Suboptimal Activity Research Articles

PHYSICAL ACTIVITY AND SLEEP PATTERNS AS DETERMINANTS OF ACADEMIC PERFORMANCE IN SECONDARY SCHOOL TEENAGERS: A DESCRIPTIVE CROSS-SECTIONAL STUDY

Background: Physical health factors, notably physical activity and sleep quality, play a crucial role in adolescents' academic performance. Regular physical activity has been associated with enhanced cognitive functions, including improved concentration and memory, as well as better mood regulation. Adequate sleep, typically 8–10 hours per night for teenagers, is essential for processes such as memory consolidation and maintaining attention. Insufficient sleep and physical inactivity have been linked to diminished academic outcomes and increased absenteeism. Objective: This study aimed to assess the levels of physical activity and sleep patterns among secondary school teenagers and to evaluate their academic performance. Methods: A descriptive cross-sectional study was conducted among 384 students from private secondary schools in Bahawalnagar. Participants were selected using a census sampling technique. Data collection instruments included the International Physical Activity Questionnaire (IPAQ) to measure physical activity levels, the Pittsburgh Sleep Quality Index (PSQI) to assess sleep quality, and the Academic Performance Scale (APS) to evaluate academic outcomes. Descriptive statistics, including means, standard deviations, frequencies, and percentages, were calculated using SPSS version 27. Results: Among the participants, 32.8% exhibited low to moderate levels of physical activity. Regarding sleep quality, 37.2% reported good sleep, while 60% experienced disturbed sleep patterns. Despite these physical health challenges, 65.6% of the students achieved excellent academic performance. The analysis indicated that both physical activity levels and sleep quality had a substantial impact on academic outcomes. Conclusion: The findings suggest that a significant portion of secondary school teenagers have suboptimal physical activity levels and sleep patterns. Nonetheless, a majority attained excellent academic performance, indicating that additional factors may contribute to academic success. Interventions aimed at improving physical activity and sleep quality could potentially enhance academic outcomes.

Comparative biophysical study of clinical surfactants using constrained drop surfactometry.

Surfactant replacement therapy is crucial in managing neonatal respiratory distress syndrome (RDS). Currently licensed clinical surfactants in the United States and Europe, including Survanta, Infasurf, Curosurf, and Alveofact, are all derived from bovine or porcine sources. We conducted a comprehensive examination of the biophysical properties of these four clinical surfactant preparations under physiologically relevant conditions, using constrained drop surfactometry (CDS). The assessed biophysical properties included the adsorption rate, quasi-static and dynamic surface activity, resistance to surfactant inhibition by meconium, and the morphology of the adsorbed surfactant films. This comparative study unveiled distinct in vitro biophysical properties of these clinical surfactants and revealed correlations between their chemical composition, lateral film structure, and biophysical functionality. Notably, at 1 mg/mL, Survanta exhibited a significantly lower adsorption rate compared with the other preparations at the same surfactant concentration. At 10 mg/mL, Infasurf, Curosurf, and Survanta all demonstrated excellent dynamic surface activity, whereas Alveofact exhibited the poorest quasi-static and dynamic surface activity. The suboptimal surface activity of Alveofact is found to be correlated with its unique monolayer-predominant morphology, in contrast to other surfactants forming multilayers. Curosurf, in particular, showcased superior resistance to biophysical inhibition by meconium compared with other preparations. Understanding the diverse biophysical behaviors of clinical surfactants provides crucial insights for precision and personalized design in treating RDS and other respiratory conditions. The findings from this study contribute valuable perspectives for the development of more efficacious and fully synthetic surfactant preparations.NEW & NOTEWORTHY A thorough investigation into the biophysical properties of four animal-derived clinical surfactant preparations was conducted through constrained drop surfactometry under physiologically relevant conditions. This comparative study unveiled unique in vitro biophysical characteristics among these clinical surfactants, establishing correlations between their chemical composition, lateral film structure, and biophysical functionality. The acquired knowledge offers essential insights for the precise and personalized design of clinical surfactant for the treatment of respiratory distress syndrome and other respiratory conditions.

