Human migration from the Levant and Arabia into Yemen since Last Glacial Maximum.

While a broad consensus about the first successful migration modern humans out of Africa seems established, the peopling of Arabia remains somewhat enigmatic. Identifying the ancestral populations that contributed to the gene pool of the current populations inhabiting Arabia and the impact of their contributions remains a challenging task. We investigate the genetic makeup of the current Yemeni population using 46 whole genomes and 169 genotype arrays derived from Yemeni individuals from all geographic regions across Yemen and 351 genotype arrays derived from neighboring populations providing regional context.

The relationship between mitochondrial health, telomerase activity and longitudinal telomere attrition, considering the role of chronic stress.

Telomere attrition is a hallmark of biological aging, contributing to cellular replicative senescence. However, few studies have examined the determinants of telomere attrition in vivo in humans. Mitochondrial Health Index (MHI), a composite marker integrating mitochondrial energy-transformation capacity and content, may be one important mediator of telomere attrition, as it could impact telomerase activity, a direct regulator of telomere maintenance.

Liver cancer multiomics reveals diverse protein kinase A disruptions convergently produce fibrolamellar hepatocellular carcinoma.

Fibrolamellar Hepatocellular Carcinoma (FLC) is a rare liver cancer characterized by a fusion oncokinase of the genes DNAJB1 and PRKACA, the catalytic subunit of protein kinase A (PKA). A few FLC-like tumors have been reported showing other alterations involving PKA. To better understand FLC pathogenesis and the relationships among FLC, FLC-like, and other liver tumors, we performed a massive multi-omics analysis.

Recent methane surges reveal heightened emissions from tropical inundated areas.

Record breaking atmospheric methane growth rates were observed in 2020 and 2021 (15.2±0.5 and 17.

Oxidized phospholipid and transcriptomic signatures of THC-related vaping associated lung injury.

E-cigarette/vaping-associated lung injury (EVALI) is strongly associated with vitamin E acetate and often occurs with concomitant tetrahydrocannabinol (THC) use. To uncover pathways associated with EVALI, we examined cytokines, transcriptomic signatures, and lipidomic profiles in bronchoalveolar lavage fluid (BALF) from THC-EVALI patients. At a single center, we prospectively enrolled mechanically ventilated patients with EVALI from THC-containing products (N = 4) and patients with non-vaping acute lung injury and airway controls (N = 5).

Future increase in compound soil drought-heat extremes exacerbated by vegetation greening.

Compound soil drought and heat extremes are expected to occur more frequently with global warming, causing wide-ranging socio-ecological repercussions. Vegetation modulates air temperature and soil moisture through biophysical processes, thereby influencing the occurrence of such extremes. Global vegetation cover is broadly expected to increase under climate change, but it remains unclear whether vegetation greening will alleviate or aggravate future increases in compound soil drought-heat events.

DDX18 coordinates nucleolus phase separation and nuclear organization to control the pluripotency of human embryonic stem cells.

Pluripotent stem cells possess a unique nuclear architecture characterized by a larger nucleus and more open chromatin, which underpins their ability to self-renew and differentiate. Here, we show that the nucleolus-specific RNA helicase DDX18 is essential for maintaining the pluripotency of human embryonic stem cells. Using techniques such as Hi-C, DNA/RNA-FISH, and biomolecular condensate analysis, we demonstrate that DDX18 regulates nucleolus phase separation and nuclear organization by interacting with NPM1 in the granular nucleolar component, driven by specific nucleolar RNAs.

Functional anatomy of zinc finger antiviral protein complexes.

ZAP is an antiviral protein that binds to and depletes viral RNA, which is often distinguished from vertebrate host RNA by its elevated CpG content. Two ZAP cofactors, TRIM25 and KHNYN, have activities that are poorly understood. Here, we show that functional interactions between ZAP, TRIM25 and KHNYN involve multiple domains of each protein, and that the ability of TRIM25 to multimerize via its RING domain augments ZAP activity and specificity.

Small-angle scattering interferometry with neutron orbital angular momentum states.

Methods to prepare and characterize neutron helical waves carrying orbital angular momentum (OAM) were recently demonstrated at small-angle neutron scattering (SANS) facilities. These methods enable access to the neutron orbital degree of freedom which provides new avenues of exploration in fundamental science experiments as well as in material characterization applications. However, it remains a challenge to recover phase profiles from SANS measurements.

Topological transformation of microbial proteins into iron single-atom sites for selective hydrogen peroxide electrosynthesis.

