Summary: The rise of multidrug-resistant (MDR) bacteria threatens global health by eroding the efficacy of existing antibiotics, underscoring the urgency of alternative therapies like phage therapy. Although bacteriophages are promising owing to their abundance, diversity, and potent bactericidal activity, their therapeutic durability is compromised by the rapid emergence of phage resistance. Here, we explore receptor complementarity as a proof-of-concept rational strategy to overcome this bottleneck. This study demonstrates that phage resistance imposes substantial fitness costs while still permitting bacterial survival under phage pressure. By isolating phages with distinct receptor dependencies, we constructed receptor-diverse phage cocktails that decreased the frequency of phage resistance. Notably, these receptor-informed cocktails suppressed phage resistance in vitro and yielded improved prophylactic and therapeutic efficacy in the Galleria mellonella preclinical in vivo model. Collectively, this work offers preclinical proof-of-concept for receptor-guided cocktail design to enhance the performance of phage-based interventions against MDR pathogens.
The rise of multidrug-resistant (MDR) bacteria threatens global health by eroding the efficacy of existing antibiotics, underscoring the urgency of alternative therapies like phage therapy. Although bacteriophages are promising owing to their abundance, diversity, and potent bactericidal activity, their therapeutic durability is compromised by the rapid emergence of phage resistance. Here, we explore receptor complementarity as a proof-of-concept rational strategy to overcome this bottleneck. This study demonstrates that phage resistance imposes substantial fitness costs while still permitting bacterial survival under phage pressure. By isolating phages with distinct receptor dependencies, we constructed receptor-diverse phage cocktails that decreased the frequency of phage resistance. Notably, these receptor-informed cocktails suppressed phage resistance in vitro and yielded improved prophylactic and therapeutic efficacy in the Galleria mellonella preclinical in vivo model. Collectively, this work offers preclinical proof-of-concept for receptor-guided cocktail design to enhance the performance of phage-based interventions against MDR pathogens.
Adjustable ring-mode (ARM) laser welding mitigates thermal asymmetry and porosity in dissimilar-thickness aluminum lap joints for power batteries. A multi-physics thermal-fluid model with combined volumetric heat source simulates 1.5 + 1 mm 1060 alloy at 100 mm/s under four power cases, validated within 14.29% error. Keyhole volume <0.55 mm3 causes unstable penetration and vapor trapping; >0.59 mm3, stable penetration ≥0.25 mm3 keeps open vapor channels and reduces porosity. Recoil-pressure spatial standard deviation (SSD) evolution, not magnitude, controls pore susceptibility: case 3 holds SSD = 151.60 Pa (70–90 ms, maintain-then-smooth trend, 2.333% porosity), while case 2 rapidly falls to 106.06 Pa with 0.504 mm3 keyhole volume and 4.251% porosity. Optimal ring-core power ratio: 0.8–1.2. Combined volume threshold and SSD evolution clarify pore suppression and guide power battery joining optimization.
Chemotherapy resistance is a challenge in the management of epithelial ovarian cancer (EOC). The regulation of N6-methyladenosine (m6A) RNA modification has emerged as a potential strategy to overcome this resistance. Peptidyl Arginine Deiminase 2 (PADI2) was found to be upregulated and highly methylated in EOC samples, correlating with a poor prognosis. Downregulation of PADI2 inhibited colony formation, cell proliferation, and cisplatin (cDDP) resistance in EOC cells. METTL3 was identified as the m6A writer of PADI2 mRNA, while YTHDF2 recognized and bound the m6A-methylated PADI2 mRNA, enhancing its translation. This activation of the JAK2/STAT3 pathway facilitated cDDP resistance in EOC cells both in vitro and in vivo. Knockdown of METTL3 or YTHDF2 decreased PADI2 mRNA expression and suppressed tumor growth and cDDP resistance. In conclusion, a mechanism was identified whereby m6A-modified PADI2 induces cDDP resistance and EOC progression, providing a potential target for the development of therapeutic strategies for EOC treatment.
Acute kidney injury (AKI) is a frequent complication in hospitalized patients and is associated with increased mortality. Despite its relevance, no targeted therapies are available. RNA-binding proteins (RBPs) are essential regulators of cellular function and have been implicated in AKI, but a comprehensive analysis of their role is lacking. We investigated RBP regulation in porcine kidneys subjected to ischemia-reperfusion injury following cardiopulmonary resuscitation. To assess evolutionary conservation, RBP profiles were also obtained from human kidney tissue. After ischemia-reperfusion injury, we found RBPs exhibiting altered RNA-binding capacity, including metabolic enzymes previously implicated in ischemic stress. These findings suggest that energy metabolism is linked to RNA regulation during kidney injury. Renal ischemia-reperfusion injury alters the RNA-binding landscape, affecting both regulatory and metabolic RBPs. The conservation of these proteins in human kidneys highlights their translational relevance and identifies RNA-protein interactions as potential therapeutic targets in AKI.
