bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of adverse reactions induced by anti-tuberculosis drugs among hospitalized patients in Wuhan, China: A retrospective study
Authors: Shi Cai , Yang Boning , Yang Jingxiang , Song Wei , Chen Ying , Zhang Shuxiao , Zhan Hanyan , Xiong Yuanguo , Rong Peipei , Luo Yi , Yang Jian
Published: May 2024

The study aims to estimate the incidence and risk factors of adverse drug reactions (ADRs) induced by anti-tuberculosis (TB) drugs. A single center retrospective analysis of patients taking anti-TB therapy from January 2016 to December 2018 in the hospital was conducted. Univariate and multivariate logistic regression analysis were used to identify these risk factors of ADRs induced by anti-TB drugs. Among 1430 patients receiving anti-TB therapy, 440 (30.77%) patients showed at least 1 ADR induced by anti-TB drugs. Hyperuricemia was the most common ADR, followed by hepatic function test abnormality, liver damage and gastrointestinal reactions. Significant differences (P < .05) were also seen in diabetes, age, treatment duration, type of TB (extrapulmonary) and some therapeutic regimens between ADR group and non-ADR group, respectively. Multivariate logistic regression analysis showed that treatment duration (OR = 1.029, 95%CI[1.018–1.040],P = .000), type of TB (extrapulmonary, OR = 1.487, 95%CI[1.134–1.952],P = .004) and some therapeutic regimens (HREZ, OR = 1.425, 95%CI[0.922–2.903],P = .001; HRZS, OR = 2.063, 95% CI[1.234–3.449],P = .006; HRZ, OR = 3.623, 95%CI[2.289–5.736],P = .000) were risk factors for ADRs induced by anti-TB drugs. Anti-TB drugs usually induced the occurrence of severe and frequent adverse effects, such as hyperuricemia. Treatment duration, HREZ, HRZS and HRZ regimens, and type of TB (extrapulmonary) should be considered as high-risk factors. Thus, it should be recommended to consider optimum management during anti-TB therapy, particularly hyperuricemia monitoring and hepatic function test.
Geographic and Racial/Ethnic Differences in Access to Methamphetamine Detoxification Services, United States, 2021
Authors: Pro George , Cantor Jonathan , Buttram Mance , Brown Clare C. , Gu Mofan , Mancino Michael , Zaller Nickolas
Published: May 2024

Introduction:

Methamphetamine detoxification before entering formal and longer term treatment may have a positive impact on treatment retention and success. Understanding geographic distribution of methamphetamine specialty detox services and differential access by race/ethnicity is critical for establishing policies that ensure equitable access across populations.

Methods:

We used the Mental health and Addiction Treatment Tracking Repository to identify treatment facilities that offered any substance use detoxification in 2021 (N=2346) as well as the census block group in which they were located. We sourced data from the US Census Bureau to identify the percentage of a census block group that was White, Black, and Hispanic. We used logistic regression to model the availability of methamphetamine-specific detox, predicted by the percentage of a block group that was Black and Hispanic. We adjusted for relevant covariates and defined state as a random effect. We calculated model-based predicted probabilities.

Results:

Over half (60%) of detox facilities offered additional detox services specifically for methamphetamine. Sixteen states had <10 methamphetamine-specific detox facilities. The predicted probability of methamphetamine-specific detox availability was 60% in census block groups with 0%–9% Black residents versus only 46% in census block groups with 90%–100% Black residents, and was 61% in census block groups with 0%–9% Hispanic residents versus 30% in census block groups with 90%–100% Hispanic residents.

Conclusions:

During an unprecedented national methamphetamine crisis, access to a critical health care service was disproportionately lower in communities that were predominately Black and Hispanic. We orient our findings around a discussion of health disparities, residential segregation, and the upstream causes of the systematic exclusion of minoritized communities from health care.
Effects of botulinum toxin type A in patients with painful temporomandibular joint disorders: a systematic review and meta-analysis
Authors: Zhu Mengjiao , Huang Ziwei , Wang Yeye , Qin Jing , Fan Mingyue
Published: May 2024

Objective:

To assess the therapeutic efficacy of botulinum toxin type A (BTX-A) for managing myofascial pain related to temporomandibular disorders (TMDs).

Methods:

This study was conducted according to the PRISMA 2020 statement guidelines. The PubMed, Embase, and Cochrane Library databases were searched. Only randomized controlled trials were included. The primary outcome was a pain score on the visual analog scale, and the secondary outcomes were maximum mouth opening and adverse effects. The Cochrane risk of bias tool was used to assess risk bias. A meta-analysis of studies with the same interventions, controls, assessment methods, and follow-up durations was performed.

Results:

A total of 519 studies were retrieved, of which 20 randomized controlled trials were included in the qualitative analysis and six were included in the meta-analysis. The results showed that, compared with placebo, BTX-A injection was more effective at relieving myofascial pain, and its effect was similar to that of conventional methods. However, there was no difference in maximum mouth opening between the two groups. After the study assessment with the RoB 2.0 tool, six studies showed a low risk of bias, 13 studies showed some concerns regarding the reported results, and only one study showed a high risk of bias. Adverse effects of BTX-A injection were observed in four studies.

