bluuebunny/crossref_metadata_2025 huggingface dataset:
Acupoint transplantation versus non-acupoint transplantation using autologous peripheral blood mononuclear cells in treating peripheral arterial disease
Authors: Guo Wenjing , Pan Ling , Yang Ruiyu , Sun Jiali , Hu Qinglin , Huang Pingping
Published: January 2024

Numerous studies have discussed the therapeutic outcomes of using cell therapy or acupuncture to treat peripheral artery disease (PAD). However, there are no long-term studies on the safety and efficacy of transplanting peripheral blood mononuclear cells (PBMNCs) via acupoints to treat PAD. We first reviewed the short-term and long-term clinical results of PAD patients treated with PBMNCs through intramuscular non-acupoint transplantation (control group; n = 45) or intramuscular acupoint transplantation (acupoint group; n = 45) at a single university hospital general medical center between December 2002 and September 2022. Pain intensity (assessed with the verbal rating scale [VRS] score) in the acupoint group was considerably lower than that in the control group at month 1 (mean ± standard deviation [SD]: 1.29 ± 0.96 vs 1.76 ± 0.82; P = 0.016) and month 3 (mean ± SD: 1.27 ± 0.90 vs 1.61 ± 0.86; P = 0.042). We observed significant improvement of VRS score (P < .001 for all) and ankle-brachial index (ABI; P < .001 for all) from baseline in both groups at months 1, 3, 6, 12, 36, and 60. The 10-year cumulative rate of major amputation–free survival (MAFS) was higher in the acupoint group as compared to the control group (81.9%, 95% confidence interval [CI]: 71.3%–94.1% vs 78.5%, 95% CI: 66.7%–92.3%; P = 0.768). Compared with the routine injection method, intramuscular transplantation of PBMNCs via selected acupoints could significantly decrease the short-term pain intensity in patients with PAD, which remains an option for consideration.
Can observational learning reinforce open-label placebo hypoalgesia?
Authors: Brączyk Justyna , Bąbel Przemysław
Published: January 2024

Previous research has indicated that an open-label placebo can reduce pain in both healthy participants and patients with chronic pain. Because nondeceptive placebos seem to be an effective and more ethical alternative to deceptive placebos, optimizing this kind of treatment is essential. Observational learning was previously shown to induce the deceptive placebo effect; therefore, this study aimed to verify its effectiveness in fortifying the open-label placebo effect. Healthy volunteers (N = 117) were randomly assigned to 4 groups: open-label placebo with observational learning (OLP + OBL), open-label placebo (OLP), deceptive placebo with observational learning (OBL), or control group. Participants underwent baseline and testing measurements, during which they self-reported pain induced by heat stimulation. Between assessments, placebo cream was openly administered in the OLP and OLP + OBL groups. The OLP + OBL group next watched a model experiencing hypoalgesia after cream application. In the OBL group, participants received placebo cream with no information about its effect, and then they watched the model. The placebo effect was successfully evoked in all experimental groups (OLP + OBL, OLP, and OBL), which confirms the effectiveness of both open-label and deceptive placebo interventions for pain reduction. However, the hypoalgesic effect was of similar magnitude in the OLP and OLP + OBL groups, which indicates that observation did not contribute to the effect. The results showed that reinforcing the open-label placebo by observational learning may be redundant, but more research is needed to confirm these findings.
Exploring the Role of YAP1 and TAZ in Pancreatic Acinar Cells and the Therapeutic Potential of VT-104 in Pancreatic Inflammation
Authors: Lopez Kevin , Deng Janice J , Xu Yi , Sharkey Francis E. , Wang Pei , Liu Jun
Published: January 2024

Background:

Increasing evidence has linked the Hippo pathway with the fibroinflammatory diseases. However, the detailed roles of key hippo components in pancreatic inflammatory diseases still remain unclear.

Method:

A series of genetic knockout mice were generated targeting the key components of Hippo pathway to examine the individual effects of YAP1 and TAZ on pancreatic inflammation. H&E staining, immunohistochemistry and immunofluorescence staining were performed to evaluate the pancreas tissue from mice with various genotypes. The therapeutic potential of a recently developed YAP1/TAZ inhibitor VT-104 was also evaluated in our mouse model.

Results:

Mice with acinar-specific knockout of YAP1/TAZ did not exhibit any histological abnormalities in the pancreas. LATS1/2 deficiency induced acinar-to-ductal metaplasia, immune cell infiltration and fibroblast activation, which were rescued by the homozygous knockout YAP1, but not TAZ. Additionally, treatment with VT-104 also decreased pathological alterations induced by deletions of LATS1 and LATS2 in acinar cells.

Conclusion:

Our findings highlight the critical role of YAP1 in modulating pancreatic inflammation and demonstrate that VT-104 holds therapeutic potential to mitigate pancreatitis-associated pathological manifestations. Further exploration is necessary to unravel the underlying mechanisms and translate these insights into clinical applications.
Risk Factors Associated with Advanced Colorectal Neoplasia in Adults Younger than Age 45
Authors: Bolwell Jacquelyn , Butler Robert , Burke Carol A. , Liska David , Macaron Carole
Published: January 2024

Background:

Colorectal cancer (CRC) is rising in young adults between ages 20 to 49 years. CRC screening is endorsed for average-risk individuals beginning at ages 45 to 49 years. Targeting screening for individuals <45 years may be warranted if risk factors for advanced neoplasia can be identified.

