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Atomistic simulations of dislocation mobility reveal that bodycentered cubic (BCC) high-entropy alloys (HEAs) are distinctly different from traditional BCC metals. HEAs are concentrated solutions in which composition fluctuation is almost inevitable. The resultant inhomogeneities, while locally promoting kink nucleation on screw dislocations, trap them against propagation with an appreciable energy barrier, replacing kink nucleation as the rate-limiting mechanism. Edge dislocations encounter a similar activated process of nanoscale segment detrapping, with comparable activation barrier. As a result, the mobility of edge dislocations, and hence their contribution to strength, becomes comparable to screw dislocations.

Introduction: Basal cell carcinoma (BCC) is the most prevalent type of skin cancer worldwide. Despite its low metastatic potential, certain subtypes present an aggressive clinical course. Part II focuses on the different dermoscopic patterns observed in BCC, depending on the lesion subtype, its location on the body, the patient’s age, the size of the tumor, and skin phototype. Methods: A search of the PubMed database was conducted for studies reporting dermoscopic findings in BCC across all body locations, histopathologic subtypes, tumor sizes, ages of onset and skin phototypes. Results: There are no dermoscopic features indicative of a particular BCC subtype. However, arborizing, truncated or glomerular vessels, shiny white lines, ulceration, white areas, absence of pink zones and large blue-gray ovoid nests suggest high-risk BCCs (morpheaform, micronodular, infiltrative, basosquamous). Pigmented features can occur in all BCC types, though increased pigmentation indicates less aggressive subtypes (nodular, superficial, fibroepithelioma of Pinkus, adenoid). BCCs most commonly develop on the head, typically presenting as nodular and non-pigmented tumors. Those on the nose, eyes and ears may be more aggressive and prone to recurrence. On the trunk, BCCs are usually superficial and pigmented. Lower limb lesions often show polymorphous vessels rather than arborizing ones, which makes the dermoscopic diagnosis challenging. Dermoscopy aids early detection, with larger tumors exhibiting more established features but no size-specific patterns. Aggressive subtypes display similar dermoscopic findings regardless of size. Conclusions: Dermoscopy is a valuable tool for the early detection of BCC, though no specific dermoscopic features can definitively identify subtypes. High-risk BCCs can be suspected when distinct vascular and structural patterns are present, particularly in lesions located on the face, especially around the nose, eyes and ears, while pigmented features may indicate less aggressive subtypes.

The approval of bedaquiline has placed energy metabolism in the limelight as an attractive target space for tuberculosis antibiotic development. While bedaquiline inhibits the mycobacterial F 1 F 0 ATP synthase, small molecules targeting other components of the oxidative phosphorylation pathway have been identified. Of particular interest is Telacebec (Q203), a phase 2 drug candidate inhibitor of the cytochrome bcc:aa 3 terminal oxidase. A functional redundancy between the cytochrome bcc:aa 3 and the cytochrome bd oxidase protects M .  tuberculosis from Q203‐induced death, highlighting the attractiveness of the bd ‐type terminal oxidase for drug development. Here, we employed a facile whole‐cell screen approach to identify the cytochrome bd inhibitor ND‐011992. Although ND‐011992 is ineffective on its own, it inhibits respiration and ATP homeostasis in combination with Q203. The drug combination was bactericidal against replicating and antibiotic‐tolerant, non‐replicating mycobacteria, and increased efficacy relative to that of a single drug in a mouse model. These findings suggest that a cytochrome bd oxidase inhibitor will add value to a drug combination targeting oxidative phosphorylation for tuberculosis treatment. Synopsis The functional redundancy of two terminal oxidases in mycobacteria limits the efficacy of phase 2 clinical candidate Telacebec (Q203). In this study we identified a cytochrome bd oxidase inhibitor ND‐011992 that together with Q203 forms a bactericidal drug combination against Mycobacterium tuberculosis . ND‐011992 was identified and validated as an inhibitor of the Cytochrome bd oxidase. ND‐011992 and Q203 jointly enhanced inhibition of oxygen respiration, intracellular ATP depletion, and bactericidal activity. The drug combination was active against M. tuberculosis clinical isolates of various lineages as well as against MDR‐ and XDR‐TB isolates. The addition of ND‐011992 to Q203 treatment did not significantly alter the frequency of resistance to treatment, suggesting there is limited added risk of rapid emergence of escape mutants. The ND‐011992‐Q203 combination showed enhanced killing effect in the animal study compared to that of single drugs, demonstrating translatability in an in vivo model. Graphical Abstract The functional redundancy of two terminal oxidases in mycobacteria limits the efficacy of phase 2 clinical candidate Telacebec (Q203). In this study we identified a cytochrome bd oxidase inhibitor ND‐011992 that together with Q203 forms a bactericidal drug combination against Mycobacterium tuberculosis .