Conclusions:

In conclusion, BTX-A is effective at relieving pain in TMD patients but does not improve mouth opening. To minimize adverse effects, we recommend a low dose of BTX-A for TMD patients who do not experience complete pain relief from conservative treatments.
A perplexing case report of concomitant multiple sclerosis and myasthenia gravis
Authors: Al-Mollah Mustafa , Hussein Moaiad , Qiqieh Jamil , Sidhu Hardeep , Ryalat Nosaiba , Bahou Yacoub
Published: May 2024

Introduction and importance:

The co-occurrence of multiple sclerosis (MS) and myasthenia gravis (MG) within the Middle East and North African Region (MENA) has been scarcely reported in current literature. This rare case report explores the pathophysiological mechanisms and potential avenues of treatment modalities. Such insights can potentially facilitate the development of more efficacious and targeted treatment modalities and perhaps pave the way for disease prevention.

Case description:

Twenty-nine-year-old female patient presented with diplopia of two weeks duration associated with occasional blurred vision in the left eye. On physical examination, she was discovered to have marked left eye ptosis. A visual evoked potential (VEP) test was performed, which revealed asymmetrical delay. MRI imaging revealed a few white matter hyperintense foci noted at both periventricular regions and the corpus callosum with the characteristic appearance of Dawson’s fingers, and thus MS was diagnosed. An anti-acetylcholine receptor antibody test returned positive, confirming the diagnosis of concurrent MG.

Clinical discussion:

Proposed pathophysiological mechanisms underlying the concurrent manifestation of both diseases include, among others, the involvement of HLA haplotype and non-HLA genotypes, as well as the immunogenetic influence of specific transcription factors. Notable HLA haplotype genes include DRB1 and HLA-DQ5 genes. In contrast, non-HLA genes include the interleukin-4 receptor (IL4RA) and factor forkhead box P3 (FOXP3).

Conclusion:

Considering the similar immunological background of the two diseases, ideally, a single therapeutic modality could be used for management. This will hopefully simplify the patient’s treatment regimen and may ultimately reduce the treatment cost and patient burden.
Reliability of Publicly Available Digital Endoscopes in Otolaryngology: A Pilot Study
Authors: McWilliams Michael P. , Quinn Kevin , Lee Lawrance , Manzoor Nauman F. , Coelho Daniel H.
Published: May 2024

Objective:

To compare the utility, accuracy, and confidence of an inexpensive, commercially available endoscope (not specifically designed for medical use) with traditional methods in the diagnosis of otologic conditions.

Study Design:

This is a prospective study.

Methods:

Following institutional review board approval, patients were recruited from a tertiary university-based otology/neurotology clinic. Complete history and physical were obtained by the resident, including both traditional handheld otoscopy and image captured from a commercially available digital endoscopic device (AnyKit Digital Otoscope with 4.5-inch screen). The patient was then presented to the attending without the endoscopic images and a putative diagnosis was made. The endoscopic images were then shown and the putative diagnosis was affirmed or rejected. The attending then examined the patient and determined the final diagnosis using the microscope. Data collected included resident year, resident and attending diagnosis before and after digital-otoscopic images, confidence in diagnosis (1–5 scale), and agreement between the initial putative diagnosis and the final diagnosis. Noninferiority testing was calculated using inter-rater agreement between digital-otoscopic and final diagnoses. Differences between resident and attending confidence were analyzed. A power analysis was performed and the sample size was calculated a priori.

Results:

A total of 62 participants (114 ears examinations) were enrolled. Cohen’s kappa coefficient showed very high agreement between both resident and attending digital-otoscopic and final diagnosis (kappa = 0.868 and 0.882, respectively) suggesting noninferiority between the digital otoscope and the final diagnosis. There was no significant difference between attending confidence in diagnosis following resident presentation versus attending confidence in diagnosis after reviewing images (4.65 vs 4.61, P = 0.701). Average resident confidence in digital-otoscopic diagnosis remained above 4.2 throughout the study.

Conclusion:

Inexpensive and readily available digital endoscopes are not inferior to the traditional methods of resident-attending consultation and may provide some substantial benefits. Such devices have the potential to enhance both patient care and resident education when faculty are not immediately available (ie, inpatient and emergency room consults) and improve patient-initiated communications.
Randomized Controlled Trial of 60 minutes for Health With Rapid Antiretroviral Therapy to Reengage Persons With HIV Who Are Out of Care
Authors: Martin Thomas C. S. , Smith Laramie R. , Anderson Christy , Little Susan J.
Published: May 2024

Background:

Many persons with HIV remain out of care (PWH-OOC). We evaluated InstaCare, a complex intervention integrating the brief behavioral intervention 60 minutes for Health with the rapid restart of antiretroviral therapy (rapid ART).

Setting:

Prospective open-label randomized controlled trial among PWH-OOC in San Diego, USA.

Methods:

PWH-OOC were randomized 1:1 to InstaCare or a time-and-attention control integrating a diet-and-nutrition behavioral intervention also with rapid ART initiation (restart ≤7 days from enrollment). All participants had access to support services (free transport, HIV peer navigation, adherence counseling, and linkage to care) and primary care services (mental health, case management, social work, medication-assisted treatment, and specialist pharmacy). The primary outcomes were viral suppression (<50 copies/mL) and re-engagement with care (≥2 HIV care visits >90 days apart) by 24 weeks. Outcomes were reported on an intention-to-treat basis.