Two-Level regulation photocatalytic activity of Bi2WO6/COFs with ligand engineering and piezoelectric field for Highly-Efficient degradation of antibiotics

Covalent organic frameworks (COFs) have attracted significant attention in photocatalytic water purification due to their structural designability and sufficiently negative conduction band edges. However, the limited oxidation capacity of single COFs and the low utilization rate of photogenerated carriers result in suboptimal catalytic activity. To address these challenges, we propose a two-level regulation strategy that involves ligand engineering and the introduction of a piezoelectric field to enhance the photocatalytic performance of COF-based photocatalysts. In this study, we combined the piezoelectric material Bi2WO6 with COFs modified with different ligands to design a series of Bi2WO6/R-COFs (R=H, F, CH3O) heterojunctions. Modifying COFs with –OCH3 functional group tuned the local electron distribution, thereby remarkably improving photogenerated electrons transfer rate constant. Besides, the incorporation of Bi2WO6 generated a piezoelectric field under ultrasound, which provides a strong driving force for photocatalytic. Meanwhile, the construction of the heterojunctions offered multi-channel for the generation of reactive oxygen species. As a result, the photocatalytic degradation rate of Bi2WO6/CH3O-COFs reached 93.5 % toward sulfamethoxazole within 48 min under ultrasound-coupled light irradiation, which is nearly three times higher than Bi2WO6/H-COFs. Furthermore, Bi2WO6/CH3O-COFs demonstrated superior degradation performance for other pollutants, including p-chlorophenol, bisphenol A, tetracycline, and phenol, with degradation efficiencies of 99.0 %, 98.4 %, 93.5 % and 88.1 %, respectively. This work proposes a two-level modulation strategy that significantly enhances the antibiotic degradation performance of COF-based catalysts, offering a new perspective for the design of photocatalysts for environmental remediation.

Ionic liquid-derived carbon dots with enhanced antibacterial activity and antibiofilm capability for treatment of MRSA-infected wounds

Bacterial resistance to antibiotics has rendered bacterial infections an escalating threat to public health, prompting numerous researchers to strive towards the development of novel antimicrobial agents. Designable ionic liquids (ILs) have gained increasing prominence in the field of antibacterials. However, certain ILs exhibit suboptimal antimicrobial activity. In this study, we synthesized ionic liquid-derived carbon dots (IL-CDs: VOIMBr-CD) through vinyl and epoxy group reactions, resulting in enhanced antimicrobial efficacy. The VOIMBr-CD retains the antibacterial structure characteristic of ILs, including a positively charged imidazolium group and long alkyl chain. Moreover, VOIMBr-CD demonstrates selective antibacterial action against Staphylococcus aureus (S. aureus) while effectively inhibiting S. aureus biofilm growth. Notably, the antibacterial efficacy of VOIMBr-CD against methicillin-resistant Staphylococcus aureus (MRSA), surpasses vancomycin (Van). We conducted comprehensive investigations into the selective antibacterial mechanism of VOIMBr-CD which primarily involves electrostatic interactions, hydrophobic interactions, as well as generation of reactive oxygen species (ROS) within bacteria cells. In vivo experiments demonstrated that VOIMBr-CD significantly alleviate inflammation, facilitated collagen deposition and angiogenesis, and effectively expedited wound healing in MRSA-infected mice models; thus, highlighting their potential as therapeutic candidates for diseases resembling MRSA infection-like conditions. Importantly, this work presents a novel approach utilizing IL-based materials for developing effective antibacterials thereby offering new insights into the application prospects of IL-derived materials.

Bacteria/Nanozyme Composites: New Therapeutics for Disease Treatment.

Bacterial therapy is recognized as a cost-effective treatment for several diseases. However, its development is hindered by limited functionality, weak inherent therapeutic effects, and vulnerability to harsh microenvironmental conditions, leading to suboptimal treatment activity. Enhancing bacterial activity and therapeutic outcomes emerges as a pivotal challenge. Nanozymes have garnered significant attention due to their enzyme-mimic activities and high stability. They enable bacteria to mimic the functions of gene-edited bacteria expressing the same functional enzymes, thereby improving bacterial activity and therapeutic efficacy. This review delineates the therapeutic mechanisms of bacteria and nanozymes, followed by a summary of strategies for preparing bacteria/nanozyme composites. Additionally, the synergistic effects of such composites in biomedical applications such as gastrointestinal diseases and tumors are highlighted. Finally, the challenges of bacteria/nanozyme composites are discussed and propose potential solutions. This study aims to provide valuable insights to offer theoretical guidance for the advancement of nanomaterial-assisted bacterial therapy.

Dimensional Upgrade Induced Enriched Active Sites and Intensified Intramolecular Electron Donor–Acceptor Interaction to Boost Oxygen Reduction Electrocatalysis