The emergence of single-atom catalysts offers exciting prospects for the green production of hydrogen peroxide; however, their optimal local structure and the underlying structure-activity relationships remain unclear. Here we show trace Fe, up to 278 mg/kg and derived from microbial protein, serve as precursors to synthesize a variety of Fe single-atom catalysts containing FeNO (1 ≤ x ≤ 4) moieties through controlled pyrolysis. These moieties resemble the structural features of nonheme Fe-dependent enzymes while being effectively confined on a microbe-derived, electrically conductive carbon support, enabling high-current density electrolysis.

Robust and inducible genome editing via an all-in-one prime editor in human pluripotent stem cells.

Prime editing (PE) allows for precise genome editing in human pluripotent stem cells (hPSCs), such as introducing single nucleotide modifications, small insertions or deletions at a specific genomic locus. Here, we systematically compare a panel of prime editing conditions in hPSCs and generate a potent prime editor, "PE-Plus", through co-inhibition of mismatch repair and p53-mediated cellular stress responses. We further establish an inducible prime editing platform in hPSCs by incorporating the PE-Plus into a safe-harbor locus and demonstrated temporal control of precise editing in both hPSCs and differentiated cells.

Malate initiates a proton-sensing pathway essential for pH regulation of inflammation.

Metabolites can double as a signaling modality that initiates physiological adaptations. Metabolism, a chemical language encoding biological information, has been recognized as a powerful principle directing inflammatory responses. Cytosolic pH is a regulator of inflammatory response in macrophages.

Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis.

Proteostasis is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. However, this is challenging in neuronal projections because of their polarized morphology and constant synaptic proteome remodeling. Using high-resolution fluorescence microscopy, we discover that hippocampal and spinal cord motor neurons of mouse and human origin localize a subset of chaperone mRNAs to their dendrites and use microtubule-based transport to increase this asymmetric localization following proteotoxic stress.

Neurotransmitter-bound bestrophin channel structures reveal small molecule drug targeting sites for disease treatment.

Best1 and Best2 are two members of the bestrophin family of anion channels critically involved in the prevention of retinal degeneration and maintenance of intraocular pressure, respectively. Here, we solved glutamate- and γ-aminobutyric acid (GABA)-bound Best2 structures, which delineate an intracellular glutamate binding site and an extracellular GABA binding site on Best2, respectively, identified extracellular GABA as a permeable activator of Best2, and elucidated the co-regulation of Best2 by glutamate, GABA and glutamine synthetase in vivo. We further identified multiple small molecules as activators of the bestrophin channels.

Rapid nongenomic estrogen signaling controls alcohol drinking behavior in mice.

Ovarian-derived estrogen can signal non-canonically at membrane-associated receptors in the brain to rapidly regulate neuronal function. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high estrogen levels, but a causal role for estrogen in driving alcohol drinking has not been established. We found that female mice displayed greater binge alcohol drinking and reduced avoidance when estrogen was high during the estrous cycle than when it was low.

Global mean sea level likely higher than present during the holocene.

Global mean sea-level (GMSL) change can shed light on how the Earth system responds to warming. Glaciological evidence indicates that Earth's ice sheets retreated inland of early industrial (1850 CE) extents during the Holocene (11.7-0 ka), yet previous work suggests that Holocene GMSL never surpassed early industrial levels.

Direct perception of affective valence from vision.

Subjective feelings are thought to arise from conceptual and bodily states. We examine whether the valence of feelings may also be decoded directly from objective ecological statistics of the visual environment. We train a visual valence (VV) machine learning model of low-level image statistics on nearly 8000 emotionally charged photographs.

PSCA-targeted BPX-601 CAR T cells with pharmacological activation by rimiducid in metastatic pancreatic and prostate cancer: a phase 1 dose escalation trial.

Here we report results of a phase 1 multi-institutional, open-label, dose-escalation trial (NCT02744287) of BPX-601, an investigational autologous PSCA-directed GoCAR-T® cell product containing an inducible MyD88/CD40 ON-switch responsive to the activating dimerizer rimiducid, in patients with metastatic pancreatic (mPDAC) or castration-resistant prostate cancer (mCRPC). Primary objectives were to evaluate safety and tolerability and determine the recommended phase 2 dose/schedule (RP2D). Secondary objectives included the assessment of efficacy and characterization of the pharmacokinetics of rimiducid.

Neoadjuvant anti-PD1 immunotherapy for surgically accessible recurrent glioblastoma: clinical and molecular outcomes of a stage 2 single-arm expansion cohort.

