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BEAM conditioning regimen (carmustine [BCNU], etoposide, cytarabine, and melphalan) has been widely used for autologous stem cell transplantation in patients with relapsed or refractory lymphoma. However, BCNU-associated toxicities have prompted research to explore other options. This study aimed to assess the feasibility of bendamustine as an alternative to BCNU. We compared 71 patients who received either bendamustine (Benda-EAM group) or BCNU (BEAM group) conditioning. Considering previous reports of increased cardiotoxicity, nephrotoxicity, and mucositis, we adopted a lower bendamustine dose of 160 mg/m2/day administered for 2 days. There was no increase in nephrotoxicity and cardiotoxicity. Further, positive results were also obtained for neutrophil and platelet engraftment, appearing earlier in patients treated with Benda-EAM (10 vs. 14 days and 16 vs. 27 days, respectively). However, caution is warranted because an increased frequency of Grade 3 mucositis was observed in the Benda-EAM group (82.4% vs. 48%). This was accompanied by an increased need for parenteral nutrition. Despite the lower dose of bendamustine, the overall and progression-free survival rates were comparable between the Benda-EAM and BEAM groups. In conclusion, a lower dose of bendamustine may be an attractive alternative to BCNU as a tolerable treatment modality for patients with relapsed/refractory lymphoma.
The investigators characterized the occurrence of maxillofacial injuries in cyclists and biomechanically analyzed the mechanisms of mandible fractures.
We retrospectively analyzed injury data and performed biomechanical analyses with finite element models. Hospital records from 2011 through 2019 were reviewed to identify patients who had sustained oral and maxillofacial injuries while riding a bicycle. Patients with maxillofacial fractures were compared to those without. Logistic regression analysis was performed to identify which variables were independently associated with the occurrence of maxillofacial fractures. To reconstruct the injury scenario (one in which a person falls from a bicycle and contacts the road surface with their face), computer simulations using The Total Human Model for Safety model were performed.
The hospital records of 94 patients (62 men, 32 women; 26.1±17.3years of age) who sustained oral and maxillofacial injuries while riding a bicycle were reviewed. Twenty patients (21.3%a bicycle and their lower face strikes the road's surface.The neocortex, the seat of our higher cognitive abilities, has expanded in size during the evolution of certain mammals such as primates, including humans. This expansion occurs during development and is linked to the proliferative capacity of neural stem and progenitor cells (NPCs) in the neocortex. A number of cell-intrinsic and cell-extrinsic factors have been implicated in increasing NPC proliferative capacity. However, NPC metabolism has only recently emerged as major regulator of NPC proliferation. In this Perspective, we summarize recent insights into the role of NPC metabolism in neocortical development and neurodevelopmental disorders and its relevance for neocortex evolution. We discuss certain human-specific genes and microcephaly-implicated genes that operate in, or at, the mitochondria of NPCs and stimulate their proliferation by promoting glutaminolysis. We also discuss other metabolic pathways and develop a perspective on how metabolism mechanistically regulates NPC proliferation in neocortical development and how this contributed to neocortex evolution.Proteins are known to undergo structural changes upon binding to partner proteins. However, the prevalence, extent, location, and function of change in protein dynamics due to transient protein-protein interactions is not well documented. Here, we have analyzed a dataset of 58 protein-protein complexes of known three-dimensional structure and structures of their corresponding unbound forms to evaluate dynamics changes induced by binding. Fifty-five percent of cases showed significant dynamics change away from the interfaces. This change is not always accompanied by an observed structural change. Binding of protein partner is found to alter inter-residue communication within the tertiary structure in about 90% of cases. Also, residue motions accessible to proteins in unbound form were not always maintained in the bound form. Further analyses revealed functional roles for the distant site where dynamics change was observed. Overall, the results presented here strongly suggest that alteration of protein dynamics due to binding of a partner protein commonly occurs.Lymphocyte migration is essential for adaptive immune surveillance. Binimetinib research buy However, our current understanding of this process is rudimentary, because most human studies have been restricted to immunological analyses of blood and various tissues. To address this knowledge gap, we used an integrated approach to characterize tissue-emigrant lineages in thoracic duct lymph (TDL). The most prevalent immune cells in human and non-human primate efferent lymph were T cells. Cytolytic CD8+ T cell subsets with effector-like epigenetic and transcriptional signatures were clonotypically skewed and selectively confined to the intravascular circulation, whereas non-cytolytic CD8+ T cell subsets with stem-like epigenetic and transcriptional signatures predominated in tissues and TDL. Moreover, these anatomically distinct gene expression profiles were recapitulated within individual clonotypes, suggesting parallel differentiation programs independent of the expressed antigen receptor. Our collective dataset provides an atlas of the migratory immune system and defines the nature of