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Proteostasis collapse, the diminished ability to maintain protein homeostasis, has been established as a hallmark of nematode aging. However, whether proteostasis collapse occurs in humans has remained unclear. Here, we demonstrate that proteostasis decline is intrinsic to human senescence. Using transcriptome-wide characterization of gene expression, splicing, and translation, we found a significant deterioration in the transcriptional activation of the heat shock response in stressed senescent cells. Furthermore, phosphorylated HSF1 nuclear localization and distribution were impaired in senescence. Interestingly, alternative splicing regulation was also dampened. Surprisingly, we found a decoupling between different unfolded protein response (UPR) branches in stressed senescent cells. While young cells initiated UPR-related translational and transcriptional regulatory responses, senescent cells showed enhanced translational regulation and endoplasmic reticulum (ER) stress sensing; however, they were unable to trigger UPR-related transcriptional responses. This was accompanied by diminished ATF6 nuclear localization in stressed senescent cells. Finally, we found that proteasome function was impaired following heat stress in senescent cells, and did not recover upon return to normal temperature. Together, our data unraveled a deterioration in the ability to mount dynamic stress transcriptional programs upon human senescence with broad implications on proteostasis control and connected proteostasis decline to human aging.

Exposure to certain stresses leads to readthrough transcription. Here we found that readthrough transcription often proceeds into the proximal gene downstream, in a phenomenon termed 'read-in'. Using polyA-selected RNA-seq data from mouse fibroblasts, we identified widespread read-in in heat shock, oxidative and osmotic stress conditions. We found that read-in genes share distinctive genomic characteristics; they are extremely short, and highly GC rich. Furthermore, using ribosome footprint profiling we found that translation of read-in genes is significantly reduced. Strikingly, read-in genes show extremely high levels of intron retention during stress, mostly in their first intron, which is not explained by features usually associated with intron retention, such as short introns and high GC content. Finally, we found that first introns in read-in genes have weaker splice sites. Our data portray a relationship between read-in and intron retention, suggesting it may have co-evolved to facilitate reduced translation of read-in genes during stress. Competing Interest Statement The authors have declared no competing interest.

Abstract Proteostasis collapse, the diminished ability to maintain protein homeostasis, has been established as a hallmark of nematode aging. However, whether proteostasis collapse occurs in humans has remained unclear. Here we demonstrate that proteostasis decline is intrinsic to human senescence. Using transcriptome-wide characterization of gene expression, splicing and translation, we found a significant deterioration in the transcriptional activation of the heat shock response in stressed senescent cells. Furthermore, phosphorylated HSF1 nuclear localization and distribution were impaired in senescence. Interestingly, alternative splicing regulation was also dampened. Surprisingly, we found a decoupling between different Unfolded Protein Response (UPR) branches in stressed senescent cells. While young cells initiated UPR-related translational and transcriptional regulatory responses, senescent cells showed enhanced translational regulation and ER stress sensing, however they were unable to trigger UPR-related transcriptional responses. This was accompanied by diminished ATF6 nuclear localization in stressed senescent cells. Finally, we revealed a deterioration of proteasome function in senescence following heat stress, which did not recover upon return to normal temperature. Together, our data unraveled a deterioration in the ability to mount dynamic stress transcriptional programs upon human senescence with broad implications on proteostasis control, and connected proteostasis decline to human aging. Significance Protein homeostasis (proteostasis), the balance between protein synthesis, folding, and degradation, is thought to deteriorate with age, and the prevalence of protein misfolding diseases, e.g. Alzheimer’s, Parkinson’s etc., with human aging is increased. However, while in worms this phenomenon has been well established, in humans it remained unclear. Here we show that proteostasis is declined in human senescence, i.e. cellular aging. We found that while stress sensing is enhanced in senescent cells, and their response at the level of protein synthesis is intact, they fail to properly activate multiple programs required for stress adaptation at the level of gene transcription. Our findings support the notion that proteostasis decline may have major implications on human aging. Competing Interest Statement The authors have declared no competing interest.

