Basic Science and Pathogenesis.

Background: In amyotrophic lateral sclerosis and behavioral-variant frontotemporal degeneration, the presence of secondary cognitive-behavioral or motor symptoms, respectively, is associated with shorter survival. However, factors influencing the risk of secondary symptom development remain largely unexplored and time-to-event characterization for developing secondary symptoms is important for prognostic clinical decision-making.

Method: We performed a retrospective evaluation of the entire disease course of individuals in the Penn Integrated Neurodegenerative Disease Database with a primary clinical phenotype of amyotrophic lateral sclerosis (n = 173) or behavioral-variant frontotemporal degeneration (n = 69).

Water, Solute, and Ion Transport in De Novo-Designed Membrane Protein Channels.

Biological organisms engineer peptide sequences to fold into membrane pore proteins capable of performing a wide variety of transport functions. Synthetic de novo-designed membrane pores can mimic this approach to achieve a potentially even larger set of functions. Here we explore water, solute, and ion transport in three de novo designed β-barrel membrane channels in the 5-10 Å pore size range.

Efficacy and Safety of Venetoclax Plus Azacitidine for Patients With Treatment-Naive High-Risk Myelodysplastic Syndromes.

Patients with higher-risk myelodysplastic syndromes (HR MDS) have a median survival of ~1.5 years with azacitidine, and hematopoietic stem cell transplantation is their only curative option. Therefore, improved therapies are needed.

Impact of DNA extraction, PCR amplification, sequencing, and bioinformatic analysis on food-associated mock communities using PacBio long-read amplicon sequencing.

Background: Long-read 16S rRNA gene amplicon sequencing has a high potential for characterizing food-associated microbiomes. The advantage results from sequencing the full-length (1,500 bp) gene, enabling taxonomic resolution at species level. Here we present a benchmarking study using mock communities representative of milking machine biofilms and raw meat, revealing challenges relevant to food-associated habitats.

Bone marrow microenvironment signatures associate with patient survival after guadecitabine and atezolizumab therapy in HMA-resistant MDS.

Almost 50% of patients with myelodysplastic syndrome (MDS) are refractory to first-line hypomethylating agents (HMAs), which presents a significant clinical challenge considering the lack of options for salvage. Past work revealed that immune checkpoint molecules on peripheral myeloblasts and immune cells are up-regulated after HMA treatment. Therefore, we conducted a Phase I/II clinical trial combining guadecitabine (an HMA) and atezolizumab (an immune checkpoint inhibitor) to treat HMA-relapsed or refractory (HMA-R/R) MDS patients.

Enhanced CO Coordinates the Spatial Recruitment of Diazotrophs in Rice Via Root Development.

Understanding the reciprocal interaction between root development and coadapted beneficial microbes in response to elevated CO (eCO) will facilitate the identification of nutrient-efficient cultivars for sustainable agriculture. Here, systematic morphological, anatomical, chemical and gene expression assays performed under low-nitrogen conditions revealed that eCO drove the development of the endodermal barrier with respect to L-/S-shaped lateral roots (LRs) in rice. Next, we applied metabolome and endodermal-cell-specific RNA sequencing and showed that rice adapts to eCO by spatially recruiting diazotrophs via flavonoid secretion in L-shaped LRs.

Formation, chemical evolution and solidification of the dense liquid phase of calcium (bi)carbonate.

Metal carbonates, which are ubiquitous in the near-surface mineral record, are a major product of biomineralizing organisms and serve as important targets for capturing anthropogenic CO emissions. However, pathways of carbonate mineralization typically diverge from classical predictions due to the involvement of disordered precursors, such as the dense liquid phase (DLP), yet little is known about DLP formation or solidification processes. Using in situ methods we report that a highly hydrated bicarbonate DLP forms via liquid-liquid phase separation and transforms into hollow hydrated amorphous CaCO particles.

A phase 1 study of the amino acid modulator pegcrisantaspase and venetoclax for relapsed/refractory acute myeloid leukemia.

Glutamine dependency has been shown to be a metabolic vulnerability in acute myeloid leukemia (AML). Prior studies using several in vivo AML models showed that depletion of plasma glutamine induced by the long-acting crisantaspase (pegcrisantaspase or PegC) was synergistic with the BCL-2 inhibitor venetoclax (Ven), resulting in significantly reduced leukemia burden and enhanced survival. Here, we report a phase 1 study (NCT04666649) of Ven and PegC combination (VenPegC) for treating adult patients with relapsed or refractory AML, including patients who had previously received Ven.

CellKine clinical trial: first report from a phase 1 trial of allogeneic bone marrow-derived mesenchymal stem cells in subjects with painful lumbar facet joint arthropathy.

Background: Lumbar facet joint arthropathy (LFJA) is a major cause of low back pain (LBP), with current treatments offering limited long-term benefits. Bone marrow-derived mesenchymal stem cells (BM-MSCs) show promise due to their immunomodulatory and trophic effects, potentially addressing underlying degenerative processes in LFJA.

Objectives: This initial report describes the outcomes of the first treated patient in an ongoing mutidisciplinary phase 1 clinical trial evaluating the safety and feasibility of intra-articular allogeneic BM-MSCs for painful LFJA.

A multicenter phase 2 clinical trial of low-dose subcutaneous decitabine in myelofibrosis.