Results:

Between November 2020 and August 2022, 52 PWH-OOC were enrolled. Baseline substance use in the preceding month (49%), unstable housing (51%), moderate/severe depression (49%), and moderate/severe anxiety (41.7%) were prevalent. Rapid ART was provided for all participants. At week 24, the proportion with HIV viral load <50 copies/mL was 37.3% (19/51) (InstaCare 28.0%, control 46.2%, P = 0.25). Fourteen (27.5%) were engaged with care (InstaCare 7/25 [28.0%], control 7/26 [26.9%], P = 1.00). Most participants (94%) reported low or very low emotional distress associated with rapid ART. Study lost to follow-up by week 24 was high (23/51, 45%).

Conclusions:

The InstaCare complex intervention did not improve viral suppression or reengagement with care among PWH-OOC. Investigation of high-intensity, individually adapted interventions is needed among PWH-OOC.
Preoperative Risk Assessment of Early Kidney Graft Loss
Authors: Eerola Verner , Sallinen Ville , Lyden Grace , Snyder Jon , Lempinen Marko , Helanterä Ilkka
Published: May 2024

Background.

A large proportion of potential organ donors are not utilized for kidney transplantation out of risk of early allograft loss because of donor-related characteristics. These can be summarized using kidney donor profile index (KDPI). Because KDPI affects the choice of the recipient, the predictive ability of KDPI is tied to recipient attributes. These have been questioned to explain most of the predictive ability of KDPI. This study aims to quantify the effect of the donor on early graft loss (EGL) by accounting for nonrandom allocation.

Methods.

This study included patients undergoing kidney transplantation from deceased donors between 2014 and 2020 from the Scientific Registry of Transplantation Recipients. EGL, defined as a return to dialysis or retransplantation during the first posttransplant year, was the primary endpoint. Nonrandom allocation and donor–recipient matching by KDPI necessitated the use of inverse probability treatment weighting, which served to assess the effect of KDPI and mitigate selection bias in a weighted Cox regression model.

Results.

The study comprised 89 290 transplantations in 88 720 individual patients. Inverse probability treatment weighting resulted in a good balance of recipient covariates across values of continuous KDPI. Weighted analysis showed KDPI to be a significant predictor for short-term outcomes. A comparable (in terms of age, time on dialysis, previous transplants, gender, diabetes status, computed panel-reactive antibodies, and HLA mismatches) average recipient, receiving a kidney from a donor with KDPI 40–60 had a 3.5% risk of EGL increased to a risk of 7.5% if received a kidney from a KDPI >95 donor (hazard ratio, 2.3; 95% confidence interval, 1.9-2.7). However, for all-cause survival KDPI was less influential.

Conclusions.

The predictive ability of KDPI does not stem from recipient confounding alone. In this large sample-sized study, modeling methods accounting for nonindependence of recipient selection verify graft quality to effectively predict short-term transplantation outcomes.
Absence of IL-6 Receptor Blockade Effect on the Outcomes of Transplant Glomerulopathy in the Absence of Anti-HLA Donor-specific Antibodies
Authors: Mella Alberto , Lavacca Antonio , Dodoi Diana Teodora , Presta Roberto , Fop Fabrizio , Campagna Marco , Manzione Ana Maria , Dolla Caterina , Gallo Ester , Abbasciano Isabella , Gai Chiara , Camussi Giovanni , Barreca Antonella , Caorsi Cristiana , Giovinazzo Gloria , Biancone Luigi
Published: May 2024

Background.

Transplant glomerulopathy (TG) is the hallmark of chronic antibody-mediated rejection but often occurs without anti-HLA donor-specific antibodies (DSAs) in the assumption that other DSAs may be the effectors of the tissue injury. Recently, we reported a positive effect of interleukin-6 (IL-6) receptor blocker tocilizumab (TCZ) in TG/DSA+. In the present study, we investigate the effect of TCZ in a cohort of TG cases without detectable anti-HLA DSAs.

Methods.

Single-center retrospective analysis of TG cases without anti-HLA DSAs (TG/DSA) treated with TCZ for chronic antibody-mediated rejection as first-line therapy evaluated through clinical, protocol biopsies, and gene expression analyses was included.

Results.

Differently from TG/DSA+, TG/DSA– showed a progressive reduction in the estimated glomerular filtration rate at 12 mo and after that with no significant modification in microvascular inflammation or C4d+. No upregulation in tight junction protein-1, aldo-keto reductase family 1 member C3, and calcium/calmodulin-dependent serine protein kinase, documented in TG/DSA+, was noted in post-TCZ biopsies. The reduction of microvascular inflammation was associated with natural killer-cell reduction in TG/DSA+, whereas TG/DSA– tends to maintain or increase periglomerular/interstitial infiltration.

Conclusions.

In the absence of anti-HLA DSAs, TG behavior seems not to be modified by IL-6 receptor blockade. These results are at variance with observational studies and previous trials with IL-6 inhibitors in TG associated with anti-HLA DSAs. These data may fuel the hypothesis of different mechanisms underlying TGs (including the potentially different roles of natural killer cells) and suggest carefully selecting patients with TG for clinical trials or off-label treatment based on their antidonor serologic status.
Deceased Donors With HIV in the Era of the HOPE Act: Referrals and Procurement
Authors: Liang Tao , Salas Jordan H. , Bowring Mary G. , Kusemiju Oyinkan , Barnaba Brittany , Wingler Matthew , McRann Deborah , Salama Alghidak , Wood R. Patrick , Massie Allan , Werbel William , Tobian Aaron A. R. , Segev Dorry L. , Durand Christine M.
Published: May 2024

Background.