AbstractConjugated 2D covalent organic frameworks (2D‐COFs) have garnered interest as potential cost‐efficient noble‐metal‐free electrocatalysts, owing to their structural flexibility, well‐defined molecular architecture, high compatibility, and environmental sustainability. However, their suboptimal activity, primarily attributed to their low active site utilization and limited electron transfer ability, considerably impedes their implementation in real‐world electrocatalytic systems. Herein, the molecular dimensionality of a 2D‐COF containing tris‐triazine ring (2D‐Tr‐COF) is upgraded to generate its 3D counterpart (3D‐Tr‐COF), enabling a direct comparison between 2D‐ and 3D‐ COFs. These findings reveal that slightly altering the spatial structure in plane (from 2D to 3D) by substituting amine building blocks leads to significant variations in molecular architecture and performance for oxygen reduction reaction. The results indicate that 3D‐Tr‐COF with enlarged lattice spacing, more active species, and reduced conjugated degree, possesses enriched active sites. Moreover, the intensified intramolecular electron donor–acceptor interaction between the tris‐triazine ring and its neighboring imino linkage of 3D‐Tr‐COF optimizes the electronic/band structure and facilitates the charge transfer, resulting in enhanced intrinsic activity compared to 2D‐Tr‐COF. The extensively optimized 3D‐Tr‐COF demonstrates a half‐wave potential of 0.833 V, on par with the state‐of‐the‐art Pt/C. These findings offer valuable insights into dimension modulation strategies for COF‐based electrocatalyst designing.

Chimeric antigen receptor T-cell therapy for T-cell acute lymphoblastic leukemia.

Chimeric antigen receptor (CAR) T-cell therapy is a new and effective treatment for patients with hematologic malignancies. Clinical responses to CAR T cells in leukemia, lymphoma, and multiple myeloma have provided strong evidence of the antitumor activity of these cells. In patients with refractory or relapsed B-cell acute lymphoblastic leukemia (ALL), the infusion of autologous anti-CD19 CAR T cells is rapidly gaining standard-of-care status and might eventually be incorporated into frontline treatment. In T-ALL, however, leukemic cells generally lack surface molecules recognized by established CAR, such as CD19 and CD22. Such deficiency is particularly important, as outcome is dismal for patients with T-ALL that is refractory to standard chemotherapy and/or hematopoietic stem cell transplant. Recently, CAR T-cell technologies directed against T-cell malignancies have been developed and are beginning to be tested clinically. The main technical obstacles stem from the fact that malignant and normal T cells share most surface antigens. Therefore, CAR T cells directed against T-ALL targets might be susceptible to self-elimination during manufacturing and/or have suboptimal activity after infusion. Moreover, removing leukemic cells that might be present in the cell source used for CAR T-cell manufacturing might be problematic. Finally, reconstitution of T cells and natural killer cells after CAR T-cell infusion might be impaired. In this article, we discuss potential targets for CAR T-cell therapy of T-ALL with an emphasis on CD7, and review CAR configurations as well as early clinical results.

Comprehensive characterization of octahedral Co3O4 doped with Cu induces oxygen vacancies as a battery-type redox active electrode material for supercapacitors

The urgent need to combat global warming has spurred the exploration of renewable energy solutions, among which the supercapacitor has emerged as a promising contender for efficient energy storage in crucial applications. While battery-type electrode materials (BTMs), notably Co3O4, have shown impressive electrochemical performance in recent years, their inherent limitations, such as low conductivity, restricted surface area, and suboptimal electrochemical activity, pose challenges to their utility. Doping has emerged as a strategic solution to address these issues by modifying the crystal structure, surface morphology, specific surface area, electronic conductivity, and chemical stability of the host material, thereby enhancing its electrochemical performance. This study uses a combustion synthesis method to engineer octahedral Co3O4 with Cu-doping. We obtained three different samples of Co3O4: one undoped Co3O4, doped with 3 % Cu (3%Cu–Co3O4), and 6 % Cu (6%Cu–Co3O4). The addition of Cu not only changed the crystal structure and surface morphology but also impacted the surface area and defects (oxygen vacancies) in Co3O4, affecting its electrochemical performance. This doping method effectively controlled the oxygen vacancy defect content, as verified meticulously by X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), Raman spectroscopy, and UV–Vis diffuse reflectance spectroscopy (UV–Vis DRS). Particularly, the 6%Cu–Co3O4 configuration demonstrated significantly improved specific capacity (155.5 mA h g−1/559.8C g−1 at 1 A g−1) and rate performance (67 %), outperforming both 3%Cu–Co3O4 and undoped Co3O4. Additionally, it exhibited superior cycling stability with 91 % retention of the maximum specific capacity after 5000 cycles. Consequently, this study offers valuable insights into designing defect-engineered battery-type electrode materials for hybrid supercapacitors, which could significantly enrich their efficiency.