Aim:

To identify factors associated with advanced colorectal neoplasia in adults aged <45 years.

Method:

Individuals ages 18 to 44 years who underwent colonoscopy at Cleveland Clinic between 2011 and 2021 with ≥1 advanced neoplasm (AN) were included. Patients with inflammatory bowel disease or inherited CRC syndromes were excluded. Demographics, comorbidities, family history of CRC, and colonoscopy indication were obtained. Patients with a normal colonoscopy constituted the control group. A multivariable logistic regression model was used to investigate the relationship between clinical variables and the presence of advanced colorectal neoplasia.

Results:

In all, 13,006 patients were included, of which 651 (5%) patients had AN: 404 (62%) with tubular adenoma ≥10 mm, 29 (4.5%) tubular adenoma with high-grade dysplasia, 210 (32%) tubulovillous adenomas, 27 (4%) traditional serrated adenomas, 82 (13%) sessile serrated lesions ≥10 mm, 7(2%) sessile serrated lesions with dysplasia, and 29 (4.4%) patients had a CRC. Factors associated with AN were older age (means 38.5 vs. 36.6 y), history of smoking, diabetes, non-White race, higher body mass index (29.9 vs. 28.5 kg/m2), and lower vitamin D (27.6 vs. 32.2 ng/dl), all P<0.001. In the reduced multivariable model, factors associated with AN included tobacco use (OR 2.026 (current vs. never, P<0.0001), age (OR increase by 1.06 per year, P<0.0001), male gender (OR 1.476, P<0.0001), family history of CRC (OR 3.91, P<0.0001), aspirin use (1.31, P=0.035), and diabetes (OR 2.106, P 0.001).

Conclusion:

Increasing age, male gender, exposure to tobacco, family history of CRC, diabetes, and aspirin use were independently associated with advanced neoplasia in adults younger than 45. Targeted early screening to young adults with these risk factors may be justified. Large collaborative prospective studies are needed to validate our findings.
Antithrombotic Usage, Including Three-Year Outcomes With Dabigatran and Vitamin K Antagonists for Atrial Fibrillation, in Eastern Europe: A Descriptive Analysis From Phase 3 of the GLORIA-AF Registry
Authors: Bergler-Klein Jutta , Gotcheva Nina , Kalējs Oskars , Kalarus Zbigniew , Kovačić Dragan , Peršić Viktor , Shlyakhto Evgeny , Uuetoa Tiina , Huisman Menno V. , Lip Gregory Y. H. , Vinereanu Dragos ,   on behalf of the GLORIA-AF Investigators
Published: January 2024

Background:

Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) is a prospective registry of outcomes from patients with newly diagnosed AF at risk of stroke. In the propensity score (PS)-matched global population of phase 3 GLORIA-AF, at 3 years, dabigatran-treated patients experienced reduced risk for major bleeding, and similar risk for stroke and myocardial infarction, compared with vitamin K antagonist (VKA)-treated patients.

Study Question:

Do patients in Eastern Europe benefit from treatment with dabigatran versus VKA?

Study Design:

Descriptive analysis, without PS matching. To contextualize the Eastern Europe results of GLORIA-AF phase 3, we also descriptively analyzed the global population without PS matching. Consecutive patients with newly diagnosed AF and CHA2DS2-VASc-score ≥1 were enrolled until December 2016 in 38 countries (9 in Eastern Europe).

Measures and Outcomes:

Three-year outcomes with dabigatran and VKA.

Results:

In Eastern Europe, 1341 patients were eligible (6% of patients globally), and incidence rates (per 100 patient-years) for the following outcomes were numerically lower with dabigatran (N = 498) versus VKA (N = 466): major bleeding (0.26 vs. 0.90), all-cause death (2.04 vs. 3.50), and a composite of stroke, systemic embolism, myocardial infarction, life-threatening bleeding, and vascular death (1.37 vs. 1.92); stroke was comparable (0.51 vs. 0.50). All incidence rates were numerically lower in Eastern Europe versus the global population for both treatments. Chronic concomitant use of high bleeding risk medications (eg, nonsteroidal anti-inflammatories) was lower in Eastern Europe (dabigatran 3.8%, VKA 9.3%) than globally (dabigatran 14.8%, VKA 20.6%) and persistence with dabigatran was higher in Eastern Europe (76%) than globally (64%).

Conclusions:

Dabigatran was associated with numerically reduced major bleeding, all-cause death, and cardiovascular (CV) composite, with comparable risk of stroke versus VKA, in Eastern Europe. Limitations of this descriptive analysis include few CV events (n = 11 for stroke, in the dabigatran and VKA groups combined) and a lack of statistical analysis and PS matching, which precludes definitive conclusions; however, the CV outcomes in Eastern Europe were consistent with the beneficial impact of dabigatran versus VKA in the statistically analyzed global population with PS matching.
A Review of Parental Bereavement Interventions
Authors: Dias Nancy , Floyd Abigail , Ramkumar Rhea , Horvick Savannah , Haberstroh Amanda , Hendricks-Ferguson Verna L. , Fasolino Tracy
Published: January 2024