The HIV Organ Policy Equity Act legalizes organ procurement from donors with HIV (HIV D+). A prior survey of Organ Procurement Organizations (OPOs) estimated >2000 HIV D+ referrals/year; however, only 30–35 HIV D+/year have had organs procured. Given this gap, we sought to understand HIV D+ referrals and procurements in practice.

Methods.

We prospectively collected data on all OPO-reported HIV D+ referrals, including reasons for nonprocurement. We evaluated trends and compared HIV D+ characteristics by procurement status using regression, chi-squared tests, and Wilcoxon rank-sum tests.

Results.

From December 23, 2015 to May 31, 2021, there were 710 HIV D+ referrals from 49 OPOs, of which 171 (24%) had organs procured. HIV D+ referrals increased from 7 to 15 per month (P < 0.001), and the procurement rate increased from 10% to 39% (P < 0.001). Compared with HIV D+ without procurement, HIV D+ with procurement were younger (median age 36 versus 50 y), more commonly White (46% versus 36%), and more often had trauma-related deaths (29% versus 8%) (all P < 0.001). Nonprocurement was attributed to medical reasons in 63% of cases, of which 36% were AIDS-defining infections and 64% were HIV-unrelated, commonly due to organ failure (36%), high neurologic function (31%), and cancer (14%). Nonprocurement was attributed to nonmedical reasons in 26% of cases, commonly due to no authorization (42%), no waitlist candidates (21%), or no transplant center interest (20%).

Conclusions.

In the early years of the HIV Organ Policy Equity Act, actual HIV D+ referrals were much lower than prior estimates; however, the numbers and procurement rates increased over time. Nonprocurement was attributed to both medical and nonmedical issues, and addressing these issues could increase organ availability.
Safety and Immunogenicity of SARS-CoV-2 mRNA Vaccine Booster Doses in Kidney Transplant Recipients: Results of a 12-mo Follow-up From a Prospective Observational Study
Authors: Petr Vojtech , Zahradka Ivan , Modos Istvan , Roder Matej , Fialova Martina , Machkova Jana , Kabrtova Katerina , Hruba Petra , Magicova Maria , Slavcev Antonij , Striz Ilja , Viklicky Ondrej
Published: May 2024

Background.

Booster doses of SARS-CoV-2 mRNA vaccines are commonly used in kidney transplant recipients (KTRs). However, there is uncertainty regarding the waning of vaccination responses and immunological safety in KTRs.

Methods.

A total of 123 KTRs were included in the final analysis of this prospective observational cohort study. The aim was to evaluate the immunogenicity and immunological safety. SARS-CoV-2 antispike IgG antibodies and anti-HLA antibodies were measured at baseline and then at months 3, 6, and 12 after vaccination with the first booster dose (ie, the third vaccine dose). Antibodies against S1 and S2 subunits of SARS-CoV-2 were evaluated using an immunochemiluminescent assay (cutoff 9.5 AU/mL, sensitivity 91.2%, and specificity 90.2%). Anti-HLA antibodies were analyzed using single-antigen bead technology.

Results.

Seroconversion was reached in 65% of KTRs previously nonresponding to 2-dose mRNA vaccination; the overall seroconversion rate 3 mo after the first booster dose was 83%. Vaccination induced a durable humoral response, and the antibody levels were stable during the 12-mo study follow-up. Higher age (exponentiated beta coefficient [eβ] 0.97; 95% confidence interval [CI], 0.943-0.997) and a full dose of mycophenolate (eβ 0.296; 95% CI, 0.089-0.984) were negatively associated with SARS-CoV-2 IgG antibody levels, whereas better graft function (eβ1.021; 95% CI, 1.005-1.037) was associated positively. There were no systematic signs of anti-HLA antibody development after vaccination. However, during the follow-up, there was a nonsignificant signal of an increase in anti-HLA antibodies in those who developed COVID-19.

Conclusions.

Additional booster doses of SARS-CoV-2 mRNA vaccines induce durable antibody response even in a large subset of previous nonresponders and are not associated with the risk of allosensitization. Furthermore, a signal linking COVID-19 to the development of anti-HLA antibodies was observed, and this should be confirmed and further examined (NCT05483725).
Adipose microenvironment promotes hypersialylation of ovarian cancer cells
Authors: Fox Alexandra , Leonard Garry D. , Adzibolosu Nicholas , Wong Terrence , Tedja Roslyn , Sharma Sapna , Gogoi Radhika , Morris Robert , Mor Gil , Fehl Charlie , Alvero Ayesha B.
Published: May 2024