Enhanced CO2 methanation activity of Ni-Rutile-based catalyst by tuning the metal−support interaction with Fe doping

CO2 methanation is an effective way for CO2 recycling, and nickel-based catalysts have attracted much attention in this field due to their excellent CH4 selectivity and cost-effectiveness; however, their applications are limited by their suboptimal catalytic activity. In this work, the catalytic activity of Ni-rutile-based catalysts was increased by almost an order of magnitude simply by doping the rutile with Fe. Series characterizations show that three factors that mainly contributed to the improved catalytic performance of the Ni/Fe-Rutile, which are the reduction of the Ni size, the increase of the basic sites, and the inhibition of the encapsulation of the Ni particles by the support. With Fe doping, the OH and oxygen vacancies on the rutile surface were reduced, which made the support difficult to reduce and thus suppressed the encapsulation of Ni by the support. As a result, the number of exposed active sites on the Ni/Fe-Rutile which with a smaller Ni size was further successfully increased, and the catalytic activity was significantly improved. This study provides new ideas for the design of activity-enhanced supported catalysts from the perspective of tuning the metal-support interaction and may be applicable to other reducible oxide-supported metal catalysts.

Abstract 3915: BMS-986442 (AGEN1777), a novel TIGIT/CD96 bispecific antibody, demonstrates superior monotherapy and combination activity versus conventional anti-TIGIT antibodies in preclinical models

Abstract TIGIT immune checkpoint blockade can enhance anti-tumor immunity, however conventional anti-TIGIT antibodies have shown suboptimal activity in the clinic. Here, we present the first preclinical disclosure of BMS-986442 (AGEN1777), a novel and fully human Fc-enhanced bispecific antibody against TIGIT and CD96 co-receptor, that demonstrates superior pharmacological activity compared to conventional TIGIT monospecific antibodies (mAbs). Gene expression of TIGIT, CD96, and the co-stimulatory counter-receptor CD226 in tumor samples from patients with cancer was identified using bulk and single cell RNA-sequencing. To target this interaction, Fc-engineered knob-in-hole bispecific antibodies against TIGIT and CD96 were developed and affinity optimized to achieve potent and complete blockade of TIGIT and CD96 ligand interactions. BMS-986442 and corresponding monospecific anti-TIGIT and anti-CD96 monoclonal antibodies were evaluated with or without anti-PD-1 in a variety of human T and NK cell stimulation assays. Mouse surrogate TIGIT/CD96 bispecific antibodies were developed and evaluated as monotherapy or together with anti-PD-1 in colorectal CT26 and breast orthotopic 4T1 tumor bearing mice. In CT26 and 4T1 tumor-bearing mouse models, the Fc-enhanced TIGIT/CD96 bispecific antibody demonstrated superior tumor control compared to either anti-TIGIT, anti-CD96, or the combination of anti-TIGIT and anti-CD96 mAbs. Tumor control was dependent on co-engaging activating Fcγ receptors, as an Fc-silent bispecific antibody lacked anti-tumor activity. In the tumor microenvironment, efficacy was associated with increased frequency of CD226+ effector and TCF-1+ GrzB- memory precursor CD8 T cells, increased frequency and activation of cytotoxic NK cells, and increased activation of professional APCs, including B cells, MHC Class II monocytes, and dendritic cells as determined by expression of CD40, CD83, and CD86. In primary human in vitro assays, BMS-986442 potently enhanced T cell responsiveness and activation compared with conventional anti-TIGIT mAbs alone and in combination with anti-PD-1 (nivolumab). Lastly, BMS-986442 promoted superior NK cell activation in tumor co-culture assays. In conclusion, BMS-986442 demonstrated a differentiated FcγR-dependent mechanism-of-action to enhance innate and adaptive immune responses compared with anti-TIGIT or anti-CD96 mAbs. BMS-986442 is currently advancing in phase I clinical studies in patients with advanced solid cancers (NCT05543629). Citation Format: Rebecca Ward, Nicola Ramsay, Spencer Campbell, Hema Patel, Mark Bushell, Benjamin M. Morin, Beth Wensley, David A. Savitsky, Pilar Garcia-Broncano, Bishnu Joshi, Emmanuel Briend, Olga Ignatovich, Zahra Jawad, Nils-Petter Rudqvist, Nicholas Wilson, Dhan Chand. BMS-986442 (AGEN1777), a novel TIGIT/CD96 bispecific antibody, demonstrates superior monotherapy and combination activity versus conventional anti-TIGIT antibodies in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3915.

PKLR mutations in pyruvate kinase deficient Polish patients: Functional characteristics of c.101-1G > A and c.1058delAAG variants

Pyruvate kinase (PK) deficiency is a rare autosomal recessive disorder characterized by chronic hemolytic anemia of variable severity. Nine Polish patients with severe hemolytic anemia but normal PK activity were found to carry mutations in the PKLR gene encoding PK, five already known ones and one novel (c.178C > T). We characterized two of the known variants by molecular modeling (c.1058delAAG) and minigene splicing analysis (c.101-1G > A). The former gives a partially destabilized PK tetramer, likely of suboptimal activity, and the c.101-1G > A variant gives alternatively spliced mRNA carrying a premature stop codon, encoding a severely truncated PK and likely undergoing nonsense-mediated decay.