The untimely death of a child is an incredibly traumatic experience for parents and their loved ones. It uproots every aspect of their life, leading the bereaved parents to be far more likely to have poorer physical and mental health outcomes. This traumatic form of bereavement should have comprehensive grief-focused, high-quality interventions available for parents and extended family members. The purpose of this rapid review was to explore and describe the bereavement interventions available for parents and family that have been published within the past 5 years. Records identified 123 full-text articles that were reviewed, and 14 of those were included for data extraction and synthesis, using Cochrane Rapid Reviews Methods Group with the addition of keyword searches. The 14 articles were analyzed by evaluating description of bereaved parents, accessibility of interventions, who delivered interventions, and the type and delivery time of interventions. Four types of interventions were identified, including Web-based, community-based, hospital-based, and psychotherapy interventions. This rapid review has implications for clinical practice, research, and health care policy that can increase the availability of support and quality of interventions for bereaved parents and family members.
Three novel rare TP53 fusion mutations in a patient with multiple primary cancers: a case report
Authors: Lu Mengyao , Zhang Xuemei , Chu Qian , Chen Yuan , Zhang Peng
Published: January 2024

As survival rates improve and detection technologies advance, the occurrence of multiple primary cancers (MPCs) has been increasing. Approximately 16% of cancer survivors develop a subsequent malignancy, with lung cancer often developing after esophageal cancer due to potential “field cancerization” effects. Despite this observation, the genetic heterogeneity underlying MPCs remains understudied. However, the recent emergence of genetic testing has expanded the scope of investigations into MPCs to investigate signatures underlying cancer predisposition. This report reveals 3 unprecedented TP53 fusion mutations in a Chinese patient afflicted by MPCs, namely, AP1M2–TP53 (A1;T11) fusion, TP53–ILF3 (T10;I13) fusion, and SLC44A2–TP53 (S5;T11) fusion. This patient exhibited an extended period of survival after diagnosis of extensive-stage small cell lung cancer, which occurred 6 years after the diagnosis of esophageal squamous cell cancer. This unique report may provide supplementary data that enhance our understanding of the genetic landscape of MPCs.
Cognitive Behavioral Therapy Approaches for Chronic Suicidality
Authors: Royter Evgenia , Sudak Donna , Plakun Eric M.
Published: January 2024

This review provides an overview of research evidence from the past 5 years concerning cognitive behavioral therapy for suicide prevention. The authors then discuss the clinical implementation of this approach in patients with chronic suicidal behavior.
Anticipating Patient Safety Events in Psychiatric Care
Authors: YERSTEIN MARIA C. , SUNDARARAJ DEEPIKA , MCLEAN MARISSA , KROLL DAVID S.
Published: January 2024

Objectives:

Although suicide prevention often dominates patient safety efforts in psychiatry and behavioral health, patients who seek such services are also prone to other kinds of adverse events. The purpose of this study was to more fully characterize the types of safety events that occur in the context of psychiatric care.

Methods:

This was a retrospective study of safety events that had been reported to a hospital-based psychiatry department during a 4-year period. The authors reviewed each incident, developed new and more precise event categories, and assigned each report to a category. Events that could not be categorized were assigned to an “Other” category. The percentages of categorizable events between the new and old frameworks were compared.

Results:

A total of 366 reports were filed. In the updated framework, 324 events (89%) could be categorized compared to 225 (61%) in the original registry.

Conclusions:

Understanding the kinds of safety events that clinicians are likely to encounter in the context of psychiatric care may help to expand patient safety efforts beyond suicide risk prevention.
Virological, weight, and drug resistance outcomes among patients initiating a dolutegravir-based first-line antiretroviral therapy regimen in Zimbabwe
Authors: Kouamou Vinie , Washaya Tendai , Mapangisana Tichaona , Ndhlovu Chiratidzo Ellen , Manasa Justen
Published: January 2024

Objective:

Dolutegravir (DTG)-based antiretroviral therapy (ART) is being scaled up in Africa. However, clinical experience with DTG and patterns of HIV drug resistance (HIVDR) are sparse in Zimbabwe. We assessed virological, weight, and HIVDR outcomes among individuals initiating on a DTG-based ART.

Design:

We conducted a prospective cohort study among HIV-infected adult (≥18 years old) individuals attending care at Parirenyatwa hospital, Harare, Zimbabwe between October 2021 and April 2023.

Methods:

Viral load and weight were assessed at both baseline and follow-up (≥24weeks) visits. HIVDR genotyping was performed by Sanger sequencing among participants with virological failure (viral load ≥1000 copies/ml) at follow-up visit. Factors associated with weight gain were determined using logistic regression analysis on STATA 17.0.

Results:

One hundred and seventy-two participants were enrolled in the study. The median [interquartile range (IQR) age was 39 (29–48)] years whilst the median (IQR) CD4+ cell count and log10 viral load at enrolment was 175 (58–328) cells/μl and 5.41 (4.80–5.74), respectively. After a median (IQR) duration of 27 (25–30) weeks on DTG, of the 131 participants with follow-up viral load data available, 129 (98%) had viral load less than 1000 copies/ml and among the 2 (2%) participants with viral load at least 1000 copies/ml, no emergent HIVDR was detected. We observed a significant increase in weight among the participants. The average weight gain was 5.25 kgs (P < 0.0001). Baseline CD4+ cell count at least 200 cells/μl was significantly associated with at a smaller weight gain [odds ratio (OR) = 0.26; 95% confidence interval (CI) 0.12–0.58, P = 0.001].

Conclusion:

We found high virological suppression and an increased weight among people initiating on DTG in a resource-limited setting. Encouragingly, HIVDR to DTG remains rare.
Post–Hair Transplantation Complication: Kinky or Severely Curly Hair
Authors: Park Jae Hyun , Kim Narae , Manonukul Kotchamol
Published: January 2024

Objective:

To investigate the etiology and preventive measures of posttransplant kinky or curly hair growth after female hairline correction surgery.