The increasing prevalence and worldwide distribution of multidrug-resistant bacterial pathogens is an imminent danger to public health and threatens virtually all aspects of modern medicine. Particularly concerning, yet insufficiently addressed, are the members of the Burkholderia cepacia complex (Bcc), a group of at least twenty opportunistic, hospital-transmitted, and notoriously drug-resistant species, which infect and cause morbidity in patients who are immunocompromised and those afflicted with chronic illnesses, including cystic fibrosis (CF) and chronic granulomatous disease (CGD). One potential solution to the antimicrobial resistance crisis is phage therapy—the use of phages for the treatment of bacterial infections. Although phage therapy has a long and somewhat checkered history, an impressive volume of modern research has been amassed in the past decades to show that when applied through specific, scientifically supported treatment strategies, phage therapy is highly efficacious and is a promising avenue against drug-resistant and difficult-to-treat pathogens, such as the Bcc. In this review, we discuss the clinical significance of the Bcc, the advantages of phage therapy, and the theoretical and clinical advancements made in phage therapy in general over the past decades, and apply these concepts specifically to the nascent, but growing and rapidly developing, field of Bcc phage therapy.

We report the observation of extraordinarily robust zero-resistance superconductivity in the pressurized (TaNb)0.67(HfZrTi)0.33 high-entropy alloy—a material with a body-centered-cubic crystal structure made from five randomly distributed transition-metal elements. The transition to superconductivity (TC ) increases from an initial temperature of 7.7 K at ambient pressure to 10 K at ∼60 GPa, and then slowly decreases to 9 K by 190.6 GPa, a pressure that falls within that of the outer core of the earth. We infer that the continuous existence of the zero-resistance superconductivity from 1 atm up to such a high pressure requires a special combination of electronic and mechanical characteristics. This high-entropy alloy superconductor thus may have a bright future for applications under extreme conditions, and also poses a challenge for understanding the underlying quantum physics.

Energy efficiency is motivating the search for new high-temperature (high-T) metals. Some new body-centered-cubic (BCC) random multicomponent “high-entropy alloys (HEAs)” based on refractory elements (Cr-Mo-Nb-Ta-V-W-Hf-Ti-Zr) possess exceptional strengths at high temperatures but the physical origins of this outstanding behavior are not known. Here we show, using integrated in-situ neutron-diffraction (ND), high-resolution transmission electron microscopy (HRTEM), and recent theory, that the high strength and strength retention of a NbTaTiV alloy and a high-strength/low-density CrMoNbV alloy are attributable to edge dislocations. This finding is surprising because plastic flows in BCC elemental metals and dilute alloys are generally controlled by screw dislocations. We use the insight and theory to perform a computationally-guided search over 10 7 BCC HEAs and identify over 10 6 possible ultra-strong high-T alloy compositions for future exploration. The strength in BCC high-entropy alloys is associated with the type of mobile dislocations. Here the authors demonstrate by means of an ample array of experimental techniques that edge dislocations can control the strength of BCC high-entropy alloys.