Effect of calcination temperature on Co/sepiolite catalyst for hydrogen production by ethanol steam reforming: Co speciation from phyllosilicate to spinel

Hydrogen production via ethanol steam reforming (ESR) was conducted over amorphous sepiolite (SEP) supported Co based catalysts, deeming as a green and sustainable strategy for renewable energy. However, the subtle regulation to the ESR reactivity of Co/SEP catalysts still remains a challenge. Given the structure sensitive property of ESR, calcination temperature, as a vital regulation parameter, was used to control the key physicochemical properties of catalysts. By various characterization techniques, the results revealed that a calcination temperature mediated metal-support interaction was manifested in the form of Co speciation evolution. With increasing calcination temperature, the occurrence states of Co species change from Co oxides to Co-phyllosilicate then to Co-Al spinel. The ESR experiments indicated that Co/SEP-600 catalyst possessed a suboptimal activity via a dehydrogenation route and a 50 h stability due to a compromising among Co-phyllosilicate dominated MSI, texture, Co0 nanoparticle size and acid-base property. The further improvement of calcination temperature only brought about a poor stability of Co/SEP-700 with a phase transformation or a low activity of Co/SEP-800 with an irreducible Co-Al spinel. Hence, the interaction type of Co with SEP framework Si/Al atoms determined the ESR reactivity of the catalysts, which was modulated by the calcination temperature. Additionally, abundant graphitic coke deposition on the agglomerated Co0 grains was attributed the weak MSI, such as Co/SEP-400, while a slight coke deposition appeared at Co/SEP-800 with an irreducible Co-Al spinel phase.

Compliance of patients with hypertension to muscular exercise and healthy diet: a cross-sectional study from Arar, Saudi Arabia

Objective: This study aimed to examine the compliance of patients with hypertension with muscular exercise and a healthy diet in Arar, Saudi Arabia. Methods: This prospective cross-sectional study was conducted among adults diagnosed with hypertension, who were recruited from healthcare facilities in Arar. Sociodemographic data were collected alongside the questionnaires namely Rapid Assessment of Physical Activity (RAPA) for physical activity assessment and the Rapid Eating Assessment for Participants - Shortened Version (REAPS) for dietary assessment. Results: Regarding the REAPS score, 27.6% out of 387 participants had a high-quality diet, 45.7% had a moderate-quality diet, and 26.6% had a low-quality diet. However, in terms of the RAPA score, 57.4% had suboptimal physical activity, while 42.6% had optimal physical activity levels. Moreover, the RAPA score had a statistically significant relation to education level (p-value=0.035) and occupational status (p-value=0.006). It also showed a statistically insignificant relation to gender. While REAPS score had a statistically insignificant relation to gender, education level, and occupation. Conclusion: The study revealed that a significant portion of patients with hypertension had suboptimal levels of compliance with muscular exercise and a healthy diet. While a notable percentage had a moderate-quality diet, a substantial proportion exhibited low-quality diets. Additionally, the majority of participants were categorized under suboptimal physical activity levels.

Two birds with one stone: Gold “bridging” both nanozyme and immunosensor for sensitive double-response detection of T-2 toxin

Developing immunosensors with nanozymes as signal labels has made a great deal of progress and is no longer a novel concept. But even then, several research obstacles, e.g., suboptimal activity, uncertain antibody coupling, and redundant processes, still remain and must be tackled in this frontier. In this study, we constructed a colorimetric and fluorescent double-response enzyme-linked immunosorbent assay using CeO2@Au heterojunctions as signal labels (CeO2@Au-TFNLISA) for sensitive detection of T-2 toxin. Gold nanoparticles (AuNPs) acting as a bridge for CeO2 can connect and realize the bidirectional improvement of CeO2@Au heterojunctions: (1) enhancing the nanozyme activity significantly by multiple effects (charge transfer, AuNPs assistance, substrate affinity, and oxygen vacancy, etc.); (2) improving the affinity between antibodies and labels through electrostatic incorporation. Meanwhile, in this system, nanozyme catalysis generates the first signal, and fluorescence quenching forms the second signal via the inner-filter effect (IFE) to avoid the inaccuracy result brought on by the off-laboratory environment. The CeO2@Au-TFNLISA has increased the sensitivity by 42 and 18 times in colorimetric (TNLISA) and fluorescent modes (FNLISA) compared with traditional ELISA (0.00852 ng/mL for TNLISA, 0.02011 ng/mL for FNLISA, 0.36492 ng/mL for traditional ELISA), respectively, and saved half of the detection time (from 135 min to 50 min) due to the weakened non-specific adsorption. As a result, the CeO2@Au-TFNLISA method is expected to gain strong momentum to advance the rapid and precise detection of T-2 in food.