Myelofibrosis (MF) in the chronic phase is a challenging disease to treat, and conventional treatment options are geared toward symptom palliation. In this prospective, multicenter, phase 2 trial, 21 patients with MF (18 chronic phase, 2 accelerated phase, and 1 blast phase) were treated with a 10-day schedule of subcutaneous decitabine at 0.3 mg/kg per day.

Outcomes of Patients with Myeloid Malignancies and Cardiovascular Disease Undergoing Allogeneic Stem Cell Transplantation.

Introduction/background: Reduced-intensity conditioning (RIC) and nonmyeloablative (NMA) regimens have enabled patients with cardiovascular disease (CVD) to undergo allogeneic stem cell transplantation (allo-HSCT). However, little is known about long-term outcomes, including cardiovascular (CV) complications.

Methods: We retrospectively studied 99 consecutive patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who underwent allo-HSCT between September 1, 2013, and November 30, 2020.

Quasi-Classical Trajectory Calculations on a Two-State Potential Energy Surface Including Nonadiabatic Coupling Terms as Friction for D + H Collisions.

Akin to the traditional quasi-classical trajectory method for investigating the dynamics on a single adiabatic potential energy surface for an elementary chemical reaction, we carry out the dynamics on a 2-state ab initio potential energy surface including nonadiabatic coupling terms as friction terms for D + H collisions. It is shown that the resulting dynamics correctly accounts for nonreactive charge transfer, reactive non-charge transfer and reactive charge transfer processes. In addition, it leads to the formation of triatomic DH species as well.

Self-Assembling and Pore-Forming Peptoids as Antimicrobial Biomaterials.

Bacterial infections have been a serious threat to mankind throughout history. Natural antimicrobial peptides (AMPs) and their membrane disruption mechanism have generated immense interest in the design and development of synthetic mimetics that could overcome the intrinsic drawbacks of AMPs, such as their susceptibility to proteolytic degradation and low bioavailability. Herein, by exploiting the self-assembly and pore-forming capabilities of sequence-defined peptoids, we discovered a family of low-molecular weight peptoid antibiotics that exhibit excellent broad-spectrum activity and high selectivity toward a panel of clinically significant Gram-positive and Gram-negative bacterial strains, including vancomycin-resistant (VREF), methicillin-resistant (MRSA), methicillin-resistant (MRSE), , , and .

Augmented future: tracing the trajectory of location-based augmented reality gaming for the next ten years.

Location-based games are a highly technology-dependent game genre that has witnessed an exponential increase in popularity with the democratisation of smartphones as well as ubiquitous mobile data and access to satellite navigation. Moving forward into the future, location-based games can be expected to evolve as the technologies underlying the genre improve. In this conceptual work, we review the current state of the art in location-based games, and identify key trajectories and trends.

Rational Tuning of the Concentration-independent Enrichment of Prion-like Domains in Stress Granules.

Stress granules (SGs) are large ribonucleoprotein assemblies that form in response to acute stress in eukaryotes. SG formation is thought to be initiated by liquid-liquid phase separation (LLPS) of key proteins and RNA. These molecules serve as a scaffold for recruitment of client molecules.

Lateral root enriched Massilia associated with plant flowering in maize.

Background: Beneficial associations between plants and soil microorganisms are critical for crop fitness and resilience. However, it remains obscure how microorganisms are assembled across different root compartments and to what extent such recruited microbiomes determine crop performance. Here, we surveyed the root transcriptome and the root and rhizosphere microbiome via RNA sequencing and full-length (V1-V9) 16S rRNA gene sequencing from genetically distinct monogenic root mutants of maize (Zea mays L.

Molecular mechanism of trehalose 6-phosphate inhibition of the plant metabolic sensor kinase SnRK1.

SUCROSE-NON-FERMENTING1-RELATED PROTEIN KINASE1 (SnRK1), a central plant metabolic sensor kinase, phosphorylates its target proteins, triggering a global shift from anabolism to catabolism. Molecular modeling revealed that upon binding of KIN10 to GEMINIVIRUS REP-INTERACTING KINASE1 (GRIK1), KIN10's activation T-loop reorients into GRIK1's active site, enabling its phosphorylation and activation. Trehalose 6-phosphate (T6P) is a proxy for cellular sugar status and a potent inhibitor of SnRK1.

repeat expansions modify risk for secondary motor and cognitive-behavioral symptoms in behavioral-variant frontotemporal degeneration and amyotrophic lateral sclerosis.

In behavioral-variant frontotemporal degeneration (bvFTD) and amyotrophic lateral sclerosis (ALS), secondary motor or cognitive-behavioral symptoms, respectively, are associated with shorter survival. However, factors influencing secondary symptom development remain largely unexplored. We performed a retrospective evaluation of the entire disease course of individuals with ALS (n=172) and bvFTD (n=69).

Ponatinib vs Imatinib in Frontline Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Randomized Clinical Trial.

Importance: In newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), disease progression due to acquired resistance to first- or second-generation BCR::ABL1 tyrosine kinase inhibitors is common. Ponatinib inhibits BCR::ABL1 and all single-mutation variants, including T315I.

Objective: To compare frontline ponatinib vs imatinib in adults with newly diagnosed Ph+ ALL.