Particles analysis, such as cell counting and differentiation, are widely used for the diagnosis and monitoring of several medical conditions, such as during inflammation. Three-dimensional-printed lab-on-a-chip (LOC) devices, which can utilize one of the cell counting methods, can bring this technology to remote locations through its cost-efficient advantages and easy handling. We present a three-dimensional-printed LOC device with integrated electrodes. To overcome the limited resolution of a 3D printer, we utilized a flow-focusing design. We modeled and simulated the mass transfer and flow dynamics in the LOC by incorporating a flow-focusing design and reached an optimal channel diameter of 0.5 mm, resulting in a flow-focusing distance of <60 µm. We also used electrochemical impedance spectroscopy to enable the dependence of the electrode–solution interface on the flow-focusing properties. Finally, we highlighted the proof-of-concept detection of microspheres (6 µm diameter), which model biological cells that flow in the channel, by recording the electrochemical impedance at 10 kHz, thus showing the potential of a future point-of-care (POC) device.

We investigated transfer of artificial grammar learning in adults with and without dyslexia in 3 experiments. In Experiment 1, participants implicitly learned an artificial grammar system and were tested on new items that included the same symbols. In Experiment 2, participants were given practice with letter strings and then tested on strings created with a different letter set. In Experiment 3, participants were given practice with shapes and then tested on strings created with different shapes. Results show that in Experiment 1, both groups demonstrated utilization of pre-trained instances in the subsequent grammaticality judgement task, while in Experiments 2 (orthographic) and 3 (nonorthographic), only typically developed participants demonstrated application of knowledge from training to test. A post hoc analysis comparing between the experiments suggests that being trained and tested on an orthographic task leads to better performance than a nonorthographic task among typically developed adults but not among adults with dyslexia. Taken together, it appears that following extensive training, individuals with dyslexia are able to form stable representations from sequential stimuli and use them in a subsequent task that utilizes strings of similar symbols. However, the manipulation of the symbols challenges this ability.

Avoidant/restrictive food intake disorder (ARFID) is a relatively new diagnostic category. We sought to determine whether the Stanford Feeding Questionnaire (SFQ), an instrument for assessing picky eating, can differentiate children with ARFID from control children, and whether children with ARFID would show more nonfeeding/eating emotional problems than controls. Fifty children with ARFID were compared to 98 controls. Parents completed the SFQ, Screen for Child Anxiety Related Emotional Disorders (SCARED), Strength and Difficulties Questionnaire (SDQ), and Sensory Responsiveness Questionnaire (SRQ). On the SFQ, 12 items represented child ARFID behaviors (SFQ-ARFID Scale), and another 15 items represented parental feeding problems (SFQ-PFP Scale). We found that the SFQ-ARFID and SFQ-PFP Scale scores were significantly higher in children with ARFID vs. controls. Children with ARFID demonstrated higher SDQ-Total-Difficulties, higher SDQ-Internalizing-Difficulties and lower SRQ-Hedonic scores compared with controls. Of all parameters, the SFQ-ARFID Scale best differentiated children with ARFID from control children (area under receiver operating characteristics curve = 0.939, 95% CI, 0.895–0.983, p < 0.001). These findings suggest that parental reports show more eating problems and emotional disturbances in children with ARFID vs. controls, and more parental feeding problems. Further research is required to determine whether the SFQ-ARFID Scale may serve as an effective screening tool for the identification of ARFID.

SARS-CoV-2 is evolving with increased transmission, host range, pathogenicity, and virulence. The original and mutant viruses escape host innate (Interferon) immunity and adaptive (Antibody) immunity, emphasizing unmet needs for high-yield, commercial-scale manufacturing to produce inexpensive vaccines/boosters for global/equitable distribution. We developed DYAI-100A85, a SARS-CoV-2 spike receptor binding domain (RBD) subunit antigen vaccine expressed in genetically modified thermophilic filamentous fungus, Thermothelomyces heterothallica C1, and secreted at high levels into fermentation medium. The RBD-C-tag antigen strongly binds ACE2 receptors in vitro. Alhydrogel®‘85’-adjuvanted RDB-C-tag-based vaccine candidate (DYAI-100A85) demonstrates strong immunogenicity, and antiviral efficacy, including in vivo protection against lethal intranasal SARS-CoV-2 (D614G) challenge in human ACE2-transgenic mice. No loss of body weight or adverse events occurred. DYAI-100A85 also demonstrates excellent safety profile in repeat-dose GLP toxicity study. In summary, subcutaneous prime/boost DYAI-100A85 inoculation induces high titers of RBD-specific neutralizing antibodies and protection of hACE2-transgenic mice against lethal challenge with SARS-CoV-2. Given its demonstrated safety, efficacy, and low production cost, vaccine candidate DYAI-100 received regulatory approval to initiate a Phase 1 clinical trial to demonstrate its safety and efficacy in humans.