Discovery of Novel, First-in-Class Allosteric Modulators of MALT1 Scaffolding Function with Differentiated Pharmacology for NFκB-Driven Malignancies

Constitutive activation of NFκB is an oncogenic driver for many lymphoid and selected solid tumor malignancies. BTK inhibitors, which affect the upstream NFκB pathway, have been successfully used in some diseases, but their utility is limited. The majority of DLBCL patients, for instance, are insensitive to BTK inhibition, supporting the need for alternative mechanisms to block NFκB-driven tumor progression. Knockdown of MALT1, a key component of the CBMT complex (CARD-BCL10-MALT1-TRAF6) involved in direct signal transduction of NFκB, is able to block NFκB-dependent DLBCL tumor growth in BTKi sensitive or resistant tumors, but pharmacologic modulation has been challenged by the dual-functionality of MALT1 in a complexed signalosome. MALT1 functions as the scaffolding component of the CBMT complex. Activated MALT1 recruits multiple proteins and directly activates NFκB canonical signaling. MALT1 also has protease activity that fine-tunes various signaling pathways including NFκB via the cleavage of many substrates. The scaffolding activity of MALT1 is critical for cancer cell survival. Most MALT1 inhibitors discovered so far only block protease activity, which results in incomplete NFκB inhibition, suboptimal anti-tumor activity, and the induction of severe autoimmunity due to protease inhibition. Using our Smart Allostery platform, we elucidated and then drugged a natural hotspot on MALT1 that selectively impacts scaffolding but not protease function. The series of scaffolding modulators demonstrate potent inhibition of MALT1 scaffolding activity with cellular IC 50 values ranging from 15 to 250 nM, while exerting minimal influence on MALT1 protease function. Unlike protease inhibitors, which only partially affect NFκB activity, scaffolding modulators completely inhibit the NFκB downstream signaling manifested by the suppression of NFκB activity with cellular IC 50 values ranging from 2 to 90 nM. Consequently, scaffolding modulators exhibit a superior and broader anti-proliferation profile compared to MALT1 protease inhibitors and BTK inhibitors in a panel of lymphoma cell lines. Pathway and genetic analyses indicate that B-cell lymphoma lines driven by NFκB are especially sensitive to scaffolding modulators. In vivo studies demonstrate a robust, dose-dependent tumor growth inhibition (TGI) by one representative scaffolding modulator in several B-cell lymphoma xenograft models. In a protease inhibitor sensitive ABC-DLBCL model, OCI-LY10, our scaffolding modulator achieved a maximal TGI of 94%, while a clinical MALT1 protease inhibitor showed 62% maximal TGI (p<0.001). In protease resistant NFκB driven DLBCL models, MALT1 scaffolding modulation resulted in tumor regression or stasis. These findings highlight the differentiated pharmacology of our scaffolding modulators. Distinct from protease inhibitors that suppress T cell activation and Treg population in vivo, scaffolding modulators also did not deplete Treg cells nor suppress T cell activation in a 14-day study. This potentially mitigates the risk of development of autoimmune disease caused by chronic MALT1 protease inhibition. In summary, we have discovered novel, first-in-class allosteric modulators of MALT1 scaffolding activities. These scaffolding modulators drive enhanced and broader anti-tumor effect in models resistant to MALT1 protease or BTK inhibitors and do so without immune dysregulation. Scaffolding modulation represents a potential best-in-class therapeutic opportunity to modulate MALT1 in patients with NFκB-driven malignancies.

2172. Activity of Cefiderocol and Comparator Agents Against Molecularly Characterized Multidrug-resistant Enterobacterales Clinical Isolates from United States Hospitals (2020–2022)

