In vivo simultaneous visualization of the dynamic changes in biomarkers within the tumor microenvironment (TME) is crucial for elucidating the mechanisms underlying tumor initiation and progression and providing pivotal insights for tumor management. Herein, we develop an acidosis- and inorganic phosphate-dual-responsive fluorinated core-shell nanoprobe (Zr@Zn-MOF) from corresponding metal ions and fluorinated ligands for visualizing the TME in vivo via multiplexed 19F magnetic resonance imaging (MRI). In normal tissues, the insignificant dual-channel 19F MRI signals of Zr@Zn-MOF could be ascribed to the close packing of 19F nuclei within Zr@Zn-MOF, which strengthens magnetic dipolar interactions. In contrast, activated by the low pH and high phosphate level of the TME, the core-shell nanoprobe undergoes rapid degradation to release fluorinated ligands, resulting in the intensification of dual-channel signals for multicolor 19F MRI. A series of imaging experiments validates the mechanism of this nanoprobe and illustrates its favorable performance of reassuring visualization of the TME with high penetration depth and low biological background. Our study demonstrates the promising potential of this nanoprobe for imaging-related tumor management and the success of our strategy that takes advantage of core-shell MOFs for the construction of multiple stimuli-responsive 19F MRI nanoprobes.

A 13-year-old girl, born to third-degree consanguineous parents, presented with acute flaccid paralysis. There was a past history of a similar episode at 5 years of age. Her current laboratory investigations revealed hypokalemia and normal anion gap-metabolic acidosis. Pure tone audiometry showed bilateral sensorineural hearing loss (SNHL). There was no nephrocalcinosis, ataxia, or epilepsy. Whole exome sequencing detected a homozygous deletion (c.269_270del) in exon 4 of KCNJ16 gene that led to frameshift and premature truncation of the protein (p. Ser90CysfsTer15; ENST00000392671.6). She was managed with potassium citrate. KCNJ16 tubulopathy should be considered in the differential diagnosis of children presenting with metabolic acidosis, hypokalemia, and SNHL. In literature, clinical phenotypes of hypokalemic metabolic acidosis as well as salt-losing tubulopathies with hypokalemic metabolic alkalosis are described in this disorder. This is the first report of a child with p.Ser90CysfsTer15 homozygous frameshift KCNJ16 mutation, who presented with hypokalemia and metabolic acidosis, and had severe clinical manifestations.

Integrating physicochemical environmental cues with pathogen detection is essential for an effective and balanced host defense. While Toll-like receptors (TLRs) detect pathogen-associated molecular patterns (PAMPs), transient receptor potential (TRP) ion channels detect specific physicochemical shifts characteristic of inflamed tissues, including extracellular acidosis, hyperosmolarity, oxidative stress, and mechanical perturbations of the lipid bilayer. Emerging evidence indicates that these two sensory systems interact via a bidirectional signaling axis. This review summarizes recent advances in the molecular mechanisms of TRP-TLR crosstalk, focusing on the three principal modes: direct physical coupling, indirect functional coupling via second messengers, and spatial co-organization within membrane microdomains. We examine how TLR signaling regulates TRP channel expression and post-translational modification. Reciprocally, we detail how TRP-mediated ionic fluxes modulate TLR ligand recognition, signal amplification, and effector functions, including phagocytosis and cytokine secretion. Crucially, we illustrate how the dysregulation of this subcellular crosstalk scales up to drive tissue pathologies, including neuropathic pain sensitization, central neuroinflammation, and barrier organ dysfunction. The TRP-TLR axis represents a convergence of immune and sensory signaling. Understanding this interaction provides a basis for identifying novel therapeutic targets for infectious and inflammatory diseases.