Sialylation, the addition of negatively charged sialic acid sugars to terminal ends of glycans, is upregulated in most cancers. Hypersialylation supports multiple pro-tumor mechanisms such as enhanced migration and invasion, resistance to apoptosis and immune evasion. A current gap in knowledge is the lack of understanding on how the tumor microenvironment regulates cancer cell sialylation. The adipose niche is a main component of most peritoneal cancers’ microenvironment. This includes ovarian cancer (OC), which causes most deaths from all gynecologic cancers. In this report, we demonstrate that the adipose microenvironment is a critical regulator of OC cell sialylation.In vitroadipose conditioning led to an increase in both ⍺2,3- and ⍺2,6-linked cell surface sialic acids in both human and mouse models of OC. Adipose-induced sialylation reprogramming was also observedin vivofrom intra-peritoneal OC tumors seeded in the adipose-rich omentum. Mechanistically, we observed upregulation of at least three sialyltransferases, ST3GAL1, ST6GAL1 and ST3GALNAC3. Hypersialylated OC cells consistently formed intra-peritoneal tumors in both immune-competent mice and immune-compromised athymic nude mice. In contrast, hyposiaylated OC cells persistently formed tumors only in athymic nude mice demonstrating that sialylation impacts OC tumor formation in an immune dependent manner. To our knowledge, this is the first demonstration of the effect of adipose microenvironment on OC tumor sialylation. Our results set the stage for translational applications targeting sialic acid pathways in OC and other peritoneal cancers.
Finite element analysis of a neural implant for cytostatic hypothermia and a novel heat management system
Authors: Enam Syed Faaiz , Chen Reed , Bellamkonda Ravi
Published: May 2024

The treatment of glioblastoma (GBM) presents significant challenges, with median survival rates remaining low despite standard-of-care therapies. This study expands upon the findings of a novel approach to managing GBM, namely cytostatic hypothermia, through the computational evaluation of a fully implantable system. Our proposed system utilizes a multi-probe array and a novel artificial internal circulation system (AICS) to achieve homogeneous cooling within the brain without overheating any portion of the body. Finite-element modeling was employed to simulate bioheat transfer and fluid dynamics. Our results indicate that the multi-probe array can attain local tissue temperatures within the cytostatic range (20 to 28degC) while minimizing thermal gradients. The use of multiple narrow, thermally conductive probes enhances cooling uniformity with minimal tissue displacement. The revolutionary AICS provides a form of heat management that has not previously been attempted to the best of our knowledge. In this study, it successfully facilitates the transfer of heat from the intracranial region to the skin in the body. Future work will focus on device prototyping and validation through in vitro and in vivo studies in large animal models. These simulations suggest that the proposed intracranial cooling system makes cytostatic hypothermia a practicable approach against GBM. Furthermore, this approach to internal heat management may also open new avenues for treating neurological conditions through local and chronic hypothermia, extending beyond the short-duration (acute) cooling methods currently tested.
Molecular counting of myosin force generators in growing filopodia
Authors: Fitz Gillian N. , Tyska Matthew J.
Published: May 2024

Animal cells build actin-based surface protrusions to enable biological activities ranging from cell motility to mechanosensation to solute uptake. Long-standing models of protrusion growth suggest that actin filament polymerization provides the primary mechanical force for “pushing” the plasma membrane outward at the distal tip. Expanding on these actin-centric models, our recent studies used a chemically inducible system to establish that plasma membrane-bound myosin motors, which are abundant in protrusions and accumulate at the distal tips, can also power robust filopodial growth. How protrusion resident myosins coordinate with actin polymerization to drive elongation remains unclear, in part because the number of force generators and thus, the scale of their mechanical contributions remain undefined. To address this gap, we leveraged the SunTag system to count membrane-bound myosin motors in actively growing filopodia. Using this approach, we found that the number of myosins is log-normally distributed with a mean of 12.0 ± 2.5 motors [GeoMean ± GeoSD] per filopodium. Together with unitary force values and duty ratio estimates derived from biophysical studies for the motor used in these experiments, we calculate that a distal tip population of myosins could generate a time averaged force of ∼tens of pN to elongate filopodia. This range is comparable to the expected force production of actin polymerization in this system, a point that necessitates revision of popular physical models for protrusion growth.

SIGNIFICANCE STATEMENT

This study describes the results of in-cell molecular counting experiments to define the number of myosin motors that are mechanically active in growing filopodia. This data should be used to constrain future physical models of the formation of actin-based protrusions.
Effects of Drought and Salinity,etc.on Root Pressure ofDracaena sanderiana
Authors: Zhang Weizhi , Song Jinfeng , Sang Ying , Zhang Min , Zheng Jiaqi , Liu Yuyang
Published: May 2024

Aim

Root pressure plays a crucial role in maintaining tissue hydration and ensuring the functionality of the plant’s hydraulic system while facilitating cellular and tissue growth. The study focuses on investigating the impact of drought, salinity,etc.on root pressure ofDracaena sanderiana.

Methods

Pressure sensors (PX26-100GV) were used to measure the diurnal variations in root pressure of soil-cultured and hydroponicD. sanderianawith heights ranging from 60 to 80 cm. The study also examined various influencing factors such as drought stress, salinity stress, temperatures, mineral concentration, change in leaves and roots that affect root pressure. This approach provides valuable insights into the role of root pressure in mediating water upward movement in xylem.