Background:

Hair transplant surgery can be accompanied by various adverse effects, one of which is severely kinky or curly hair after surgery. Posttransplant kinky or curly hair is not well-understood for its cause or prevention.

Methods:

The study was targeted at a total of 980 patients who were confirmed whether they developed kinky or curly hair after female hairline correction surgery. Incidence, surgical method, degree of curliness, predisposed location, characteristics, hair caliber (thin, medium, and thick), and left-right differences were examined.

Results:

Among the total 980 patients, posttransplant curly hair (PTCH) was manifested in 38(3.9%) patients. None of the patients who underwent surgery at the present clinic developed posttransplant kinky hair; all 38 patients showed PTCH growth. In 36 cases, transplanted hair started to grow in curly patterns around 4 months after surgery. However, the remaining 2 cases showed no curly growth pattern when the transplanted hair was short at postoperative 4 months, but started to grow curly starting at 6 to 8 months after surgery as the hair growth direction was obstructed or compressed by the existing hair.

Conclusion:

Familiarity with the cause, prevention, and management of posttransplant kinky hair and PTCH will be of great help to hair surgeons.
Current Status of Difficult Airway Information Dissemination at a Tertiary Pediatric Hospital
Authors: Shi Yun , Lan Dongyi , Zhang Songchunyuan , Dong Chenbin
Published: January 2024

Objective:

Difficult airway is one of the most common potential risk factors for increased fatality in craniofacial/plastic surgery patients. To date, there is no well-established and all-around difficult airway notification system in China, which has recently been recommended by existing guidelines to improve the care of patients with known difficult airways. This study aimed to investigate the current status of critical information communication concerning difficult airway management in our institute.

Methods:

Vital information required to establish a difficult airway registry and notification system was collected through a literature review and expert suggestions. After approval by the Research Ethics Board, 3 online questionnaires were developed and sent to surgeons, anesthesiologists, and proxies of the patients. Knowledge of difficult airways, the willingness to be involved in the difficult airway notification system, and the way to disseminate the information were investigated in the 3 groups. The specific information that was disseminated, required, and available was investigated in the anesthesiologist group.

Results:

Compared with the surgeons and anesthesiologists, significantly fewer patients knew the definition of a difficult airway and thought it was a potential risk factor. There were no significant differences in the willingness to be informed of the difficulty encountered during airway management. Significant differences were detected in the willingness and way to disseminate the airway information when the participants communicated with different groups. Significantly more patients would disseminate the information to the surgeon and significantly more surgeons would disseminate the information to the patient and the other surgeon. Significantly more anesthesiologists would disseminate the information to the patient and the other anesthesiologists. A significant difference was observed between what was expected and what was available for the anesthesiologist to retrieve the airway information of a patient with known airway difficulty. Significantly more anesthesiologists would notify only the patient of the diagnosis of a difficult airway both oral and written, whereas significantly more anesthesiologists would notify the other anesthesiologist of the specific difficulties in oral only. Most participants agreed to be involved in the difficult airway notification system despite the significantly lower percentage in the patient group (89%).

Conclusions:

Difficult airway information dissemination is, at the time of this writing, ineffective, which leads to a large gap between the expectation and practice of the anesthesiologist when caring for a patient with a difficult airway. Thus, a difficult airway registry and notification system should be developed, that has a solid foundation in all the participants.
Self-testing knowledge and beliefs on HIV self-testing use in central Uganda
Authors: Nsereko Gerald Mukisa , Kobusingye Loyce Kiiza , Musanje Khamisi , Nangendo Joanita , Nantamu Simon , Baluku Martin Mabunda
Published: January 2024

The government of Uganda and its implementing partners have made significant investments in HIV self-testing (HST) services to reduce clinic-related barriers to HIV testing. However, although HSTs have been around for a reasonable time, their uptake, especially among unskilled working individuals, has remained suboptimal, which threatens the efforts to achieve the 95-95-95 UNAIDS goals to end HIV by 2030.

This study set out to examine whether knowledge and individual beliefs about self-testing influence the use of HIV self-tests among causal workers in Kampala. This cross-sectional study was conducted among 453 participants selected via systematic random sampling from Darling Uganda Ltd. in Wakiso district between July and August 2023. Standardized questionnaires were used, and the analysis was performed using Pearson Correlations and Linear Regression in SPSS.

The findings indicate that HIV self-testing (HST) knowledge was positively related to HST use (r=.387, p≤.01), perceived susceptibility (r=.212, p≤.01), perceived benefits (r=.152, p≤.01), and perceived barriers (r=.101, p≤.05). Individual beliefs, that is, perceived susceptibility (r=.355, p≤.01), perceived benefits (r=.487, p≤.01), and perceived barriers (r=.148, p≤.01), were significantly related to HST use. Perceived benefits were the best predictor of HST use among this population (β=.442,p=.000). Therefore, (44.2%) of HST use was attributed to the benefits attached to the service.

