Biology subjects

Uddin, A.

Publications and source records attributed to Uddin, A..

6 recordsLinked to original sources

bioRxiv2026

Differences between males and females in psychostimulant/sucrose self-administration (when observed) may not necessarily be driven by biological sex.

BackgroundSex differences in psychostimulant-related behaviors are often attributed to biological sex; however, individual variability may also strongly influence behavioral outcomes. The new MISSING (Mapping Intrinsic Sex Similarities as an Integral quality of Normalized Groups) model identifies mixed-sex behavioral groups in which differences are driven primarily by individual variability rather than sex. The goal of this study was to validate the MISSING model for psychostimulant/sucrose self-administration. MethodsLong Evans rats self-administered methamphetamine (METH, male n = 25, female n = 32, 0.1 mg/kg/infusion, FR1, 6h per day for 20 days), sucrose (male n = 20, female n = 22, one-20 mg pellet/delivery, all other conditions being equal) and saline (male n = 3, female n = 10, other things being equal). We developed a new Quantitative Structure of Curve Analytical (QSCAn) model (using exponential-plateau and linear fit) for the assessment of individual drug self-administration time curve profiles irrespective of biological sex. We analyzed our data using regression analysis and ANOVA. ResultsQSCAn identified three distinct self-administration profiles (consisting of both sexes), which we named exponential-plateau negative (EP-), exponential-plateau positive (EP+), and undefined (EP0). There were no differences in self-administration profiles when we compared males and females within the same group. Differences between sexes (when observed) were due to mismatched comparisons (males from one group versus females from a different group). ConclusionsOur study reinforces the MISSING model for psychostimulant and sucrose self-administration by indicating that differences between males and females (when observed) may not necessarily be driven by biological sex. Significance StatementCurrent approaches often interpret variability in psychostimulant self-administration between males and females primarily through the lens of biological sex. However, this framework may overlook meaningful behavioral phenotypes shared across sexes. The present quantitative model suggests that individual patterns of behavior may better account for variability than sex alone, particularly in behaviors not strongly driven by sex-hormone-dependent mechanisms such as drug self-administration. By classifying animals according to behavioral profiles rather than biological sex, this approach may foster the identification of clinically and biologically relevant phenotypes underlying psychostimulant reinforcement.

neuroscience↗

bioRxiv2026

The recreational-to-habitual shift in psychostimulant use is an economic demand parameter that is unrelated to drug consumption levels (under normal and punishment conditions).

RationaleThe progression of psychostimulant abuse is associated with a shift from recreational to habitual use (R2H-shift). Because this R2H-shift can be modeled using behavioral economics, we developed a novel Behavioral Economic model for the Analysis of Self-administration Time-curve (BEAST) to obtain R2H-shift variable(s). The relationship(s) between R2H-shift variables and drug intake (under normal and/or punishment conditions) is/are unknown. Our goal was to determine if the R2H-shift variable and intake variables obtained during the initial self-administration training phase were related to 1) drug intake at that time, and subsequent drug intake under 2) normal, 3) punishment, 4) post-punishment, and 5) price-constrained conditions. MethodLong Evans rats self-administered methamphetamine (METH, males n = 16, females n = 14), sucrose (males n = 22, females n = 22) and/or saline (males n = 3, females n = 10) under FR1 for 6 h per day for 20 days to obtain 1) followed by the assessment of subsequent drug intake under different conditions (2-5 above). We obtained all variables referenced above. We determined the relationships between all variables (multivariate analysis). ResultsThere were no sex differences detected in the METH and sucrose studies. For METH and sucrose, prior drug intake levels could predict drug intake under normal/punishment but not under price-constrained conditions. The R2H-shift variable could predict drug intake under a consumption-price curve but could not predict intake under normal/punishment conditions. ConclusionsWhile related to economic demand, the recreational-to-habitual shift rate was unrelated to drug intake levels (under normal and punishment conditions).

neuroscience↗

bioRxiv2026

Disulfide engineering reveals unexpected pro- and anti-aggregation conformers of human α-synuclein

Intrinsically disordered proteins can aggregate in many distinct conformations (polymorphs). Polymorphs are a striking example of fold-switching: one primary structure able to form distinct tertiary structures. Distinct polymorphs can yield distinct molecular, cellular, and disease phenotypes. Disulfide crosslinks canalize disordered proteins into distinct regions of the conformational landscape, even if the monomer remains disordered. Human -synuclein is a disordered, natively Cys-free protein involved in synaptic transmission. Its amyloid aggregation is implicated in Parkinsons disease and other synucleinopathies. Recent cryo-EM fibril structures have revealed distinct classes of amyloid polymorphs that wild-type human -synuclein can adopt. We created three double-Cys -synuclein variants predicted to form intramolecular disulfide bridges compatible with known amyloid polymorphs, plus three other double-Cys variants at arbitrary positions as controls. We purified all six variants as intramolecularly disulfide-crosslinked monomers in solution. Two of the three predicted pro-aggregation variants formed amyloid fibrils as expected, and two of the three control variants did not. Surprisingly, one of the controls formed amyloid fibrils with a distinctive morphology by negative-stain TEM, suggesting the possibility of a previously unknown polymorph. Conversely, the crosslinked variant that failed to aggregate as expected showed sub-stoichiometric, dose-dependent anti-aggregation activity, strongly suppressing amyloid formation by wild-type -synuclein.