Glioblastoma is immunologically "cold" and resistant to single-agent immune-checkpoint inhibitors (ICI). Our previous study of neoadjuvant pembrolizumab in surgically-accessible recurrent glioblastoma identified a molecular signature of response to ICI and suggested that neoadjuvant pembrolizumab may improve survival. To increase the power of this observation, we enrolled an additional 25 patients with a primary endpoint of evaluating the cell cycle gene signature associated with neoadjuvant pembrolizumab and performed bulk-RNA seq on resected tumor tissue (NCT02852655).

World-making for a future with sentient AI.

The ways people imagine possible futures with artificial intelligence (AI) affects future world-making-how the future is produced through cultural propagation, design, engineering, policy, and social interaction-yet there has been little empirical study of everyday people's expectations for AI futures. We addressed this by analysing two waves (2021 and 2023) of USA nationally representative data from the Artificial Intelligence, Morality, and Sentience (AIMS) survey on the public's forecasts about an imagined future world with widespread AI sentience (total N = 2401). Average responses to six forecasts (exploiting AI labour, treating AI cruelly, using AI research subjects, AI welfare, AI rights advocacy, AI unhappiness reduction) showed mixed expectations for humanity's future with AI.

Combined Autologous Breast Reconstruction and Gynecologic Procedures: Does Timing Affect Clinical and Patient-Reported Outcomes?

Background: Patients with or at risk for breast cancer may opt for risk-reducing gynecologic surgeries, including bilateral salpingo-oophorectomies and/or total abdominal hysterectomy. The timing and safety of combining these procedures with autologous breast reconstruction (ABR) are debated. This study assesses the impact of concurrent ABR and gynecologic surgeries on clinical and patient-reported outcomes.

Spatial proteomic differences in chronic traumatic encephalopathy, Alzheimer's disease, and primary age-related tauopathy hippocampi.

Introduction: Alzheimer's disease (AD), primary age-related tauopathy (PART), and chronic traumatic encephalopathy (CTE) all feature hyperphosphorylated tau (p-tau)-immunoreactive neurofibrillary degeneration, but differ in neuroanatomical distribution and progression of neurofibrillary degeneration and amyloid beta (Aβ) deposition.

Methods: We used Nanostring GeoMx Digital Spatial Profiling to compare the expression of 70 proteins in neurofibrillary tangle (NFT)-bearing and non-NFT-bearing neurons in hippocampal CA1, CA2, and CA4 subregions and entorhinal cortex of cases with autopsy-confirmed AD (n = 8), PART (n = 7), and CTE (n = 5).

Results: There were numerous subregion-specific differences related to Aβ processing, autophagy/proteostasis, inflammation, gliosis, oxidative stress, neuronal/synaptic integrity, and p-tau epitopes among these different disorders.

Moving Towards the Outpatient DIEP Flap: Factors Influencing Early Discharge.

Background: Enhanced Recovery After Surgery (ERAS) protocols can reduce the length of stay (LOS) for surgical patients, including those undergoing unilateral deep inferior epigastric artery perforator (DIEP) flap breast reconstruction, allowing most patients to be discharged by postoperative day 2. However, some patients require a prolonged inpatient stay due to difficulty completing postoperative milestones. This study aims to identify factors associated with increased LOS after DIEP flap breast reconstruction and assess safety of earlier discharge.

Non-Analog Behaviour of Eastern African Herbivore Communities During the Last Glacial Period.

Modern African ungulates navigate seasonal variation in resource availability through diet-switching (primarily mixed-feeders) and/or migrating (primarily grass grazers). These ecological generalisations are well-documented today, but the extent to which they apply to the non-analog ecosystems of the Pleistocene are unclear. Drawing from serially-sampled stable isotope measurements from 18 Kenyan large herbivore species from the Last Glacial Period (LGP), we evaluate how diet, diet-switching, and migration compare to observations from present-day settings.

Improving the Evaluation of Aesthetic Outcomes in DIEP Flap Breast Reconstruction: Validation of the Aesthetic Grading Tool.

Introduction: This study aimed to develop and validate an aesthetic grading tool (AGT) for bilateral DIEP flap breast reconstruction and investigate the correlation of BREAST-Q scores with perceived aesthetic outcomes.

Methods: The AGT utilized a Likert scale to rate aesthetic outcomes based on photographs of post-reconstruction breasts. The validation involved iterative testing with healthcare providers and patients.