Therefore, increasing awareness regarding the benefits of HST among such populations increases the chances of HIV testing, particularly among men. This can pave the way for the 95-95-95 goal by 2030 of UNAIDS.
Experimental evaluation of a direct fitness effect of thede novoevolved mouse genePldi
Authors: Linnenbrink Miriam , Breton Gwenna , Misra Pallavi , Pfeifle Christine , Dutheil Julien Y. , Tautz Diethard
Published: January 2024

De novoevolved genes emerge from random non-coding sequences and have, therefore, no homologs from which a function could be inferred. While expression analysis and knockout experiments can provide insights into the function, they do not directly test whether the gene is beneficial for its carrier. Here, we have used a seminatural environment experiment to test the fitness of the previously identified denovoevolved mouse genePldi, which is thought to be involved in sperm differentiation. We used a knockout mouse strain for this gene and competed it against its parental wildtype strain for several generations of free reproduction. We found that the knockout (ko) allele frequency decreased consistently across three replicates of the experiment. Using an approximate Bayesian computation framework that simulated the data under a demographic scenario mimicking the experiment’s demography, we could estimate a fitness coefficient ranging between 0.15 to 0.67 for the wildtype allele compared to the ko allele in males. We conclude that a gene that has evolvedde novofrom a random intergenic sequence can have a measurable fitness benefit.
Value construction through sequential sampling explains serial dependencies in decision making
Authors: Zylberberg Ariel , Bakkour Akram , Shohamy Daphna , Shadlen Michael N
Published: January 2024

Many decisions are expressed as a preference for one item over another. When these items are familiar, it is often assumed that the decision maker assigns a value to each of the items and chooses the item with the highest value. These values may be imperfectly recalled, but are assumed to be stable over the course of an interview or psychological experiment. Choices that are inconsistent with a stated valuation are thought to occur because of unspecified noise that corrupts the neural representation of value. Assuming that the noise is uncorrelated over time, the pattern of choices and response times in value-based decisions are modeled within the framework of Bounded Evidence Accumulation (BEA), similar to that used in perceptual decision-making. In BEA, noisy evidence samples accumulate over time until the accumulated evidence for one of the options reaches a threshold. Here, we argue that the assumption of temporally uncorrelated noise, while reasonable for perceptual decisions, is not reasonable for value-based decisions. Subjective values depend on the internal state of the decision maker, including their desires, needs, priorities, attentional state, and goals. These internal states may change over time, or undergo revaluation, as will the subjective values. We reasoned that these hypothetical value changes should be detectable in the pattern of choices made over a sequence of decisions. We reanalyzed data from a well-studied task in which participants were presented with pairs of snacks and asked to choose the one they preferred. Using a novel algorithm (Reval), we show that the subjective value of the items changes significantly during a short experimental session (about 1 hour). Values derived withRevalexplain choice and response time better than explicitly stated values. They also better explain the BOLD signal in the ventromedial prefrontal cortex, known to represent the value of decision alternatives. Revaluation is also observed in a BEA model in which successive evidence samples are not assumed to be independent. We argue that revaluation is a consequence of the process by which values are constructed during deliberation to resolve preference choices.
“Bayesian anchoring” and the fourfold pattern of risk attitudes
Authors: Fumarola Francesco , Kusmierz Lukasz , Dekker Ronald B.
Published: January 2024

Experiments on decision making under uncertainty are known to display a classical pattern of risk aversion and risk seeking referred to as “fourfold pattern” (or “reflection effect”), but recent experiments varying the speed and order of mental processing have brought to light a more nuanced phenomenology. We model experiments though a Bayesian formalization of the anchor-and-adjust heuristic observed in empirical studies on cognitive bias. Using only elementary assumptions on constrained information processing, we are able to infer three separate effects found in recent observations: (1) the reported enhancement of the fourfold pattern for quicker decision processes; (2) the observed decrease of fluctuations for slower decision-making trials; (3) the reported dependence of the outcome on the order in which options are processed. The application of Bayesian modeling offers a solution to recent empirical riddles by bridging two heretofore separate domains of experimental inquiry on bounded rationality.
CD4 T Cells Acquire Cytotoxic Properties to Modulate Cellular Senescence and Aging
Authors: Elyahu Yehezqel , Feygin Ilana , Pinkas Noa , Zemer Alon , Shicht Amit , Berner Omer , Eremenko Ekaterina , Nemirovsky Anna , Reshef Keren , Roitman Lior , Krizhanovsky Valery , Monsonego Alon
Published: January 2024

Aging is characterized by the progressive deterioration of tissue structure and function, leading to increased vulnerability to diseases and, eventually, death. One prominent process in aging is the accumulation of senescent cells. Although the immune system has been recognized as crucial for the elimination of senescent cells, the associated mechanisms remain incompletely understood. Here we show that CD4 T cells differentiate into cytotoxic T lymphocytes (CTLs) in a senescent cell-rich environment and that a reduction in the senescent cell load, achieved using chemical senolytic drugs, was sufficient to halt this differentiation. We further demonstrate that eliminating CD4 CTLs in the context of late aging by selectively deleting the Eomes transcription factor in CD4 T cells resulted in the increased accumulation of senescent cells, profound physical deterioration, and a decreased life span. In liver cirrhosis, a model of localized chronic inflammation, CD4 CTL elimination increased the senescent load and worsened the disease. Collectively, our findings demonstrate the fundamental role of CD4 CTLs in modulating tissue senescence and unveil a new aspect of age-related T-cell biology implicated in disease susceptibility and longevity.
Intricate response dynamics enhances stimulus discrimination in the resource-limitedC. eleganschemosensory system
Authors: Bokman Eduard , Pritz Christian O. , Ruach Rotem , Itskovits Eyal , Sharvit Hadar , Zaslaver Alon
Published: January 2024