Abstract Background Cefiderocol (CFDC) is a siderophore cephalosporin that hijacks the iron transport system of Gram-negative bacteria to facilitate cell entry and reach its target. CFDC remains stable to hydrolysis in the presence of serine β-lactamases (ESBLs, KPC, and OXA-type carbapenemases) and metallo-β-lactamases (MBL). CFDC and comparator activities were analyzed against Enterobacterales (ENT), including molecularly characterized isolates, as part of the US SENTRY Antimicrobial Surveillance Program. Methods 11,884 ENT were collected from 33 sites in the USA in 2020–2022. Susceptibility (S) testing was performed by broth microdilution. CFDC testing utilized iron-depleted media. CLSI breakpoints were used. E. coli, K. pneumoniae, and P. mirabilis with ceftriaxone, ceftazidime, or aztreonam MIC ≥ 2 μg/mL plus any ENT displaying an MIC ≥ 2 μg/mL for imipenem (excluding P. mirabilis, P. penneri, and indole-positive Proteeae) or meropenem (MER) were subjected to genome sequencing and screening of β-lactamase genes. Results CFDC (99.8%S), imipenem-relebactam (IMR; 98.0%S), meropenem-vaborbactam (MEV; 100%S), and ceftazidime-avibactam (CZA; 100%S) were active against carbapenem-susceptible ENT that carried ESBL and/or AmpC genes (Table). CFDC (MIC50/90, 0.5/4 μg/mL; 97.6%S) and CZA (MIC50/90, 1/8 μg/mL; 91.5%S) were the most active agents against carbapenem-nonS isolates, whereas IMR (MIC50/90, 0.25/4 μg/mL; 81.2%S) and MEV (MIC50/90, 0.12/8 μg/mL; 87.9%S) had suboptimal activity. CFDC (MIC50/90, 0.5/4 μg/mL), IMR (MIC50/90, 0.12/0.5 μg/mL), MEV (MIC50/90, 0.03/1 μg/mL), and CZA (MIC50/90, 1/2 μg/mL) were active (98.7–100%S) against the KPC subset. CFDC (MIC, 2/4 μg/mL; 90.9%S) was also active against ENT carrying MBL genes, whereas CFDC (MIC, 0.5-2 μg/mL; 100%S) and CZA (0.5-4 μg/mL; 100%S) were active against isolates carrying blaOXA-48–like. Conclusion CFDC activity against ENT was consistent, regardless of isolate phenotypes or genotypes, including against isolates carrying carbapenemase genes other than blaKPC, where approved β-lactam/β-lactamase inhibitor combinations showed limited activity. These data emphasize CFDC as an important option for the treatment of infections caused by ENT and resistant subsets. Disclosures Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support John H. Kimbrough, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Valerie Kantro, BA, AbbVie: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Dee Shortridge, PhD, Melinta: Grant/Research Support|Shionogi: Grant/Research Support Helio S. Sader, MD, PhD, FIDSA, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Entasis: Grant/Research Support|Melinta: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support

Protection against Aβ-induced neuronal damage by KU-32: PDHK1 inhibition as important target.

A feature of most neurodegenerative diseases is the presence of "mis-folded proteins" that form aggregates, suggesting suboptimal activity of neuronal molecular chaperones. Heat shock protein 90 (Hsp90) is the master regulator of cell responses to "proteotoxic" stresses. Some Hsp90 modulators activate cascades leading to upregulation of additional chaperones. Novobiocin is a modulator at the C-terminal ATP-binding site of Hsp90. Of several novobiocin analogs synthesized and tested for protection against amyloid beta (Aβ)-induced neuronal death, "KU-32" was the most potent in protecting primary neurons, but did not increase expression of other chaperones believed to help clear misfolded proteins. However, KU-32 reversed Aβ-induced superoxide formation, activated Complex I of the electron transfer chain in mitochondria, and blocked the Aβ-induced inhibition of Complex I in neuroblastoma cells. A mechanism for these effects of KU-32 on mitochondrial metabolism appeared to be the inhibition of pyruvate dehydrogenase kinase (PDHK), both in isolated brain mitochondria and in SH-SY5Y cells. PDHK inhibition by the classic enzyme inhibitor, dichloroacetate, led to neuroprotection from Aβ25-35-induced cell injury similarly to KU-32. Inhibition of PDHK in neurons would lead to activation of the PDH complex, increased acetyl-CoA generation, stimulation of the tricarboxylic acid cycle and Complex I in the electron transfer chain, and enhanced oxidative phosphorylation. A focus of future studies may be on the potential value of PDHK as a target in AD therapy.

Lifestyle Behaviors and Health-Related Quality of Life in Cancer Survivors: A Latent Class Analysis.

Healthy lifestyle behaviors can improve health-related quality of life (HRQOL) in cancer survivors; but the combination of behaviors most important for HRQOL is not known. This study investigated the patterns of lifestyle behaviors among cancer survivors and differences in HRQOL between behavioral classes. Cancer survivors (n = 2,463) were invited to participate in a cross-sectional survey. Participants (N = 591) were predominately female (63%) and non-Hispanic White (90%). Survey items included self-reported physical activity, diet, smoking, sleep, HRQOL, and demographics. Behavioral classes were estimated by latent class analysis. Differences between classes were assessed by latent class regression. Compared with the "healthy lifestyles" class (higher probabilities of meeting aerobic/strength-based activity guidelines, high fruit/vegetable intake, and no sleep problems; 11% of sample), the "sleep and diet problems with inconsistent physical activity" class (higher probabilities of not meeting strength-based guidelines, low fruit/vegetable intake, some sleep problems; marginally higher probability of meeting aerobic guidelines; 41%) had poorer general and physical HRQOL. The "poor physical activity and diet" class (higher probabilities of not meeting aerobic/strength-based guidelines, low fruit/vegetable intake, and some sleep problems; 48%) had poorer general, physical, and mental HRQOL. Few participants exhibited healthy lifestyle patterns associated with HRQOL. The findings provide opportunities to develop differentiated multiple behavior-change interventions, targeted to two common patterns of behavior. A large subgroup of cancer survivors was susceptible to suboptimal physical activity and diet, warranting interventions exclusively targeting these behaviors. Another subgroup was susceptible to suboptimal physical activity, diet, and sleep, indicating interventions for this group should include strategies targeting these three behaviors.

