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Kirsten rat sarcoma (KRAS) is an oncoprotein responsible for ∼ 20% of all human cancers. So far, only two covalent drugs are approved by the U.S. Food and Drug Administration (FDA) for the treatment of KRAS (G12C)-driven non-small cell lung cancer. However, their reliance on a covalent bond with cysteine at position 12 limits their effectiveness for treating other cancers driven by non-G12C KRAS mutations, and the emergence of resistance against allele-specific inhibitors means that considerable effort is being directed toward developing noncovalent KRAS inhibitors. Currently, multiple noncovalent inhibitors are in various stages of clinical trials. While some of these may eventually come to fruition, none has so far been approved for market use, underscoring the need for new inhibitors. Here, we report a set of small molecules obtained from virtual screening of a physiochemically tailored ligand library against multiple KRAS mutants. Initial binding and cell proliferation experiments show that some of the predicted hits exhibit high affinity (single digit nM) binding to KRAS and sub-to-low micromolar inhibitory activity in pancreatic cancer cell lines harboring G12D, G12V, or G12C KRAS mutations. Predicted to bind to the p2 (also called switch II) pocket of KRAS, these ligands harbor unique scaffolds compared to existing drugs or leads and may serve as useful starting points for the development of allele-specific or pan-KRAS inhibitors.

The ability to access atomically tailored complex peptides and proteins provides powerful opportunities for dissecting molecular functions and advancing applications in chemical biology, therapeutics, and (bio)-materials science. Robust precision-engineering strategies are essential to construct well-defined protein architectures while preserving native folding and activity. To do so, chemoselective bioconjugation techniques have been developed to modify specific side chains of amino acids. This allowed for the selective introduction of functionalities on predetermined amino acids. However, ultimate control can be achieved only through site-selective modifications that precisely define both the nature of the linkage and the exact position of conjugation on elongated peptide sequences or fully assembled proteins. Cysteine residues are of particular interest, as their highly nucleophilic thiols offer excellent chemoselectivity and typically occur in low abundance in their reduced form. Here, we examine chemoselective transformations targeting cysteine residues that have been further refined to occur exclusively at predefined positions within a peptide or protein, thereby achieving a high degree of site-selectivity. This review focuses exclusively on chemical strategies for cysteine modification, offering guidance for future synthetic developments within the field of precision chemistry. Achieving this level of precision requires advanced chemical strategies that exploit the local environment of the targeted cysteine. One approach involves leveraging neighboring functional groups, for example, engaging the thiol together with the α-amine or carboxylate to enable selective N- or C-terminal modification, respectively. In such designs, the cysteine side chain may contribute through transient interactions, direct incorporation into the covalent linkage, or the stabilization of the desired product. Recently, a promising strategy has attracted increasing attention in which site-selectivity is enabled by temporary interaction with a proximal amine, thus being applicable to differentiate also between internal cysteines. Together, these strategies highlight that site-selective protein modification has evolved into a powerful tool for the rational design and functional control of complex biomolecules, redefining what is achievable in chemical biology, therapeutics, and biomaterials science. We anticipate that increasingly routine or user-friendly approaches such as the programmable TriTEx method will further accelerate the adoption of precision biomolecule conjugates in both research and industrial settings.

Freeform 3D ice printing is emerging as a promising additive manufacturing method with potential applications in engineering, medicine, science, and art. Printing ice at the micrometer-millimeter scale is a challenging, high-frequency additive manufacturing process. Freeform ice 3D printing though is an early stage manufacturing process where complex geometries require significant time to design manually through an empirical trial-and-error approach, due to the nonlinear nature of droplet deposition and solidification along with unavoidable uncertainties and noise. This process would be tremendously improved with better understanding and harnessing the ability to visualize, analyze and adjust the printing process in real time. For this automation, using approaches such as closed loop control that have allowed tremendous advances in other fields like self-driving cars, plane autopilot, etc. would be very useful. In order to use closed loop control for this process, ice position and shape must be determined and transformed into in situ actionable data, which is complicated further by the transparency of ice and speed required for the phase transition from water to ice. We implemented vision techniques to build a data set to train a machine learning algorithm though an ice segmentation approach using a convolutional filter. We also implemented a hybrid optical flow algorithm (Farneback-FAST) to create a segmented video frame data set for training a neural network, Icenet. This approach was faster than the Farneback-FAST, segmenting frames in 25 ms, which allows for single and low multi droplet control. Our approaches will enable future closed loop control of the printing process and will be useful in a variety of areas including additive manufacturing, organ on a chip systems, and biomanufacturing.