Sensory systems evolved intricate designs to accurately encode perplexing environments. However, this encoding task may become particularly challenging for animals harboring a small number of sensory neurons. Here, we studied how the compact resource-limited chemosensory system ofC. elegansuniquely encodes a range of chemical stimuli. We find that each stimulus is encoded using a small and unique subset of neurons, where only a portion of the encoding neurons sense the stimulus directly, and the rest are recruited via inter-neuronal communication. Furthermore, while most neurons show stereotypical response dynamics, some neurons exhibit versatile dynamics that are either stimulus specific or network-activity dependent. Notably, it is the collective dynamics of all responding neurons which provides valuable information that ultimately enhances stimulus identification, particularly when required to discriminate between closely-related stimuli. Together, these findings demonstrate how a compact and resource-limited chemosensory system can efficiently encode and discriminate a diverse range of chemical stimuli.
Functional diversity in the Hsp60 ofSulfolobus acidocaldarius: mosaic of Group I and Group II chaperonin
Authors: Bhakta Koustav , Roy Mousam , Samanta Shirsha , Ghosh Abhrajyoti
Published: January 2024

External stress can disrupt protein homeostasis in organisms, necessitating the involvement of heat shock proteins (Hsps) to restore equilibrium and ensure survival. Unlike other organisms, the thermoacidophilic crenarchaeonSulfolobus acidocaldariuslacks Hsp100, Hsp90, and Hsp70, possessing only two small heat shock proteins (Hsp14 and Hsp20) and one group II chaperonin, Hsp60. This raises questions about how protein substrates are protected and transferred to Hsp60 for refolding without other chaperones. Our study focused on ATP-dependent Hsp60 inS. acidocaldarius, revealing its formation of oligomeric structures in the presence of ATP. While ATP hydrolysis is not essential for oligomer formation and lid closure, it is crucial for Hsp60’s chaperone activity, effectively folding stress-denatured substrate proteins by stabilizing their folded conformations. The mechanism involves hydrophobic recognition of unfolded substrates, encapsulating and releasing them in a more folded state. Negatively charged inner surface of the ring seems to be responsible for driving the folding of the substrate. Importantly, Hsp14 was found to transfer substrate proteins to Hsp60αβ, orchestrating their refolding into an active state. Beyond protein folding, Hsp60β protects the membrane under stress, contributing to maintaining membrane rigidity. Hsp60 exhibits nested cooperativity in ATPase activity, adapting to ATP concentration changes and interestingly Hsp60β and Hsp60αβ complex shows a mosaic behaviour during ATP hydrolysis belonging to both group I and group II chaperonin respectively. In conclusion, our study provides insights into the intricate mechanisms employed by Hsp60 inS. acidocaldariusto maintain protein homeostasis. It offers a comprehensive understanding of Hsp60’s role in the heat shock response pathway, shedding light on fundamental cellular processes in extremophilic archaea.
Endogenous glucocorticoids are required for normal macrophage activation and gastricHelicobacter pyloriimmunity
Authors: Khadka Stuti , Dziadowicz Sebastian A. , Xu Xiaojiang , Wang Lei , Hu Gangqing , Busada Jonathan T.
Published: January 2024

Glucocorticoids are steroid hormones well-known for their potent anti-inflammatory effects. However, their immunomodulatory properties are multifaceted. Increasing evidence suggests that glucocorticoid signaling promotes effective immunity and that disruption of glucocorticoid signaling impairs immune function. In this study, we conditionally deleted the glucocorticoid receptor (GR) in the myeloid lineage using theLysM-Credriver (myGRKO). We examined the impact on macrophage activation and gastric immune responses toHelicobacter pylori, the best-known risk factor of gastric cancer. Our results indicate that compared to WT, GRKO macrophages exhibited higher expression of proinflammatory genes in steroid-free conditions. However, when challenged in vivo, GRKO macrophages exhibited aberrant chromatin landscapes and impaired proinflammatory gene expression profiles. Moreover, gastric colonization withHelicobacterrevealed impaired gastric immune responses and reduced T cell recruitment in myGRKO mice. As a result, myGRKO mice were protected from atrophic gastritis and pyloric metaplasia development. These results demonstrate a dual role for glucocorticoid signaling in preparing macrophages to respond to bacterial infection but limiting their pathogenic activation. In addition, our results support that macrophages are critical for gastric anti-Helicobacterimmunity.

Graphical Abstract
Altering subjective time perception leads to correlated changes in neural activity and delay discounting impulsivity
Authors: Lee Sangil , Kable Joseph W. , Jung Wi Hoon
Published: January 2024

Several accounts of delay discounting suggest subjective time perception as a contributing factor to individually varying discount rates. That is, one may seem impatient if their subjective perception of delay is longer than others’ perception of it. Here we build upon the behavioral and neural research on time perception, and we investigate the effects of manipulating an individual’s subjective time perception on their discount rates and neural activity. Using a novel time- counting task, we found that participants’ discount rates are affected by our manipulations of time perception and that neural activity also correlates with our manipulations in brain regions, such as the anterior insula and the superior temporal gyri, which have been implicated in time perception. We link these behavioral and neural findings together by showing that the degree of neural activity change in response to our manipulation is predictive of the degree of change in the participants’ discount rates.
Generation and benchmarking of a collection of hiPSC lines from Schizophrenia Patients with Diverse Clinical Profiles
Authors: Vecchi Elena Rita , Olmeda Claudia Vittoria , Bottai Daniele , Finelli Palma , Salavarria Marilyn Marlene Angulo , Gervasini Cristina , Mangiaterra Laura , Lombardi Francesco , Sanguineti Claudio , Onorati Marco , Conti Luciano , D’Agostino Armando
Published: January 2024