Essential findings

The research showed: (1) Both soil-cultured and hydroponicD. sanderianaexhibited positive root pressure throughout the day, demonstrating apparent diurnal pattern of high pressures at the day and low pressures at night. The maximum root pressure measured in the experiments was 96 kPa; (2) For soil-culturedD. sanderiana, root pressure decreased under drought and salinization (NaCl), while the diurnal rhythm remained unchanged; (3) For hydroponicD. sanderiana, under simulated drought (PEG 6000) and salt stress (NaCl), the rate of decrease in root pressure accelerated with increasing concentrations of PEG 6000 and NaCl, displaying diurnal rhythm at low concentrations but losing this pattern at high concentrations; (4) Under room temperature, root pressure of hydroponicD. sanderianadecreased with lower water temperature and increased with higher temperatures, but did not increase at 40℃; low concentrations of nitrate (KNO3) generally increased root pressure, however, root pressure decreased when con-centration reached 4 g·L-1, and the diurnal rhythm remained unaffected; (5) For hydroponicD. sanderiana, the presence of leaves on the stem below the root pressure measurement point resulted in significantly lower root pressure compared to plants without leaves on the stem, while still maintaining a regular diurnal rhythm. Removal of all root hairs and the entire root system led to a rapid decline in root pressure to negative values, followed by a slow recovery to around 0 kPa. In conclusion, relative to its height, the root pressure ofD. sanderianais sufficient to transport water required for transpiration to the top of the plant, effectively countering the impact and function of transpirational pull. Moreover, root pressure shows a stable diurnal rhythm of higher values during the day and lower at night. Environmental factors such as drought, salinity stress, temperatures, mineral con-centration, and changes in leaves and roots significantly affect root pressure.
Selective molecular inhibition of the HDAC6 ZnF-UBP binding domain impairs multiple myeloma cell proliferation
Authors: Rincon Rafael , Coira Isabel F , Richieu Antoine , Attana Fedaa , Urwyler Muriel , Haider Shozeb , Bourquin Carole , Bertrand Philippe , Cuendet Muriel
Published: May 2024

Multiple myeloma is a plasma cell malignancy with poor prognosis despite the recent development of new therapeutic options. Histone deacetylase 6 (HDAC6) is overexpressed in multiple myeloma patients and may be involved in the acquisition of resistance to conventional anti-proteasome treatments. Beyond displaying a deacetylase catalytic activity, HDAC6 can recognize ubiquitinated motifs from misfolded proteins through its C-terminal ZnF-UBP binding domain and send the defective proteins to the aggresome for degradation. Here, we explore the role of the ZnF-UBP binding domain of HDAC6 in the function of multiple myeloma cells. A non-functional ZnF-UBP domain containing a 2-residue mutation in the binding site was designed and the absence of ubiquitin binding was confirmed in a cell-free assay. Molecular docking simulations and electrostatic calculations revealed a significant decrease in the electrostatic potential of the mutated peptide, which is crucial for the stability of the complex with ubiquitin. A multiple myeloma cell line containing the non-functional ZnF-UBP domain was then engineered. Although the deacetylase activity of HDAC6 was maintained in these cells, they showed reduced cell growth, impaired aggresome formation and a dysregulated gene expression profile that was more pronounced than cells entirely deficient in HDAC6. These results indicate that a non-functional ZnF-UBP binding domain impacts the function of multiple myeloma cells. Based on these findings, a series of quinazolinylpropanoic acid derivatives was synthesized to explore the inhibitory activity of small molecules to this domain. We propose that ZnF-UBP binding domain inhibitors should be further evaluated as potential therapeutic agents in multiple myeloma.
Quantitative imaging of species-specific lipid transport in mammalian cells
Authors: Iglesias-Artola Juan M. , Schuhmann Kai , Böhlig Kristin , Lennartz H. Mathilda , Schuhmacher Milena , Barahtjan Pavel , Jiménez López Cristina , Šachl Radek , Pombo-Garcia Karina , Lohmann Annett , Riegerová Petra , Hof Martin , Drobot Björn , Shevchenko Andrej , Honigmann Alf , Nadler André
Published: May 2024

Eukaryotic cells produce over 1000 different lipid species which tune organelle membrane properties, control signalling and store energy1,2. How lipid species are selectively sorted between organelles to maintain specific membrane identities is largely unknown due to the difficulty to image lipid transport in cells3. Here, we measured transport and metabolism of individual lipid species in mammalian cells using time-resolved fluorescence imaging of bifunctional lipid probes in combination with ultra-high resolution mass spectrometry and mathematical modelling. Quantification of lipid flux between organelles revealed that directional, non-vesicular lipid transport is responsible for fast, species-selective lipid sorting compared to slow, unspecific vesicular membrane trafficking. Using genetic perturbations, we found that coupling between active lipid flipping and passive non-vesicular transport is a mechanism for directional lipid transport. Comparison of metabolic conversion and transport rates showed that non-vesicular transport dominates the organelle distribution of lipids while species-specific phospholipid metabolism controls neutral lipid accumulation. Our results provide the first quantitative map of retrograde lipid flux in cells4. We anticipate that our pipeline for quantitative mapping of lipid flux through physical and chemical space in cells will boost our understanding of lipids in cell biology and disease.
A chromosome-scale genome assembly of Timorese crabgrass (Digitaria radicosa): a useful genomic resource for the Poaceae
Authors: Minoji Koki , Sakai Toshiyuki
Published: May 2024