tissue-emigrant CD8+ T cells that recirculate via TDL.The December 2019 outbreak of a novel respiratory virus, SARS-CoV-2, has become an ongoing global pandemic due in part to the challenge of identifying symptomatic, asymptomatic, and pre-symptomatic carriers of the virus. CRISPR diagnostics can augment gold-standard PCR-based testing if they can be made rapid, portable, and accurate. Here, we report the development of an amplification-free CRISPR-Cas13a assay for direct detection of SARS-CoV-2 from nasal swab RNA that can be read with a mobile phone microscope. The assay achieved ∼100 copies/μL sensitivity in under 30 min of measurement time and accurately detected pre-extracted RNA from a set of positive clinical samples in under 5 min. We combined crRNAs targeting SARS-CoV-2 RNA to improve sensitivity and specificity and directly quantified viral load using enzyme kinetics. Integrated with a reader device based on a mobile phone, this assay has the potential to enable rapid, low-cost, point-of-care screening for SARS-CoV-2.Ticks transmit a diverse array of microbes to vertebrate hosts, including human pathogens, which has led to a human-centric focus in this vector system. Far less is known about pathogens of ticks themselves. Here, we discover that a toxin in blacklegged ticks (Ixodes scapularis) horizontally acquired from bacteria-called domesticated amidase effector 2 (dae2)-has evolved to kill mammalian skin microbes with remarkable efficiency. Secreted into the saliva and gut of ticks, Dae2 limits skin-associated staphylococci in ticks while feeding. In contrast, Dae2 has no intrinsic ability to kill Borrelia burgdorferi, the tick-borne Lyme disease bacterial pathogen. These findings suggest ticks resist their own pathogens while tolerating symbionts. Thus, just as tick symbionts can be pathogenic to humans, mammalian commensals can be harmful to ticks. Our study underscores how virulence is context-dependent and bolsters the idea that "pathogen" is a status and not an identity.Hendra (HeV) and Nipah (NiV) viruses are emerging zoonotic pathogens in the Henipavirus genus causing outbreaks of disease with very high case fatality rates. Here, we report the first naturally occurring human monoclonal antibodies (mAbs) against HeV receptor binding protein (RBP). All isolated mAbs neutralized HeV, and some also neutralized NiV. Epitope binning experiments identified five major antigenic sites on HeV-RBP. Animal studies demonstrated that the most potent cross-reactive neutralizing mAbs, HENV-26 and HENV-32, protected ferrets in lethal models of infection with NiV Bangladesh 3 days after exposure. We solved the crystal structures of mAb HENV-26 in complex with both HeV-RBP and NiV-RBP and of mAb HENV-32 in complex with HeV-RBP. The studies reveal diverse sites of vulnerability on RBP recognized by potent human mAbs that inhibit virus by multiple mechanisms. These studies identify promising prophylactic antibodies and define protective epitopes that can be used in rational vaccine design.Early embryogenesis is a conserved and self-organized process. In the mammalian embryo, the potential for self-organization is manifested in its extraordinary developmental plasticity, allowing a correctly patterned embryo to arise despite experimental perturbation. The underlying mechanisms enabling such regulative development have long been a topic of study. In this Review, we summarize our current understanding of the self-organizing principles behind the regulative nature of the early mammalian embryo. We argue that geometrical constraints, feedback between mechanical and biochemical factors, and cellular heterogeneity are all required to ensure the developmental plasticity of mammalian embryo development.In this issue of Cell, Zuccaro and colleagues show that on-target Cas9-mediated double-strand breaks cause chromosome loss or mis-repair of the disease allele in > 90% of human embryos. End joining repair pathways dominate, causing small insertions or deletions, which raises serious questions about using double-strand breaks for "gene surgery".Defining the principles underlying the organization of biomolecules within cells is a key challenge of current cell biology research. Persson et al. now identify a powerful layer of regulation that allows cells to decouple diffusion from temperature by modulating their intracellular viscosity. This so-called viscoadaptation is mediated through trehalose and glycogen activities, which alter diffusion dynamics and self-assembly propensity inside the cell globally.Coral reefs are on a steep trajectory of decline, with natural recovery in many areas unlikely.1-3 Eutrophication, overfishing, climate change, and disease have fueled the supremacy of seaweeds on reefs,4,5 particularly in the Caribbean, where many reefs have undergone an ecological phase shift so that seaweeds now dominate previously coral-rich reefs.6-8 Discovery of the powerful grazing capability of the Caribbean's largest herbivorous crab (Maguimithrax spinosissimus)9 led us to test the effectiveness of their grazing on seaweed removal and coral reef recovery in two experiments conducted sequentially at separate locations 15 km apart in the Florida Keys (USA). In those experiments, we transplanted crabs onto several patch reefs, leaving others as controls (n = 24 reefs total; each 10-20 m2 in area) and then monitored benthic cover, coral recruitment, and fish community structure on each patch reef for a year. We also compared the effectiveness of crab herbivory to scrubbing reefs by hand to remove algae. Crabs reduced the cover of seaweeds by 50%-80%, resulting in a commensurate 3-5-fold increase in coral recruitment and reef fish community abundance and diversity.
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