Live Cell and Hybrid Material Based Bio-Photoelectrochemical Cells for Clean Solar Energy Conversion

Photosynthetic organisms and complexes are attractive starting materials for solar energy conversion (SEC). I will describe here how the remarkable photocatalytic activity of the photosynthetic apparatus can provide overall water splitting with oxygen and hydrogen production in Bio-Photo-Electro-Chemical (BPEC) cells (Fig. 1). Use of isolated photosynthetic systems tightly associated with different electrodes has the benefit of potentially high reaction center density. However, the cross-section for light absorption is poor, leading to sub-optimal activity. Disconnection from biological repair mechanisms leads to limited lifetime. On the other hand, use of intact, live systems have the benefit of evolutionarily optimized light harvesting antennas for improved energy absorption and transfer, and all of these organisms have excellent repair systems leading to essentially endless activity. However, how these intact systems can be functionally connected to the BPEC depends on the morphology, permeability and flux of electron carriers. We will show here that we can obtain significant electrical current using a variety of live photosynthetic organisms, each with benefits and drawbacks. Cyanobacteria1,2 and microalgae3 are applied directly to the BPEC anode, providing continuous current densities in the 10’s of μA/cm2. Use of photosynthetic tissues from macroalgae (seaweeds)4 or higher plants5 require tight association with metallic anodes (stainless steel, aluminum, etc.) leading to current densities of >50mA/cm2, with high ionic strength electrolyte solutions supporting these increased current densities. Succulents can serve as their own BPEC6. In all cases, the major electron carrier is NADPH which is released by the cells and tissues into the electrolyte. A different strategy is to use isolated photosynthetic complexes and chemically connect them to the electrochemical cell. To overcome the problem of lower number of light absorbing chromophores connected to each reaction center we can use either isolated biological light harvesting (LH) complexes or nanoparticles (NPs). As Photosystem II (PSII) is the only enzyme that catalyzes light-induced water oxidation, we focus on its use in these systems. PSII can be isolated from a wide variety of organisms, each with relative benefits or disadvantages: isolation ease and cost, quantity per cell, stability to heat or other external stress, etc. PSII contains chlorophyll a which absorbs well in the 400-500nm and 600-700nm region, limiting the quantum efficiency in the gap in the green absorption region (500 - 600 nm). To overcome this limitation, we have used two strategies: stabilizing the interaction between PSII and isolated thermophilic cyanobacterial Phycobilisomes LH complex within an Os-complex-modified hydrogel on macro-porous indium tin oxide electrodes (MP-ITO). This results in notably improved, wavelength dependent, incident photon-to-electron conversion efficiencies7. Another strategy was to isolate market-purchased spinach PSII (cheap and abundant) and associate them via a unique binding shell to gold-nanoparticles (Au-NPs)8. These Au-NP were shown to serve as both light harvesting modules in the green gap, as well as conduits of electrons from the bound PSII to the BPEC, leading to record current densities were obtained. Figure 1

Oncolytic herpes simplex virus armed with a bacterial GBP1 degrader improves antitumor activity

Oncolytic viruses (OVs) encoding various transgenes are being evaluated for cancer immunotherapy. Diverse factors such as cytokines,immune checkpoint inhibitors, tumor-associated antigens, and Tcell engagers have been exploited as transgenes. These modifications are primarily aimed to reverse the immunosuppressive tumor microenvironment. By contrast, antiviral restriction factors that inhibit the replication of OVs and result in suboptimal oncolytic activity have received far less attention. Here, we report that guanylate-binding protein 1 (GBP1) is potently induced duringHSV-1 infection and restricts HSV-1 replication. Mechanistically, GBP1 remodels cytoskeletal organization to impede nuclear entry of HSV-1 genome. Previous studies have established that IpaH9.8, a bacterial E3 ubiquitin ligase, targets GBPs for proteasomal degradation. We therefore engineered an oncolytic HSV-1 to express IpaH9.8 and found that the modified OV effectively antagonized GBP1, replicated to a higher titer invitro and showed superior antitumor activity invivo. Our study features a strategy for improving the replication of OVs via targeting a restriction factor and achieving promising therapeutic efficacy.