Timorese crabgrass (Digitaria radicosa) is a grass species commonly found in Southeast Asia and Oceania. Digitaria species have high intraspecific and interspecific genetic and phenotypic diversity, suggesting their potential usefulness as a genetic resource. However, as the only high-quality reference genome available is for a tetraploid Digitaria species, a reference genome of the diploid species D. radicosa would be a useful resource for genomic studies of Digitaria and Poaceae plants. Here, we present a chromosome-level genome assembly of D. radicosa and describe its genetic characteristics; we also illustrate its usefulness as a genomic resource for Poaceae. We constructed a 441.6 Mb draft assembly consisting of 61 scaffolds with an N50 scaffold length of 41.5 Mb, using PacBio HiFi long reads. Thirty scaffolds, encompassing 440.8 Mb, were anchored to nine pseudochromosomes. We predicted 26,577 protein-coding genes, reaching a BUSCO score of 96.5%. To demonstrate the usefulness of the D. radicosa reference genome, we investigated the evolution of Digitaria species and the genetic diversity of Japanese Digitaria plants based on our new reference genome. We also defined the syntenic blocks between D. radicosa and Poaceae crops and the diverse distribution of representative resistance genes in D. radicosa. The D. radicosa reference genome presented here should help elucidate the genetic relatedness of Digitaria species and the genetic diversity of Digitaria plants. In addition, the D. radicosa genome will be an important genomic resource for Poaceae genomics and crop breeding.
Scalable Production and Purification of Engineered ARRDC1-Mediated Microvesicles in a HEK293 Suspension Cell System
Authors: Luther Kristin , Navaei Ali , Gens Leah , Semple Carson , Moharil Pearl , Passalacqua Ilaria , Vyas Komal , Wang Qiyu , Liu Shu-Lin , Sun Lucy , Ramaswamy Senthil , Zocco Davide , Nabhan Joseph F
Published: May 2024

The engineering of human ARRDC1-mediated microvesicles (ARMMs) as new non-viral vehicles for delivery of gene therapies overcomes challenges associated with current modalities. Hurdles such as generating sufficient material to meet demand and development of appropriate characterization assays, however, persist. Our study evaluated two scalable strategies to generate GFP-loaded ARMMs, transient transfection or stable cell line-based production. The upstream ARMMs production processes utilized a suspension HEK293-derived line, termed 5B8, from Lonza. Production was evaluated in shake flasks and bioreactors. Downstream ARMMs purification processes employed Tangential Flow Filtration (TFF) and Anion Exchange Chromatography (AEX). Analytical methods included single particle analysis, ELISA, and immunoblotting. Additionally, anin vivostudy was conducted in mice to investigate the half-life and biodistribution of ARMMs administered intravenously. 5B8 cells yielded robust production of ARMMs after transient transfection with the ARMMs loading construct or using a stable cell line containing a transgene that encodes the ARMMs loading cassette, in shake flasks or a stirred tank bioreactor, respectively. Approximately 50% of all vesicles produced were payload-containing ARMMs. ARMMs were purified by ultracentrifugation (small scale) or a combination of TFF and AEX (large scale). Both purification methods produced comparable ARMMs.In vivo, ARMMs showed rapid biodistribution predominantly to the spleen and liver and, to a lesser extent, kidneys, and lungs. The successful scale-up of ARMMs production illustrates the potential of engineered extracellular vesicles (EVs). Furthermore, this study highlights the potential utility of ARMMs forin vivodelivery of therapeutic molecules.
Coordination between ESCRT function and Rab conversion during endosome maturation
Authors: Ott Daniel P. , Desai Samit , Solinger Jachen A. , Kaech Andres , Spang Anne
Published: May 2024

The endosomal pathway is essential for regulating cell signaling and cellular homeostasis. Rab5-positive early endosomes receive proteins from the plasma membrane. Dependent on a ubiquitin mark on the protein, they will be either recycled or sorted into intraluminal vesicles (ILVs) by ESCRT. During endosome maturation Rab5 will be replaced by Rab7 on endosomes that are able to fuse with lysosomes to form endolysosomes. Whether ESCRT-driven ILV formation and Rab5-to-Rab7 conversion are coordinated remains unknown. Here we show that loss of early ESCRTs leads to enlarged Rab5-positive endosomes and prohibit Rab conversion. Reduction of ubiquitinated cargo alleviated this phenotype. Moreover, ubiquitinated proteins on the endosomal limiting membrane prevented the displacement of the Rab5GEF RABX-5 by the Rab7GEF SAND-1/CCZ-1. Overexpression of Rab7 could partially overcome this block, even in the absence of SAND-1, whereby the HOPS complex presumably acts as Rab7GEF. Our data reveal a hierarchy of events in which cargo corralling by ESCRTs is upstream of Rab conversion and thereby ESCRT-0 and ubiquitinated cargo could act as timers determining the onset of Rab conversion.
ArabidopsisABCC4encodes a cytokinin efflux transporter and is involved in root system development
Authors: Uragami Takuya , Kiba Takatoshi , Kojima Mikiko , Takebayashi Yumiko , Tozawa Yuzuru , Hayashi Yuki , Kinoshita Toshinori , Sakakibara Hitoshi
Published: May 2024

The directional and sequential flow of cytokinin in plants is organized by a complex network of transporters. Genes involved in several aspects of cytokinin transport have been characterized, but a large part of the elaborate system remains elusive. In this study, we have identifiedABCC4as a cytokinin efflux transporter gene. Using a transient expression system in tobacco leaves, we screened Arabidopsis transporter genes and isolatedATP-BINDING CASSETTE TRANSPORTER C4(ABCC4). Further validation through drug-induced expression in Arabidopsis and heterologous expression in budding yeast revealed that ABCC4 effluxes the active form of cytokinins. During the seedling stage,ABCC4was highly expressed in roots, and its expression was up-regulated in response to cytokinin application. Loss-of-function mutants ofABCC4displayed enhanced primary root elongation, similar to mutants impaired in cytokinin biosynthesis or signaling, which was suppressed by exogenoustrans-zeatin treatment. In contrast, overexpression of the gene led to suppression of root elongation. These results suggest that ABCC4 plays a role in the efflux of active cytokinin, thereby contributing to root growth regulation. Our findings contribute to unraveling the many complexities of cytokinin flow and enhance our understanding of the regulatory mechanisms underlying root system development in plants.
The thylakoid lumen Deg1 protease affects non-photochemical quenching via the levels of violaxanthin de-epoxidase and PsbS
Authors: Aviv-Sharon Elinor , Sultan Laure D. , Naveh Leah , Charuvi Dana , Kupervaser Meital , Reich Ziv , Adam Zach
Published: May 2024