Limited therapeutic advancements in Schizophrenia (SCZ) depend on the heterogeneous nature of the disorder, impacting drug development and clinical trials that assume uniform therapy response, neglecting individual genetic and epigenomic variability. Disease modeling using human induced pluripotent stem cells (hiPSCs) is ideally suited for precision medicine, enabling individualized treatment approaches. Here, we describe the generation of patient-specific lines from somatic cells of SCZ individuals with well-defined diverse clinical trajectories using a Sendai virus-based reprogramming system. Karyotypically and CGH-array validated, the generated hiPSCs expressed diagnostic markers and demonstrated functional pluripotency. Converting these hiPSCs into neural progenitor cells enables the identification of aberrant cellular phenotypes associated with specific pathologically relevant neural phenotypes. This collection of hiPSC lines serves as a platform for developing therapeutic compounds targeting neural populations, potentially addressing early-stage disease alterations.
Live-cell fluorescence imaging and optogenetic control of PKA kinase activity in fission yeastSchizosaccharomyces pombe
Authors: Sakai Keiichiro , Aoki Kazuhiro , Goto Yuhei
Published: January 2024

The cAMP-PKA signaling pathway plays a crucial role in sensing and responding to nutrient availability in the fission yeastSchizosaccharomyces pombe.This pathway monitors external glucose levels to control cell growth and sexual differentiation. However, the temporal dynamics of the cAMP-PKA pathway in response to external stimuli remains unclear mainly due to the lack of tools to quantitatively visualize the activity of the pathway. Here, we report the development of the kinase translocation reporter (KTR)-based biosensor spPKA-KTR1.0, which allows us to measure the dynamics of PKA activity in fission yeast cells. The spPKA-KTR1.0 is derived from the transcription factor Rst2, which translocates from the nucleus to the cytoplasm upon PKA activation. We found that spPKA-KTR1.0 translocates between the nucleus and cytoplasm in a cAMP-PKA pathway-dependent manner, indicating that the spPKA-KTR1.0 is a reliable indicator of the PKA activity in fission yeast cells. In addition, we implemented a system that simultaneously visualizes and manipulates the cAMP-PKA signaling dynamics by introducing bPAC, a photoactivatable adenylate cyclase, in combination with spPKA-KTR1.0. This system offers an opportunity for investigating the role of the signaling dynamics of the cAMP-PKA pathway in fission yeast cells with higher temporal resolution.

Take Away

spPKA-KTR1.0 allows visualization of PKA activity at the single-cell level

Live-cell imaging reveals the transient decrease in PKA activity after M-phase

Optogenetics allows simultaneous visualization and manipulation of PKA activity
A novel hypothesis-generating approach for detecting phenotypic associations using epigenetic data
Authors: Martin Florence Z. , Easey Kayleigh E. , Howe Laura D. , Fraser Abigail , Lawlor Deborah A. , Relton Caroline L. , Sharp Gemma C.
Published: January 2024

Abstract

Background

Hypotheses about what phenotypes to include in causal analyses (that in turn can have clinical and policy implications) can be guided by hypothesis-free approaches, leveraging the epigenome for example. Materials & methods: Minimally adjusted epigenome-wide association studies (EWAS) using ALSPAC data were performed for example conditions, dysmenorrhea and heavy menstrual bleeding (HMB). Differentially methylated CpGs were searched in the EWAS Catalog and associated traits identified. Traits were compared between those with and without the example conditions in ALSPAC. Results: Seven CpG sites were associated with dysmenorrhea and two with HMB. Smoking and adverse childhood experience score were associated with both conditions in the hypothesis-testing phase. Conclusion: Hypothesis-generating EWAS can help identify associations for future analyses.

Plain language summary

To make a positive impact on policy and clinical practice, it is important that epidemiologists, those who study population health, can identify characteristics that might increase the risk of medical conditions. However, it can be difficult to know which associations should be investigated and decisions can often be biased by pre-formed opinions about what is relevant. In this study, we wanted to look for potential risk factors for dysmenorrhea (painful periods) and heavy menstrual bleeding (HMB) using a hypothesis-free approach (in other words, minimal adjustment for potential confounders), leveraging epigenetic data from a sub-sample of the Avon Longitudinal Study of Parents and Children (ALSPAC) and generating hypotheses about associations, then testing these hypotheses in the wider ALSPAC cohort. This meant looking for differentially methylated CpGs between those with and without the conditions of interest using an epigenome-wide association study (EWAS), seeing which phenotypes were associated with the CpGs in the EWAS Catalog, and testing these hypotheses in the ALSPAC cohort using measurements of each phenotype. For dysmenorrhea, we found seven differentially methylated CpGs and for HMB, we found two. These CpGs were associated with several phenotypes, which we could proxy in the wider ALSPAC cohort, creating hypotheses we tested using regression analyses. In the hypothesis-testing phase, we found that smoking and adverse childhood experience score were associated with dysmenorrhea and HMB. With this under-utilised approach, we can identify phenotypes that may be risk factors for under-studied conditions, that can be explored in other cohorts using analyses that can assess causality.

