to upgrade the diagnosis of such histologically lower-grade, IDH-wildtype, astrocytomas to GBM. The three molecular criteria include: concurrent gain of whole chromosome 7 and loss of whole chromosome 10 (+7/-10); TERT promoter mutation; epidermal growth factor receptor (EGFR) amplification. Given these changes, it is now strongly recommended to have molecular analysis of WHO grade 2/3 diffuse astrocytic, IDH-wildtype, gliomas in adult patients, as identification of any of the above mutations allows for upgrading the tumor to WHO grade 4 ("molecular GBM") with important prognostic implications. Despite at an early stage, there is active ongoing research on the unique MRI features of molecular GBM. This paper highlights the differences between "molecular" and "histopathological" GBM, with the aim of providing a basic understanding about these changes.ABBREVIATIONS: GBM=Glioblastoma; TERT=telomerase reverse transcriptase; EGFR=epidermal growth factor receptor; MGMT= methylguanine-DNA methyltransferase; NGS= next-generation sequencing; IDH= isocitrate dehydrogenase.
Human demands on marine resources and space are currently unprecedented and concerns are rising over observed declines in marine biodiversity. A quantitative understanding of the impact of industrial ...activities on the marine environment is thus essential. Life cycle assessment (LCA) is a widely applied method for quantifying the environmental impact of products and processes. LCA was originally developed to assess the impacts of land-based industries on mainly terrestrial and freshwater ecosystems. As such, impact indicators for major drivers of marine biodiversity loss are currently lacking. We review quantitative approaches for cause–effect assessment of seven major drivers of marine biodiversity loss: climate change, ocean acidification, eutrophication-induced hypoxia, seabed damage, overexploitation of biotic resources, invasive species and marine plastic debris. Our review shows that impact indicators can be developed for all identified drivers, albeit at different levels of coverage of cause–effect pathways and variable levels of uncertainty and spatial coverage. Modeling approaches to predict the spatial distribution and intensity of human-driven interventions in the marine environment are relatively well-established and can be employed to develop spatially-explicit LCA fate factors. Modeling approaches to quantify the effects of these interventions on marine biodiversity are less well-developed. We highlight specific research challenges to facilitate a coherent incorporation of marine biodiversity loss in LCA, thereby making LCA a more comprehensive and robust environmental impact assessment tool. Research challenges of particular importance include i) incorporation of the non-linear behavior of global circulation models (GCMs) within an LCA framework and ii) improving spatial differentiation, especially the representation of coastal regions in GCMs and ocean-carbon cycle models.
•Seven major drivers of marine biodiversity loss are reviewed in the context of LCA.•LCA fate factors could be developed from existing quantitative approaches.•Modeling effects of human activities on marine biodiversity is more limited.•Specific challenges for including marine biodiversity loss in LCA are highlighted.
PURPOSE To determine the prognostic significance of histologic type in radiation-associated soft tissue sarcomas (RASs) and determine whether RASs are associated with an inferior prognosis compared ...with sporadic soft tissue sarcomas (STSs). PATIENTS AND METHODS One hundred thirty primary RASs were identified from 7,649 STS patients from 1982 to 2007. Multivariate analysis of clinicopathologic factors for disease-specific survival (DSS) was performed for RASs, and a multivariate analysis of radiation exposure was also performed for RASs and sporadic sarcomas. A matched-cohort analysis was performed for radiation-associated and sporadic malignant fibrous histiocytoma (MFH). Results Most RASs were high grade (83%), deep (87%), and truncal (61.5%). The median interval between radiation therapy and RAS development was 10 years (range, 1.3 to 74 years), which varied significantly by histologic type (P = .003). The 5-year DSS was 58%, and independent predictors were size > 5 cm, margin positivity, and histologic type. Multivariate analysis of histologic types of primary, high-grade radiation-associated and sporadic STSs showed that RAS was associated with a worse DSS (hazard ratio, 1.7; range, 1.1 to 2.4; P = .007). For pleomorphic MFH-the most common RAS type-the 5-year DSS was 44% versus 66% in a matched cohort of sporadic MFH patients (P = .07). DSS was significantly worse in primary RAS malignant peripheral nerve sheath tumors (MPNSTs) compared with unmatched sporadic MPNSTs (P = .001). CONCLUSION Histologic type, margin status, and tumor size are the most important independent predictors of DSS in patients with RASs. DSS in patients with primary RAS is significantly worse compared with sporadic STS independent of sarcoma histologic type.
Hematopoietic stem cell transplantation is a life-saving therapy for many patients with cancer, as well as patients with some nonmalignant hematologic disorders, such as aplastic anemia, sickle cell ...disease, and certain congenital immune deficiencies. Kidney injury directly associated with stem cell transplantation includes a wide range of structural and functional abnormalities, which may be vascular (hypertension, thrombotic microangiopathy), glomerular (albuminuria, nephrotic glomerulopathies), and/or tubulointerstitial. AKI occurs commonly after stem cell transplant, affecting 10%-73% of patients. The cause is often multifactorial and can include sepsis, nephrotoxic medications, marrow infusion syndrome, hepatic sinusoidal obstruction syndrome, thrombotic microangiopathy, infections, and graft versus host disease. The risk of post-transplant kidney injury varies depending on patient characteristics, type of transplant (allogeneic versus autologous), and choice of chemotherapeutic conditioning regimen (myeloablative versus nonmyeloablative). Importantly, AKI is associated with substantial morbidity, including the need for KRT in approximately 5% of patients and the development of CKD in up to 60% of transplant recipients. AKI has been associated universally with higher all-cause and nonrelapse mortality regardless of transplant type, and studies have consistently shown extremely high (>80%) mortality rates in those patients requiring acute dialysis. Accordingly, prevention, early recognition, and prompt treatment of kidney injury are essential to improving kidney and patient outcomes after hematopoietic stem cell transplantation, and for realizing the full potential of this therapy.
Kidney cancer, or renal cell carcinoma (RCC), is a disease of increasing incidence that is commonly seen in the general practice of nephrology. However, RCC is under-recognized by the nephrology ...community, such that its presence in curricula and research by this group is lacking. In the most common form of RCC, clear cell renal cell carcinoma (ccRCC), inactivation of the von Hippel-Lindau tumor suppressor is nearly universal; thus, the biology of ccRCC is characterized by activation of hypoxia-relevant pathways that lead to the associated paraneoplastic syndromes. Therefore, RCC is labeled the internist's tumor. In light of this characterization and multiple other metabolic abnormalities recently associated with ccRCC, it can now be viewed as a metabolic disease. In this review, we discuss the basic biology, pathology, and approaches for treatment of RCC. It is important to distinguish between kidney confinement and distant spread of RCC, because this difference affects diagnostic and therapeutic approaches and patient survival, and it is important to recognize the key interplay between RCC, RCC therapy, and CKD. Better understanding of all aspects of this disease will lead to optimal patient care and more recognition of an increasingly prevalent nephrologic disease, which we now appropriately label the nephrologist's tumor.
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