Non-photochemical quenching (NPQ), the dissipation of excess light energy as heat, has been long recognized as a major protective mechanism that minimizes the potential for oxidative damage to photosystem II (PSII) reaction centers. Two major positive contributors to NPQ are the carotenoid zeaxanthin, generated from violaxanthin by the enzyme violaxanthin de-epoxidase (VDE or NPQ1), and the thylakoid protein PsbS (NPQ4). The involvement of the lumenal Deg proteases in the repair of PSII from photoinhibition prompted us to further explore their possible role in other responses ofArabidopsis thalianato high light. Here we show that upon exposure to high light, the singledeg1and the tripledeg158mutants display different levels and kinetics of NPQ, compared to thedeg58mutant and WT that behave alike. In response to high light, the two genotypes lacking Deg1 over-accumulate NPQ1 and NPQ4. After temporal inhibition of protein translation in vivo, the level of these two proteins indeg1is higher than in WT. Together, the results suggest that Deg1 represents a new level of regulation of the NPQ process through adjusting the quantity of NPQ1 and NPQ4 proteins, probably through their proteolysis.
The USP12/46 deubiquitinases protect integrins from ESCRT-mediated lysosomal degradation
Authors: Yu Kaikai , Guo Shiny S. , Bassermann Florian , Fässler Reinhard , Wang Guan M.
Published: May 2024

The functions of integrins are tightly regulated via multiple mechanisms including trafficking and degradation. Integrins are repeatedly internalized, routed into the endosomal system and either degraded by the lysosome or recycled back to the plasma membrane. The ubiquitin system dictates whether internalized proteins are degraded or recycled. Here, we used a genetic screen and proximity-dependent biotin identification to identify deubiquitinase(s) that control integrin surface levels. We found that a ternary deubiquitinating complex, comprised of USP12 (or the homologous USP46), WDR48 and WDR20, stabilizes β1 integrin (Itgb1) by preventing ESCRT-mediated lysosomal degradation. Mechanistically, the USP12/46-WDR48-WDR20 complex removes ubiquitin from the cytoplasmic tail of internalized Itgb1 in early endosomes, which in turn prevents ESCRT-mediated sorting and Itgb1 degradation.
CLEAN-Contact: Contrastive Learning-enabled Enzyme Functional Annotation Prediction with Structural Inference
Authors: Yang Yuxin , Jerger Abby , Feng Song , Wang Zixu , Brasfield Christina , Cheung Margaret S. , Zucker Jeremy , Guan Qiang
Published: May 2024

Recent years have witnessed the remarkable progress of deep learning within the realm of scientific disciplines, yielding a wealth of promising outcomes. A prominent challenge within this domain has been the task of predicting enzyme function, a complex problem that has seen the development of numerous computational methods, particularly those rooted in deep learning techniques. However, the majority of these methods have primarily focused on either amino acid sequence data or protein structure data, neglecting the potential synergy of combining of both modalities. To address this gap, we propose a novelContrastiveLearning framework forEnzyme functionalANnotation prediction combined with protein amino acid sequences andContactmaps (CLEAN-Contact). We rigorously evaluated the performance of our CLEAN-Contact framework against the state-of-the-art enzyme function prediction model using multiple benchmark datasets. Using CLEAN-Contact, we predicted novel enzyme functions within the proteome ofProchlorococcus marinusMED4. Our findings convincingly demonstrate the substantial superiority of our CLEAN-Contact framework, marking a significant step forward in enzyme function prediction accuracy.
The Hippo-YAP/TAZ-TEAD axis promotes multipotency in bone marrow stromal cells
Authors: Cheng Yu-Hao , Chan Chun Hei Ryan , Bian Qin , Merling Randall K. , Kuznetsov Sergei A. , Robey Pamela G. , Cahan Patrick
Published: May 2024

The mechanisms by which bone marrow stromal cells (BMSCs) maintain multilineage potency in vitro remain elusive. To identify the transcriptional regulatory circuits that contribute to BMSC multipotency, we performed paired single-nucleus multiomics of the expansion of freshly isolated BMSCs and of BMSCs undergoing tri-lineage differentiation. By computationally reconstructing the regulatory programs associated with initial stages of differentiation and early expansion, we identified the TEAD family of transcription factors, which is inhibited by Hippo signaling, as highly active in the BMSC in vitro multipotent state. Pharmacological inhibition of TEAD enhanced BMSC osteogenic and adipogenic differentiation, whereas its activation maintained BMSCs in an undifferentiated state, supporting a model whereby isolation of BMSCs coincides with a TEAD-controlled transcriptional state linked to multipotency. Our study highlights the Hippo pathway as a pivotal regulator of BMSC multipotency, and our regulatory network inferences are a reservoir of testable hypotheses that link transcription factors and their regulons to specific aspects of BMSC behavior.