Sea ice formation over open water exerts critical control on polar atmosphere‐ocean‐ice interactions, but is only crudely represented in sea ice models. In this study, a collection depth parameterization of new ice for flux polynya models is modified by including the sea ice concentration and ice growth rate as additional factors. We evaluated it in a climate model BCC‐CSM2‐MR and found that it improves simulation of Antarctic sea ice concentration and thickness in most of Indian and Atlantic sectors. Disagreement between the observed Antarctic sea ice expansion during 1981–2014 and the modeled decline still exists but is mitigated when the modified scheme is implemented. Further analysis indicates that these improvements are associated with the overcoming of premature closure of open water, which enhances the response of ocean to surface wind intensification during 1981–2014, and consequently slowdowns the sea surface temperature increase and the resulting Antarctic sea ice reduction. Plain Language Summary Open water ice formation critically modulates sea ice variations and the associated polar atmosphere‐ocean interaction, but is not well represented in sea ice models. In this study, a modified collection depth parameterization of new ice based on an existing scheme is presented after including sea ice concentration and ice growth rate as additional factors. We evaluated this modified scheme in BCC‐CSM2‐MR and found that it can improve the simulation of mean Antarctic sea ice thickness and concentration in winter as well as Antarctic sea ice expansion from 1981 to 2014. Further analysis implies that these improvements can be attributed to the overcoming of the premature closure of open water areas in model simulations. Key Points A modified collection thickness parameterization of new ice suitable for large‐scale climate simulations is presented It improves the simulation of Antarctic sea ice thickness and concentration, as well as Antarctic sea ice expansion during 1981–2014 The improved simulations can be attributed to the overcoming of the premature closure of open water areas where new ice forms

Body-centered cubic metals including steels and refractory metals suffer from an abrupt ductile-to-brittle transition (DBT) at a critical temperature, hampering their performance and applications. Temperature-dependent dislocation mobility and dislocation nucleation have been proposed as the potential factors responsible for the DBT. However, the origin of this sudden switch from toughness to brittleness still remains a mystery. Here, we discover that the ratio of screw dislocation velocity to edge dislocation velocity is a controlling factor responsible for the DBT. A physical model was conceived to correlate the efficiency of Frank–Read dislocation source with the relative mobility of screw versus edge dislocations. A sufficiently high relative mobility is a prerequisite for the coordinated movement of screw and edge segments to sustain dislocation multiplication. Nanoindentation experiments found that DBT in chromium requires a critical mobility ratio of 0.7, above which the dislocation sources transition from disposable to regeneratable ones. The proposed model is also supported by the experimental results of iron, tungsten, and aluminum.

Body-centered cubic refractory metallic materials exhibit excellent high-temperature strength, but often suffer from brittle intergranular fracture due to the recrystallization-induced enrichment of trace elements at grain boundaries (GBs). Here, we report a fully-recrystallized pure molybdenum (Mo) material with room temperature (RT) superplasticity, fabricated by a facile method of powder metallurgy, Y-type hot rolling and annealing. By engineering the ultralow concentration of O at GBs, the inherent GB brittleness of Mo can be largely eliminated, which, in conjunction with high fractions of soft texture and low angle GBs, enables a significant development of ordered dislocation networks and the effective dislocation transmission across low angle GBs. Synergy of these factors greatly suppress the brittle intergranular fracture of Mo, contributing to an enhanced deformability of 108.7% at RT. These findings should have general implication for fabricating a broad class of refractory metals and alloys toward harsh applications. Body-centered cubic refractory metals are known to exhibit excellent high-temperature strength, but often suffer from brittle fracture. Here, the authors produce a bulk pure Mo with stable fine-grain structure after powder metallurgy, Y-type hot rolling and ultra-high temperature annealing (1000~1700 °C) that exhibits room temperature superplasticity.

Basal cell carcinomas (BCCs) are common skin cancers that tend to appear on sun-exposed skin. Pathobiologically, activation of the Hedgehog signaling pathway characterizes the majority of cases. In general, BCCs are slow-growing and rarely metastasize. Nevertheless, they are locally invasive and can be destructive. While typical cases are diagnosed based on clinical findings, the clinicopathological manifestations are varied. Consequently, skin biopsy is essential to confirm the diagnosis and evaluate the risk of recurrence. In the treatment of primary lesions, the initial goal is to complete tumor removal, whether by conventional surgical excision, Mohs micrographic surgery, cryosurgery, electrodesiccation and curettage, topical application of imiquimod or fluorouracil, photodynamic therapy, or radiation therapy. Of these treatments, surgical excision and Mohs surgery are the most commonly used because of their association with a low recurrence rate and the ability to confirm residual tumor pathologically. However, other treatment options may be preferred according to patient condition, tumor location, and risk of recurrence. In the treatment of metastatic or locally advanced lesions, smoothened inhibitors, which inhibit Hedgehog signaling pathway activation, were recently approved and impressive tumor shrinkage effects have been described. Although the exact prognosis of metastatic BCC has not been analyzed, it is probably poor due to the rarity of such condition. However, emerging molecular targeting agents hold therapeutic promise.