Odontogenic pain is one of the most intense forms of orofacial pain, yet durable mechanism-directed therapies remain limited. Traditionally, tooth pain has been framed as a local consequence of pulpal, dentinal, periodontal, or periapical disease. However, contemporary orofacial pain and headache frameworks increasingly position dental pain within a broader trigeminal pain network, where nociceptive input from the teeth and surrounding tissues may contribute to referred facial pain, headache-related orofacial pain overlap, and trigeminal sensitization. In this review, we synthesize odontogenic pain as a clinically accessible model for studying peripheral-to-central trigeminal pain mechanisms. To align the review questions, scope, and content, the review is structured around five linked domains: clinically relevant phenotypes, peripheral-to-central mechanisms, phenotype-matched models and readouts, biomarker-based target engagement, and mechanism-guided therapeutic and trial-design strategies. We emphasize the hot tooth phenotype, most commonly associated with symptomatic irreversible pulpitis, as a translational state in which severe peripheral inflammation, tissue acidosis, ion-channel remodeling, local anesthetic difficulty, neuroimmune activation, and central amplification converge. We summarize key molecular and circuit-level mechanisms, including inflammatory mediator release, ion-channel and receptor pathways related to thermal, acid, purinergic, sodium, calcium, mechanosensitive, and G protein-coupled signaling, trigeminal ganglion plasticity, satellite glial activation, calcitonin gene-related peptide signaling, trigeminocervical convergence, and central sensitization. We also discuss how preclinical models and experimental readouts can be aligned with specific clinical phenotypes, including five clinical phenotype domains: dentin hypersensitivity; acute pulpitis; the hot tooth phenotype as the index severe inflammatory pulpitis state; persistent dentoalveolar or post-procedural pain, including post-traumatic trigeminal neuropathic pain; and headache-related orofacial pain overlap. By linking clinical phenotypes, mechanistic models, experimental readouts, biomarkers, target engagement, therapeutic strategies, and trial-design considerations, this framework may help bridge the gap between preclinical pain research and clinical application. Reframing odontogenic pain as a biologically informative trigeminal pain state may support the development of biomarker-guided, mechanism-informed, and more durable analgesic strategies for refractory dental and headache-related orofacial pain. Importantly, persistent or refractory odontogenic and headache-related orofacial pain is shaped not only by peripheral and central neurobiological mechanisms but also by patient-level contextual contributors such as sleep disruption, stress, prior pain and treatment experience, and affective-motivational processing, which help explain why patients with comparable dental findings differ in pain intensity, disability, and treatment response.

Poly(ADP-ribose) polymerase inhibitors (PARPi) are a first-line treatment for epithelial ovarian cancer (EOC) patients, but the development of resistance limits long-term therapeutic efficacy. Tumor acidosis is a hallmark of the tumor microenvironment that has been shown to promote resistance to cancer therapies, suggesting that it may impact PARPi response. Here, we demonstrated that the acidic tumor microenvironment drives a p300-dependent mechanism of PARPi resistance in EOC. Pathologically acidic pH enhanced DNA damage repair, reduced PARPi-induced PARP1 trapping, and attenuated the anti-tumor efficacy of PARPi. A CRISPR-Cas9 screen identified p300 as a druggable mediator of acidosis-induced PARPi resistance. Mechanistically, acidic pH activated an ERK-p300-PARP1 signaling axis that acetylated PARP1 at lysine 505 (PARP1 K505Ac), thereby alleviating PARPi-mediated PARP1 trapping and DNA damage. Elevated PARP1 K505Ac was associated with clinical resistance to PARPi and poor overall survival. In patient-derived and syngeneic EOC models, pharmacologic inhibition of p300 synergized with PARPi to suppress tumor growth. Together, these findings identify p300 as a key mediator of acidosis-induced PARPi resistance and a promising therapeutic target to enhance PARPi efficacy.

Intervertebral disc degeneration (IVDD) is commonly framed as the cumulative result of extracellular matrix loss, inflammatory activation, oxidative damage, cellular senescence and cell death. This formulation is useful, but it also fragments the disease into parallel mechanisms and obscures a central paradox: nucleus pulposus and annulus fibrosus cells normally reside in a microenvironment that would be hostile to most mammalian cells. The healthy disc is avascular, diffusion limited, hypoxic, glycolytic, relatively acidic and mechanically loaded. These features are not simply pathological insults; they are defining ecological constraints to which disc cells are continuously adapted. Here we propose that IVDD can be productively reframed as a process of stress-response exhaustion. In this view, degeneration begins when the adaptive systems that maintain disc cell viability and matrix homeostasis under chronic microenvironmental stress lose amplitude, flexibility or recovery capacity. Hypoxia-inducible factor signalling, AMPK-mTOR metabolic sensing, autophagy and mitophagy, unfolded-protein and integrated stress responses, and redox buffering are initially protective. With ageing, endplate dysfunction, nutrient diffusion failure, acidosis, abnormal mechanical loading and organelle damage, these same systems can become insufficient or maladaptive, creating a degenerative tipping point. Downstream consequences include senescence, sterile inflammation, cell death, matrix collapse and neuroimmune conversion to painful disease. This framework does not replace established mechanisms of IVDD; rather, it orders them along a temporal axis from adaptation to exhaustion. It also suggests stage-specific therapeutic logic: preserve adaptive reserve early, prevent stress-response collapse, suppress senescence and sterile inflammation, and target neuroimmune sensitization in painful degeneration.