Living kidney donation is considered the optimal treatment for patients with advanced kidney disease, but it carries risks for the donors. To assess these risks, data on donors' physical and mental health is needed. The German Living Donor Registry collects medical and psychosocial data from 32 transplant centers. The analysis provides a representative overview of the demographics, pre-operative physical and mental health, and psychosocial situation of accepted living kidney donors in Germany, accounting for gender-specific differences. From January 2020 to January 2025, 1,237 individuals aged 54.5 &#xb1; 10 years (range: 20-83 years) were examined pre-operatively. Most donors were women (63%), 56% reported at least one pre-existing disease or medication, and 13.5% had an eGFR <80 ml/min. Compared to the general German population, donors showed a higher quality of life and fewer psychological impairments and fatigue symptoms. Risk factors for impaired mental quality of life and fatigue included psychosocial stress and lower resilience. Living kidney donors in Germany do not represent a completely healthy population, but have a high quality of life. Careful, standardized medical and psychosocial evaluation is needed to identify donations with high medical or psychosocial risk and to ensure comprehensive education to protect donors.

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Glioblastoma (GBM) represents the most aggressive primary brain tumor in adults, characterized by a profoundly immunosuppressive tumor microenvironment (TME) that systematically disables cytotoxic lymphocyte function and renders conventional immunotherapy largely ineffective. While exhaustion of CD8+ T cells and natural killer (NK) cells within solid tumors has been extensively studied in other cancer types, the CNS-specific architectural, metabolic, and molecular constraints that shape cytotoxic lymphocyte heterogeneity in GBM remain insufficiently characterized. Recent advances in single-cell RNA sequencing (scRNA-seq) and spatial multiomics have begun to reveal a rich landscape of cytotoxic lymphocyte subpopulations in GBM. These include TCF-1+ progenitor-exhausted T cells (Tpex), terminally exhausted CD8+ T cells (Tex), and dysfunctional natural killer (NK) cell subsets, each distributed across anatomically distinct immune niches. This review synthesizes current knowledge across three interconnected areas: the single-cell atlas of GBM-infiltrating cytotoxic lymphocytes; the spatial organization of their dysfunction within perinecrotic, perivascular, and infiltrative-edge niches; and the epigenetic and transcriptional programs that underlie GBM-specific cytotoxic failure, including dysregulation of the TOX/TCF-1 axis and IDH-mutation-driven silencing of NKG2D ligands. Critically, we compare CD8+ T cell and NK cell exhaustion mechanisms, highlighting their mechanistic divergence and therapeutic implications. We further discuss how these multiomics insights can be translated into neurosurgically relevant strategies, including intraoperative tumor profiling, progenitor T cell expansion via epigenetic priming, NKG2A/TIGIT dual blockade, and intracavitary delivery of engineered NK cells. Together, this review proposes a spatially and cellularly resolved framework for understanding cytotoxic immune failure in GBM and outlines precision immunotherapy approaches tailored to the unique immunobiology of the CNS tumor microenvironment.

Two pillar-layered MOF membranes, CALF-20 and CALF-15, were synthesized on polymeric substrates by in situ interfacial growth under mild conditions. Owing to the ultrasmall thickness of 60 nm and ultramicroporous lattice windows, the membranes exhibited ultrahigh H2 permeance of over 7000 GPU and H2/CO2 selectivity of 30-43.

In the context of unprecedented workforce age diversity, workplace ageism is increasingly reported. This review synthesizes empirical evidence on the relationship between workplace ageism and workplace wellbeing among workers aged 50 and older, focusing on how these effects unfold (mediation) and the conditions under which they are amplified or buffered (moderation). A systematic literature review was conducted following PRISMA guidelines. Searches were conducted in major academic databases, including Web of Science, Scopus, Pubmed, among others. Of the 3,378 records identified, 22 met the inclusion criteria. Across studies, ageism showed a consistently negative and statistically significant association with workplace wellbeing outcomes, even though ageism and wellbeing were measured with heterogeneous indicators. Findings also suggest spillover beyond work, for example, via decreases in life satisfaction or subjective wellbeing. Moderation evidence was limited; when tested, social support (supervisor and coworker support) emerged as the only moderator in this association. Mediation evidence was more developed and clustered around three pathways: (1) cognitive processes (e.g., appraisals and rumination); (2) affective processes (e.g., aging anxiety); and (3) job demands-resources mechanisms. By clarifying these moderators and mechanisms, the review points to leverage points for practices that foster inclusive, intergenerational workplaces and safeguard wellbeing.