Tweetable abstract

Leveraging EWAS data can help identify novel potential risk factors for understudied conditions such as dysmenorrhea and heavy menstrual bleeding for future examination in causally motivated analyses: a proof-of-concept study in the Children of the 90’s cohort (ALSPAC)
Genomic adaptations to semi-aquatic and aquatic life in spiders
Authors: Fan Zheng , Wang Lu-Yu , Luo Bin , Ren Tian-Yu , Gao Jia-Xin , Liu Piao , Cheng Ling-Xin , Cai Yu-Jun , Tan Bing , Huang Qian , Deng Ming-Qin , Zuo Qing , Zhang Xiang-Yun , Lu Jin-Zhen , Sun Li-Na , Irfan Muhammad , Liu Ning , Tong Chao , Bai Ming , Zhang Zhi-Sheng
Published: January 2024

Spiders have primarily adapted to terrestrial life, yet a number of species have made evolutionary transitions to marine and freshwater environments. While its physiological and behavioral adaptations have been characterized, the genetic basis of semi-aquatic and aquatic adaptation in spiders remains poorly understood. Here, we provide a high-quality, chromosome-level genome assembly for the aquatic spiderArgyroneta aquatica, alongside a reference transcriptome for the semi-aquatic spiderDesis martensi. We performed comparative genomes analyses of 22 spider species, including a unique aquatic spider, two semi-aquatic spiders and 19 terrestrial spider species, with a focus on those in the marronoid clade. By integrating morphological, phylogenomic, comparative genomic, transcriptomic, and metabolomic analyses, we explored the genomic adaptations of aquatic and semi-aquatic spiders. Phylogenomic analysis suggests that aquatic and semi-aquatic spiders have independently evolved from their terrestrial ancestors and represent divergent evolutionary routes We found hundreds of genes tend to experience relaxed selection, positive selection, and evidence of horizontal gene transfer (HGT) associated with the transition to aquatic and semi-aquatic life in spiders. These genes are associated with respiratory, osmoregulatory, fat metabolism and digestion, hypoxia, and thermal functions, putatively facilitate the adaptations to diverse underwater life. Altogether, our findings highlight the divergent evolutionary mechanisms enabling spiders to thrive in diverse aquatic environments, providing insights into the genomic basis of adaptations to semi-aquatic and aquatic habitats.
KaMRaT: a C++ toolkit fork-mer count matrix dimension reduction
Authors: Xue Haoliang , Gallopin Mélina , Marchet Camille , Nguyen Ha N. , Wang Yunfeng , Lainé Antoine , Bessiere Chloé , Gautheret Daniel
Published: January 2024

KaMRaTis a program for processing largek-mer count tables extracted from high throughput sequencing data. Major functions include scoringk-mers based on count statistics, merging overlappingk-mers into longer contigs and selectingk-mers based on their presence in certain samples.KaMRaT‘s main application is the reference-free analysis of multi-sample and multi-condition datasets from RNA-seq, as well as ChiP-seq or ribo-seq experiments.KaMRaTenables the identification of condition-specific or differential sequences, irrespective of any gene or transcript annotation.

Implementation and availability

KaMRaTis implemented in C++. Source code and documentation are available viahttps://github.com/Transipedia/KaMRaT. Container images are available viahttps://hub.docker.com/r/xuehl/kamrat.
Remodeling of perturbed chromatin can initiatede novotranscriptional and post-transcriptional silencing
Authors: Carlier Florian , Castro Ramirez Sebastian , Kilani Jaafar , Chehboub Sara , Loïodice Isabelle , Taddei Angela , Gladyshev Eugene
Published: January 2024

In eukaryotes, repetitive DNA can become silencedde novo, either transcriptionally or post-transcriptionally, by processes independent of strong sequence-specific cues. The mechanistic nature of such processes remains poorly understood. We found that in the fungusNeurospora crassa,de novoinitiation of both transcriptional and post-transcriptional silencing was linked to perturbed chromatin, which was produced experimentally by the aberrant activity of transcription factors at thetetOoperator array. Transcriptional silencing was mediated by canonical constitutive heterochromatin. On the other hand, post-transcriptional silencing resembled repeat-induced quelling but occurred normally when homologous recombination was inactivated. All silencing of thetetOarray was dependent on SAD-6 (a fungal ortholog of the SWI/SNF chromatin remodeler ATRX), which was required to maintain nucleosome occupancy at the perturbed locus. In addition, we found that two other types of sequences (thelacOarray and native AT-rich DNA) could also undergo recombination-independent quelling associated with perturbed chromatin. These results suggested a model in which thede novoinitiation of transcriptional and post-transcriptional silencing is coupled to the remodeling of perturbed chromatin.

SIGNIFICANCE STATEMENT

This study addresses an enigmatic question of how transcriptional and post-transcriptional gene silencing can be initiatedde novoin the absence of strong sequence-specific cues. Using the fungusNeurospora crassaas a model organism, we found that both types of silencing can be triggered in mitotic cells by the remodeling of a transiently perturbed (nucleosome-depleted) chromatin state. In this system, the initiation of silencing requires SAD-6, a conserved SWI/SNF chromatin remodeler orthologous to ATRX that has been already implicated in repetitive DNA silencing in fungi, plants, and animals. Thus, the model proposed in this study may underpin a range of gene-silencing phenomena observed in other eukaryotes.