biophysics↗

bioRxiv2025

Native-state dimerization drives misfolding and aggregation of Cys-depleted variants of cataract-associated human lens γD-crystallin

Cataract, the leading cause of blindness worldwide, results from age-related misfolding and aggregation of long-lived crystallin proteins in the eye lens. The cytoplasm of fiber cells in the lens core becomes increasingly oxidizing with age, allowing non-native disulfides to drive light-scattering aggregation of {gamma}-crystallins. Despite this vulnerability to non-native disulfides, and despite lacking any native-state disulfides, {gamma}-crystallins are unexpectedly Cys-rich. To understand this paradox, we investigated how replacing all four Cys residues in the aggregation-prone N-terminal domain of {gamma}D-crystallin affects its stability and aggregation. Cys removal precludes the disulfide-driven aggregation pathway we reported previously. Here, we characterize two full-length human {gamma}D-crystallin variants: C18S/C32S/C41S/C78S ("NCS") and C18T/C32A/C41A/C78A ("NCA/T"). Thermodynamic and kinetic stability measurements indicate the N-terminal domain was greatly destabilized in both variants relative to WT, with NCS more destabilized than NCA/T. Upon mild heating or partial denaturation, both variants formed light-scattering aggregates, which were amorphous by transmission electron microscopy. Surprisingly, the aggregation proceeded exclusively from a dimer of natively folded molecules held together by a C-terminal disulfide bridge. These dimers form readily even in the WT protein, and evidence of them has been found in the lens. Aggregation was strongly suppressed by the lenss native chemical chaperone, myo-inositol. The aggregation rate depended linearly on protein concentration, indicating that the rate limiting step was a transformation of the natively-folded to misfolded molecules within the dimer. We propose that many age-related chemical modifications could destabilize the native fold of human {gamma}D-crystallin, favor misfolding within disulfide-bridged dimers, and thereby cause aggregation.

biochemistry↗

bioRxiv2025

High fat diet but not glucocorticoid-induced obesity results in fatty liver

Chronic stress, modeled by flattened circadian glucocorticoid (GC) oscillations, is increasingly implicated in obesity. We investigated the underlying mechanisms by disrupting GC rhythms in mice, elevating normally low GC levels during the rest period. This disruption induced substantial obesity, comparable to a 60% high-fat diet (HFD), with additive effects on fat mass, suggesting distinct mechanisms driving adiposity. Despite similar adiposity, GC-flattening and HFD produced profoundly different metabolic outcomes. HFD led to hepatic steatosis and elevated fasting glucose/fatty acid levels, reflecting typical diet-induced dysfunction. In contrast, GC-flattening maintained low fasting glucose/fatty acid levels and prevented hepatic lipid accumulation, with increased adiposity driven by a shift of glucose uptake from muscle to fat and suppression of lipolysis. This reveals a previously unrecognized mechanism of obesity development where excess fat accumulation occurs independently of the mechanisms driving metabolic dysfunction observed in diet-induced obesity. The dissociation between obesity and metabolic dysfunction in GC-flattening challenges the view that increased adiposity and persistent hyperinsulinemia inevitably leads to fatty liver disease. Understanding this pathway opens avenues for novel therapeutic interventions targeting stress-related metabolic disorders.

physiology↗

bioRxiv2022

Biological evaluation of novel side chain containing CQTrICh-analogs as antimalarials and their development as PfCDPK1 kinase inhibitors

To combat the emergence of drug resistance against the existing antimalarials, novel side chain containing 7-chloroquinoline-indole-chalcones tethered with a triazole (CQTrICh-analogs 7 (a-s) and 9) were designed and synthesized by reacting substituted 1-phenyl-3-(1-(prop-2-yn-1- yl)-1H-indol-3-yl) prop-2-en-1-one and 1-(prop-2-yn-1-yl)-1H-indole-3-carbaldehyde with 4- azido-7-chloroquinoline, respectively via a click reaction. The selected CQTrICh-analogs: 7l and 7r inhibited chloroquine-sensitive (3D7) and resistant (RKL-9) strains of Plasmodium falciparum, with IC50 values of 2.4 {micro}M & 1.8 {micro}M (7l), and 3.5 {micro}M & 2.7 {micro}M (7r), respectively, and showed insignificant hemolysis and cytotoxicity in mammalian cells. Intra-erythrocytic progression studies revealed that the active hybrids: 7l and 7r are effective against the mature stages of the parasite. Given the importance of Calcium-Dependent Protein Kinase 1 (PfCDPK1) in the parasite biology, notably during late schizogony and subsequent invasion of merozoites into host RBCs, we identified this protein as a possible molecular target of these active hybrids. In silico interaction analysis indicated that 7l and 7r stably interact with the catalytically active ATP-binding pocket of PfCDPK1, by the formation of energetically favorable H-bonds. Furthermore, in vitro Microscale Thermophoresis and kinase assays with recombinant PfCDPK1 demonstrated that the active hybrids interact with and inhibit the kinase activity, thus presumably responsible for the parasite growth inhibition. Interestingly, 7l and 7r showed no inhibitory effect on the human kinases, indicating that they are selective for the parasite kinase. Conceivably, we report the antiplasmodial potential of novel kinase targeting bio-conjugates, a step towards developing pan-kinase inhibitors, which is a prerequisite for cross-stage anti-malarial protection. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/498981v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@113574borg.highwire.dtl.DTLVardef@c81a33org.highwire.dtl.DTLVardef@1301d22org.highwire.dtl.DTLVardef@1c8cac5_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