The Cochrane Handbook's I 2 categorization system (0%-25% "low", 25%-75% "moderate", &#x2265;&#x2009;50% "high" heterogeneity) defines the standard approach to interpreting heterogeneity in meta-analysis and informs thousands of systematic reviews each year. Despite its widespread use, its logical coherence and its role as an analytical decision tool have received limited formal examination. To examine whether the Cochrane Handbook's I2 categorization system includes overlapping category definitions that create ambiguous classification, and to propose context-specific frameworks that preserve I2 as a decision tool for heterogeneity exploration. We conducted a structured genealogical analysis of key methodological sources related to the Cochrane Handbook's I 2 categorization. We examined whether individual I 2 values can satisfy more than one category. We analysed the categorization using principles from formal logic, philosophy of science, and statistical theory. We traced the development of I2 interpretation from its original formulation to current Cochrane guidance. We developed context-specific frameworks based on patient-important outcome categories. The I 2 categorization system includes overlapping definitions in which identical values satisfy more than one category (e.g., I 2&#x2009;=&#x2009;50% corresponds to both "moderate" [25%-75%] and "high" [&#x2265;&#x2009;50%]). This structure assigns single values to multiple categories and departs from principles that require consistent and mutually exclusive classification. The primary literature provides limited explicit theoretical or empirical justification for the selected thresholds. The current approach uses I 2 as an interpretive endpoint rather than as a decision tool for heterogeneity exploration. These features reduce interpretive clarity and obscure the role of clinical context in heterogeneity assessment. The current I2 categorization system introduces ambiguity and leads to inconsistent analytical decisions across outcome contexts. Evidence synthesis requires context-specific frameworks in which interpretation reflects outcome type and expected variability. We propose the PIOHA framework to align heterogeneity assessment with clinical relevance while preserving I2 as an analytical decision tool. Systematic reviews inform clinical guidelines and patient care. Context-specific heterogeneity assessment supports analytical decisions that reflect the clinical importance and expected variability of patient-important outcomes.

Prey use a variety of anti-predator behavior, including alarm calling and approaching predators, and may adjust these behaviors by evaluating their benefits and costs. However, it remains unclear how prey expresses anti-predator behavior across seasons, when both breeding status or predator diet may influence perceived risk. We conducted nine-minute playback surveys (six-minute quiet period and subsequent three-minute playback) using calls of Collared Owlet (Glaucidium brodiei), a diurnal owl that preys on passerines, at 93 sites during breeding season and non-breeding season in Taiwan. We quantified whether the small passerine birds approach and make alarm call or not to quantify mobbing response. We found that probability of making alarm calls did not differ between seasons (30.88% and 29.15% in breeding and non-breeding season, respectively), whereas probability of approaching was higher in breeding (25.63%) than in non-breeding season (13.28%). To verify that responses were specific to predator cues rather than to loud vocalizations in general, we conducted supplementary playbacks using calls of a non-predatory species, Taiwan Barbet (Psilopogon nuchalis), which elicited markedly lower mobbing responses. Together, these results indicate that small passerine birds mob in both seasons but reduce the use of higher-risk behaviors against predators during the non-breeding season, consistent with seasonal variation in predation risk.

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With increasing emphasis on patient-centric care, treatment goals for ulcerative colitis (UC) now include bowel urgency (BU), stool frequency, and rectal bleeding (RB) resolution, enhancement of overall well-being, and endoscopic remission (ER). This analysis evaluated the impact of adding BU improvement to clinical remission, defined by the modified Mayo score (RB, stool frequency, ER), on quality of life assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ). The effect of mirikizumab on achieving combined clinical, BU, and IBDQ remissions was also evaluated in the LUCENT-1 and -2 trials. In LUCENT-1, patients were randomized 3:1 (mirikizumab to placebo) every 4&#x2009;weeks. At Week 12, mirikizumab responders were re-randomized 2:1 (mirikizumab to placebo) for 40 additional weeks in LUCENT-2. BU improvement was assessed using clinically meaningful improvement (Urgency Numeric Rating Scale [UNRS] &#x2265;3-point change) and BU remission (UNRS&#x2009;=&#x2009;0 or 1). The impact of mirikizumab on achieving single and combined outcomes was determined at Weeks 12 and 52. Significant IBDQ improvement at both timepoints (P&#x2009;&#x2264;&#x2009;.01) was observed by achieving both BU improvement and clinical remission versus clinical remission alone. Significantly more mirikizumab-treated patients achieved single and combined endpoints of clinical, BU, and IBDQ remissions versus placebo (P&#x2009;&#x2264;&#x2009;.05). The addition of BU improvement in patients who had already attained clinical response or remission is associated with greater quality of life. Mirikizumab delivered comprehensive benefit for patients with UC by relieving BU symptoms, resolving endoscopic inflammation, and enhancing overall well-being concurrently.