Ketosis is one of the most prevalent metabolic disorders in dairy herds, with significant economic and welfare implications. However, existing literature often examines risk predictors in isolation, and their interactions and dependencies remain poorly understood. This study investigated how production, health, and management factors - and their interactions - are associated with ketosis risk (KR) at the animal level in German dairy cows, with a focus on German Holstein (GH) and German Simmental (SIM) breeds. Data from 76,809 cows across 717 German dairy farms collected between 2015 and 2019 were analyzed using multivariable generalized linear mixed-effects logistic regression with two-way interactions and random forest algorithms. KR was predicted using a non-invasive, widely applicable approach based on milk composition thresholds derived from monthly test-day records. Key risk factors included breed, parity, energy-corrected milk (ECM) yield, body condition, lameness, housing, and lactation stage. Twelve significant two-way interactions were identified, highlighting the multifactorial and interdependent nature of KR, most frequently involving lactation stage (six interactions), followed by ECM yield (five interactions) and breed (four interactions). The overall predicted probability of KR was 7.1%. Although high-yielding multiparous cows showed the highest absolute KR (prob. = 13.6% [95% CI 12.5-14.8]), high-yielding primiparous cows exhibited an unexpectedly elevated KR (prob. = 11.4% [95% CI 9.9-13.1]). Elevated KR was also observed in underconditioned cows during mid-early lactation (days in milk [DIM] 30-99, prob. = 21.0% [95% CI 18.6-23.5]), and SIM cows producing high ECM yields (>35 kg/day; prob. = 19.5% [95% CI 16.2-23.4]). The highest predicted KR occurred in underconditioned, first-parity cows housed in tie stalls, lame, and producing high ECM yields during mid-early lactation, indicating that specific combinations of risk factors amplify KR beyond the sum of their individual contributions. These findings highlight the importance of modeling interactions among animal-level and environmental factors to enable context-specific risk assessment. Evaluating breed, lactation stage, body condition, production level, housing, and health status jointly may support more targeted prevention strategies, particularly during the first 99 DIM, and improve identification of cows at elevated ketosis risk.

The milk fat-to-protein ratio (FPR) is an important indicator of milk quality and a useful biomarker of metabolic status in dairy cows. This study used functional single-step genome-wide association analysis (ssGWAS) incorporating performance records from 502,781 first-parity Iranian Holstein cows and SNP genotypes from 2,187 Holstein bulls to investigate the genomic architecture underlying FPR variation in this population. The heritability of FPR was estimated at 0.24. Genome-wide scanning identified 18 significant SNPs on BTA14 and 121 positional candidate genes located within ± 100 kb of these variants. Because FPR is commonly used as a biomarker for metabolic disorders such as ketosis, we additionally performed Gene Ontology (GO) enrichment analysis to identify biological pathways and genes potentially involved in subclinical ketosis risk. The major enriched pathways were related to lipid metabolism, energy utilization, and acylglycerol biosynthesis. Several significant SNPs-particularly ARS-BFGL-NGS-4939, ARS-BFGL-NGS-94,706, ARS-BFGL-NGS-103,064, ARS-BFGL-NGS-3122, and Hapmap29758-BTC-003619-were located near key functional genes such as DGAT1, CYP11B1, and GPIHBP1, which have known roles in these pathways and may contribute to FPR variability and susceptibility to subclinical ketosis. Overall, our findings provide new insight into the genomic basis of FPR and offer valuable direction for breeding strategies aimed at reducing ketosis prevalence in Iranian Holstein cattle.