Background Albuminuria is an established marker for endothelial dysfunction and cardiovascular risk in diabetes and prediabetes. Exercise induced albuminuria (EiA) appears earlier and may be a more sensitive biomarker for renal endothelial damage. We sought to examine the association between EiA, parameters of the metabolic syndrome, A1C levels, exercise ECG test results and sex related differences in a large cohort of healthy, pre-diabetic and diabetic subjects. Methods A total of 3029 participants from the Tel-Aviv Medical Center Inflammation Survey cohort (mean age 46 years, 73% men) were analyzed. Multiple physiologic and metabolic parameters including A1C were collected and albuminuria was measured in all subjects before and immediately after completing an exercise ECG test. Results Exercise increased urinary albumin to creatinine ratio (ΔEiA) by 2.8 (0–13.6) mg/g for median (IQR) compared to rest albuminuria (p < 0.001). An increase in ΔEiA was observed with accumulating parameters of the metabolic syndrome. ΔEiA showed significant interaction with sex and A1C levels; i.e. women with A1C > 6.5% had an increased risk of higher ΔEiA (p < 0.001). Using a cutoff of ΔEiA > 13 mg/g (top quartile) we found that women with ΔEiA > 13 mg/g were at greater risk for abnormal exercise ECG findings, (OR = 2.7, p = 0.001). Conclusion Exercise promotes excessive urinary albumin excretion in dysmetabolic patients. In women, a significant correlation exists between ΔEiA and A1C levels. A cutoff of ΔEiA > 13 mg/g in women may be used to identify populations at risk for abnormal exercise ECG test findings and perhaps increased cardiovascular risk. Future studies will be needed to further validate the usefulness of ΔEiA as a biomarker for cardiovascular risk in women with and without diabetes.

Data on adjuvant chemotherapy (CT) benefit in ER + HER2‒ early-stage breast cancer (EBC) patients with Recurrence Score (RS) 26-30 are limited. This real-world study evaluated the relationships between the RS, adjuvant treatments, and outcomes in 534 RS 26-30 patients tested through Clalit Health Services (N0: n = 394, 49% CT-treated; N1mi/N1: n = 140, 62% CT-treated). The CT-treated and untreated groups were imbalanced (more high-risk clinicopathologic characteristics in CT-treated patients). With median follow-up of 8 years, Kaplan–Meier estimates for overall survival (OS), distant recurrence-free survival (DRFS), and BC-specific mortality (BCSM) were not significantly different between CT-treated and untreated N0 patients. Seven-year rates (95% CI) in CT-treated vs untreated: OS, 97.9% (94.4–99.2%) vs 97.9% (94.6–99.2%); DRFS, 91.5% (86.6–94.7%) vs 91.2% (86.0–94.6%); BCSM, 0.5% (0.1–3.7%) vs 1.6% (0.5–4.7%). For N1mi/N1 patients, OS/DRFS did not differ significantly between treatment groups; whereas BCSM did (1.3% [0.2–8.6%] vs 6.2% [2.0–17.7%] for CT-treated and untreated patients, respectively, p = 0.024).

Data on using the 21-gene Recurrence Score (RS) testing on second breast cancer (BC; second primary or local recurrence) are lacking. This cohort study examined patients with first and second BC, who underwent 21-gene testing both times. It included a ‘study-cohort’ (60 N0/N1mi/N1 ER + HER2‒ BC patients with ≥2 RS results >1 year apart) and a ‘general 21-gene-tested BC-cohort’ (2044 previously described N0/N1mi/N1 patients). The median time between the first and second BC was 5.2 (IQR, 3.1–7.1) years; the second BC was ipsilateral in 68%. Patient/tumor characteristics of the first- and second-BC in the ‘study-cohort’ were similar, except for the RS which was higher in the second BC (median [IQR]: 23 [17–30] vs 17 [14–22], p < 0.001). Overall, 56 patients had follow-up data, of whom 5 experienced distant recurrence (2 RS 11–25 patients and 3 RS 26–100 patients). Studies exploring the prognostic utility of the RS in this setting are warranted.